Super Multi-Minerals Regular Strength

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Super Multi-Minerals Regular Strength uses

Super Multi-Minerals Regular Strength consists of Calcium (Calcium Carbonate), Calcium (Calcium Citrate), Calcium (Calcium Gluconate), Calcium (Calcium HVP Chelate), Calcium (Oyster Shells), Chromium (Chromium HVP Chelate), Copper (Copper Citrate), Copper (Copper Fumarate), Copper (Copper Gluconate), Copper (Copper Malate), Copper (Copper Succinate), Iodine (Kelp), Iodine (Potassium Iodide), Iron (Ferrous Citrate), Iron (Ferrous Fumarate), Iron (Ferrous Gluconate), Iron (Ferrous HVP Chelate), Iron (Ferrous Malate), Iron (Ferrous Succinate), Magnesium (Magnesium Ascorbate), Magnesium (Magnesium Citrate), Magnesium (Magnesium Fumarate), Magnesium (Magnesium Gluconate), Magnesium (Magnesium HVP Chelate), Magnesium (Magnesium Malate), Magnesium (Magnesium Oxide), Magnesium (Magnesium Succinate), Manganese (Man.

Calcium (Calcium Carbonate):


1 INDICATIONS AND USAGE

Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate is a phosphate binder indicated to reduce serum phosphorus in patients with end stage renal disease (ESRD).

- Calcium acetate is a phosphate binder indicated for the reduction of serum phosphorus in patients with end stage renal disease. (1)

2 DOSAGE AND ADMINISTRATION

The recommended initial dose of Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate for the adult dialysis patient is 2 capsules with each meal. Increase the dose gradually to lower serum phosphorus levels to the target range, as long as hypercalcemia does not develop. Most patients require 3 to 4 capsules with each meal.

- Starting dose is 2 capsules with each meal. (2)

- Titrate the dose every 2 to 3 weeks until acceptable serum phosphorus level is reached. Most patients require 3 to 4 capsules with each meal. (2)

3 DOSAGE FORMS AND STRENGTHS

Capsule: 667 mg Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate capsule.

- Capsule: 667 mg Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Super Multi-Minerals Regular Strength ) acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate. (5.1)

- Hypercalcemia may aggravate digitalis toxicity. (5.2)

5.1 Hypercalcemia

Patients with end stage renal disease may develop hypercalcemia when treated with Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)), including Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate. Avoid the use of Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) supplements, including Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) based nonprescription antacids, concurrently with Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate.

An overdose of Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) levels twice weekly. Should hypercalcemia develop, reduce the Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate dosage, or discontinue the treatment, depending on the severity of hypercalcemia

More severe hypercalcemia (Ca >12 mg/dL) is associated with confusion, delirium, stupor and coma. Severe hypercalcemia can be treated by acute hemodialysis and discontinuing Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate therapy.

Mild hypercalcemia (10.5 to 11.9 mg/dL) may be asymptomatic or manifest as constipation, anorexia, nausea, and vomiting. Mild hypercalcemia is usually controlled by reducing the Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate dose or temporarily discontinuing therapy. Decreasing or discontinuing Vitamin D therapy is recommended as well.

Chronic hypercalcemia may lead to vascular calcification and other soft-tissue calcification. Radiographic evaluation of suspected anatomical regions may be helpful in early detection of soft tissue calcification. The long term effect of Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate on the progression of vascular or soft tissue calcification has not been determined.

Hypercalcemia (>11 mg/dL) was reported in 16% of patients in a 3 month study of solid dose formulation of Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate; all cases resolved upon lowering the dose or discontinuing treatment.

Maintain the serum calcium-phosphorus (Ca x P) product below 55 mg2/dL2.

5.2 Concomitant Use with Medications

Hypercalcemia may aggravate digitalis toxicity.

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6 ADVERSE REACTIONS

Hypercalcemia is discussed elsewhere [see Warnings and Precautions ].

- The most common (>10%) adverse reactions are hypercalcemia, nausea and vomiting. (6.1)

- In clinical studies, patients have occasionally experienced nausea during Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate therapy. (6)

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical studies, Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate has been generally well tolerated.

Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate was studied in a two week double-blind, placebo-controlled, cross-over study with 69 enrolled ESRD hemodialysis patients. Adverse reactions (>2% on treatment) from these trials are presented in Table 1.


Preferred Term


Total adverse reactions reported for Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate

N=167

N (%)


3 month, open label study of Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate

N=98

N (%)


Double blind, placebo-controlled, cross-over study of liquid Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate

N=69


Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate

N (%)


Placebo

N (%)


Nausea


6 (3.6)


6 (6.1)


0 (0)


0 (0)


Vomiting


4 (2.4)


4 (4.1)


0 (0)


0 (0)


Hypercalcemia


21 (12.6)


16 (16.3)


5 (7.2)


0 (0)


Mild hypercalcemia may be asymptomatic or manifest itself as constipation, anorexia, nausea, and vomiting. More severe hypercalcemia is associated with confusion, delirium, stupor, and coma. Decreasing dialysate Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) concentration could reduce the incidence and severity of Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate-induced hypercalcemia. Isolated cases pruritus have been reported, which may represent allergic reactions.

6.2 Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or to establish a causal relationship to drug exposure.

The following additional adverse reactions have been identified during post-approval of Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate: dizziness, edema, and weakness.

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7 DRUG INTERACTIONS

The drug interaction of Super Multi-Minerals Regular Strength ) acetate is characterized by the potential of Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate and most concomitant drugs. When administering an oral medication with Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, administer the drug one hour before or three hours after Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate. Monitor blood levels of the concomitant drugs that have a narrow therapeutic range. Patients taking anti-arrhythmic medications for the control of arrhythmias and anti-seizure medications for the control of seizure disorders were excluded from the clinical trials with all forms of Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate.

- Calcium acetate may decrease the bioavailability of tetracyclines or fluoroquinolones. (7)

- When clinically significant drug interactions are expected, administer the drug at least one hour before or at least three hours after Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate or consider monitoring blood levels of the drug. (7)

7.1 Ciprofloxacin

In a study of 15 healthy subjects, a co-administered single dose of 4 Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

Super Multi-Minerals Regular Strength ) acetate capsules contains Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate. Animal reproduction studies have not been conducted with Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate, and there are no adequate and well controlled studies of Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) levels is important for maternal and fetal well being. Hypercalcemia during pregnancy may increase the risk for maternal and neonatal complications such as stillbirth, preterm delivery, and neonatal hypocalcemia and hypoparathyroidism. Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate treatment, as recommended, is not expected to harm a fetus if maternal Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Super Multi-Minerals Regular Strength ) Acetate Capsules contains Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate and is excreted in human milk. Human milk feeding by a mother receiving Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate is not expected to harm an infant, provided maternal serum Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) levels are appropriately monitored.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

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10 OVERDOSAGE

Administration of Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate acts as a phosphate binder. Its chemical name is Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate. Its molecular formula is C4H6CaO4, and its molecular weight is 158.17. Its structural formula is:


Each white opaque/blue opaque capsule contains 667 mg of Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate USP (anhydrous; Ca(CH3COO)2; MW=158.17 grams) equal to 169 mg (8.45 mEq) Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)), polyethylene glycol 8000 and magnesium stearate. Each capsule shell contains: black monogramming ink, FD&C Blue #1, FD&C Red #3, gelatin and titanium dioxide. The black monogramming ink contains: ammonium hydroxide, iron oxide black, isopropyl alcohol, n-butyl alcohol, propylene glycol and shellac glaze.

Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) Acetate Capsules are administered orally for the control of hyperphosphatemia in end-stage renal failure.

Chemical Structure

12 CLINICAL PHARMACOLOGY

Patients with ESRD retain phosphorus and can develop hyperphosphatemia. High serum phosphorus can precipitate serum Super Multi-Minerals Regular Strength ) resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate from pharmaceutical dosage forms is systemically absorbed up to approximately 40% under fasting conditions and up to approximately 30% under nonfasting conditions. This range represents data from both healthy subjects and renal dialysis patients under various conditions.

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13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate.

14 CLINICAL STUDIES

Effectiveness of Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate solid oral dosage form.

Ninety-one patients with end-stage renal disease who were undergoing hemodialysis and were hyperphosphatemic (serum phosphorus >5.5 mg/dL) following a 1 week phosphate binder washout period contributed efficacy data to an open-label, non-randomized study.

The patients received Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate 667 mg tablets at each meal for a period of 12 weeks. The initial starting dose was 2 tablets per meal for 3 meals a day, and the dose was adjusted as necessary to control serum phosphorus levels. The average final dose after 12 weeks of treatment was 3.4 tablets per meal. Although there was a decrease in serum phosphorus, in the absence of a control group the true magnitude of effect is uncertain.

The data presented in Table 2 demonstrate the efficacy of Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) levels are also presented.


* Ninety-one patients completed at least 6 weeks of the study.

ANOVA of difference in values at pre-study and study completion.

‡ Values expressed as mean ± SE.


Parameter


Pre-Study


Week 4*


Week 8


Week 12


p-value†


Phosphorus (mg/dL)‡


7.4 ± 0.17


5.9 ± 0.16


5.6 ± 0.17


5.2 ± 0.17


≤0.01


Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) (mg/dL)‡


8.9 ± 0.09


9.5 ± 0.10


9.7 ± 0.10


9.7 ± 0.10


≤0.01


There was a 30% decrease in serum phosphorus levels during the 12 week study period (p<0.01). Two-thirds of the decline occurred in the first month of the study. Serum Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) increased 9% during the study mostly in the first month of the study.

Treatment with the phosphate binder was discontinued for patients from the open-label study, and those patients whose serum phosphorus exceeded 5.5 mg/dL were eligible for entry into a double-blind, placebo-controlled, cross-over study. Patients were randomized to receive Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate or placebo, and each continued to receive the same number of tablets as had been individually established during the previous study. Following 2 weeks of treatment, patients switched to the alternative therapy for an additional 2 weeks.

The phosphate binding effect of Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate is shown in the Table 3.


* ANOVA of Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate vs. placebo after 2 weeks of treatment.

Values expressed as mean ± SEM.


Parameter


Pre-Study


Post-Treatment


p-value*


Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) Acetate


Placebo


Phosphorus (mg/dL)


7.3 ± 0.18


5.9 ± 0.24


7.8 ± 0.22


<0.01


Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) (mg/dL)


8.9 ± 0.11


9.5 ± 0.13


8.8 ± 0.12


<0.01


Overall, 2 weeks of treatment with Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) Acetate Capsules

667 mg capsule is supplied as a white opaque/blue opaque capsule, imprinted with “54 215” on the cap and body.

NDC 0615-2303-39: Blistercards of 30 Capsules

NDC 0615-2303-30: Unit-dose Boxes of 30 Capsules

STORAGE

Store at 20° to 25°C (68° to 77°F).

17 PATIENT COUNSELING INFORMATION

Inform patients to take Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) supplements including nonprescription antacids. Inform the patients about the symptoms of hypercalcemia [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ].

Advise patients who are taking an oral medication where reduction in the bioavailability of that medication would have clinically significant effect on its safety or efficacy to take the drug one hour before or three hours after Super Multi-Minerals Regular Strength (Calcium (Calcium Carbonate)) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Calcium (Calcium Citrate):


1 INDICATIONS AND USAGE

Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate is a phosphate binder indicated to reduce serum phosphorus in patients with end stage renal disease (ESRD).

- Calcium acetate is a phosphate binder indicated for the reduction of serum phosphorus in patients with end stage renal disease. (1)

2 DOSAGE AND ADMINISTRATION

The recommended initial dose of Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate for the adult dialysis patient is 2 capsules with each meal. Increase the dose gradually to lower serum phosphorus levels to the target range, as long as hypercalcemia does not develop. Most patients require 3 to 4 capsules with each meal.

- Starting dose is 2 capsules with each meal. (2)

- Titrate the dose every 2 to 3 weeks until acceptable serum phosphorus level is reached. Most patients require 3 to 4 capsules with each meal. (2)

3 DOSAGE FORMS AND STRENGTHS

Capsule: 667 mg Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate capsule.

- Capsule: 667 mg Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Super Multi-Minerals Regular Strength ) acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate. (5.1)

- Hypercalcemia may aggravate digitalis toxicity. (5.2)

5.1 Hypercalcemia

Patients with end stage renal disease may develop hypercalcemia when treated with Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)), including Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate. Avoid the use of Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) supplements, including Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) based nonprescription antacids, concurrently with Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate.

An overdose of Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) levels twice weekly. Should hypercalcemia develop, reduce the Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate dosage, or discontinue the treatment, depending on the severity of hypercalcemia

More severe hypercalcemia (Ca >12 mg/dL) is associated with confusion, delirium, stupor and coma. Severe hypercalcemia can be treated by acute hemodialysis and discontinuing Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate therapy.

Mild hypercalcemia (10.5 to 11.9 mg/dL) may be asymptomatic or manifest as constipation, anorexia, nausea, and vomiting. Mild hypercalcemia is usually controlled by reducing the Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate dose or temporarily discontinuing therapy. Decreasing or discontinuing Vitamin D therapy is recommended as well.

Chronic hypercalcemia may lead to vascular calcification and other soft-tissue calcification. Radiographic evaluation of suspected anatomical regions may be helpful in early detection of soft tissue calcification. The long term effect of Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate on the progression of vascular or soft tissue calcification has not been determined.

Hypercalcemia (>11 mg/dL) was reported in 16% of patients in a 3 month study of solid dose formulation of Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate; all cases resolved upon lowering the dose or discontinuing treatment.

Maintain the serum calcium-phosphorus (Ca x P) product below 55 mg2/dL2.

5.2 Concomitant Use with Medications

Hypercalcemia may aggravate digitalis toxicity.

6 ADVERSE REACTIONS

Hypercalcemia is discussed elsewhere [see Warnings and Precautions ].

- The most common (>10%) adverse reactions are hypercalcemia, nausea and vomiting. (6.1)

- In clinical studies, patients have occasionally experienced nausea during Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate therapy. (6)

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical studies, Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate has been generally well tolerated.

Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate was studied in a two week double-blind, placebo-controlled, cross-over study with 69 enrolled ESRD hemodialysis patients. Adverse reactions (>2% on treatment) from these trials are presented in Table 1.


Preferred Term


Total adverse reactions reported for Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate

N=167

N (%)


3 month, open label study of Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate

N=98

N (%)


Double blind, placebo-controlled, cross-over study of liquid Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate

N=69


Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate

N (%)


Placebo

N (%)


Nausea


6 (3.6)


6 (6.1)


0 (0)


0 (0)


Vomiting


4 (2.4)


4 (4.1)


0 (0)


0 (0)


Hypercalcemia


21 (12.6)


16 (16.3)


5 (7.2)


0 (0)


Mild hypercalcemia may be asymptomatic or manifest itself as constipation, anorexia, nausea, and vomiting. More severe hypercalcemia is associated with confusion, delirium, stupor, and coma. Decreasing dialysate Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) concentration could reduce the incidence and severity of Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate-induced hypercalcemia. Isolated cases pruritus have been reported, which may represent allergic reactions.

6.2 Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or to establish a causal relationship to drug exposure.

The following additional adverse reactions have been identified during post-approval of Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of Super Multi-Minerals Regular Strength ) acetate is characterized by the potential of Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate and most concomitant drugs. When administering an oral medication with Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, administer the drug one hour before or three hours after Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate. Monitor blood levels of the concomitant drugs that have a narrow therapeutic range. Patients taking anti-arrhythmic medications for the control of arrhythmias and anti-seizure medications for the control of seizure disorders were excluded from the clinical trials with all forms of Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate.

- Calcium acetate may decrease the bioavailability of tetracyclines or fluoroquinolones. (7)

- When clinically significant drug interactions are expected, administer the drug at least one hour before or at least three hours after Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate or consider monitoring blood levels of the drug. (7)

7.1 Ciprofloxacin

In a study of 15 healthy subjects, a co-administered single dose of 4 Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

Super Multi-Minerals Regular Strength ) acetate capsules contains Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate. Animal reproduction studies have not been conducted with Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate, and there are no adequate and well controlled studies of Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) levels is important for maternal and fetal well being. Hypercalcemia during pregnancy may increase the risk for maternal and neonatal complications such as stillbirth, preterm delivery, and neonatal hypocalcemia and hypoparathyroidism. Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate treatment, as recommended, is not expected to harm a fetus if maternal Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Super Multi-Minerals Regular Strength ) Acetate Capsules contains Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate and is excreted in human milk. Human milk feeding by a mother receiving Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate is not expected to harm an infant, provided maternal serum Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) levels are appropriately monitored.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

Administration of Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate acts as a phosphate binder. Its chemical name is Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate. Its molecular formula is C4H6CaO4, and its molecular weight is 158.17. Its structural formula is:


Each white opaque/blue opaque capsule contains 667 mg of Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate USP (anhydrous; Ca(CH3COO)2; MW=158.17 grams) equal to 169 mg (8.45 mEq) Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)), polyethylene glycol 8000 and magnesium stearate. Each capsule shell contains: black monogramming ink, FD&C Blue #1, FD&C Red #3, gelatin and titanium dioxide. The black monogramming ink contains: ammonium hydroxide, iron oxide black, isopropyl alcohol, n-butyl alcohol, propylene glycol and shellac glaze.

Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) Acetate Capsules are administered orally for the control of hyperphosphatemia in end-stage renal failure.

Chemical Structure

12 CLINICAL PHARMACOLOGY

Patients with ESRD retain phosphorus and can develop hyperphosphatemia. High serum phosphorus can precipitate serum Super Multi-Minerals Regular Strength ) resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate from pharmaceutical dosage forms is systemically absorbed up to approximately 40% under fasting conditions and up to approximately 30% under nonfasting conditions. This range represents data from both healthy subjects and renal dialysis patients under various conditions.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate.

14 CLINICAL STUDIES

Effectiveness of Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate solid oral dosage form.

Ninety-one patients with end-stage renal disease who were undergoing hemodialysis and were hyperphosphatemic (serum phosphorus >5.5 mg/dL) following a 1 week phosphate binder washout period contributed efficacy data to an open-label, non-randomized study.

The patients received Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate 667 mg tablets at each meal for a period of 12 weeks. The initial starting dose was 2 tablets per meal for 3 meals a day, and the dose was adjusted as necessary to control serum phosphorus levels. The average final dose after 12 weeks of treatment was 3.4 tablets per meal. Although there was a decrease in serum phosphorus, in the absence of a control group the true magnitude of effect is uncertain.

The data presented in Table 2 demonstrate the efficacy of Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) levels are also presented.


* Ninety-one patients completed at least 6 weeks of the study.

ANOVA of difference in values at pre-study and study completion.

‡ Values expressed as mean ± SE.


Parameter


Pre-Study


Week 4*


Week 8


Week 12


p-value†


Phosphorus (mg/dL)‡


7.4 ± 0.17


5.9 ± 0.16


5.6 ± 0.17


5.2 ± 0.17


≤0.01


Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) (mg/dL)‡


8.9 ± 0.09


9.5 ± 0.10


9.7 ± 0.10


9.7 ± 0.10


≤0.01


There was a 30% decrease in serum phosphorus levels during the 12 week study period (p<0.01). Two-thirds of the decline occurred in the first month of the study. Serum Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) increased 9% during the study mostly in the first month of the study.

Treatment with the phosphate binder was discontinued for patients from the open-label study, and those patients whose serum phosphorus exceeded 5.5 mg/dL were eligible for entry into a double-blind, placebo-controlled, cross-over study. Patients were randomized to receive Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate or placebo, and each continued to receive the same number of tablets as had been individually established during the previous study. Following 2 weeks of treatment, patients switched to the alternative therapy for an additional 2 weeks.

The phosphate binding effect of Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate is shown in the Table 3.


* ANOVA of Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate vs. placebo after 2 weeks of treatment.

Values expressed as mean ± SEM.


Parameter


Pre-Study


Post-Treatment


p-value*


Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) Acetate


Placebo


Phosphorus (mg/dL)


7.3 ± 0.18


5.9 ± 0.24


7.8 ± 0.22


<0.01


Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) (mg/dL)


8.9 ± 0.11


9.5 ± 0.13


8.8 ± 0.12


<0.01


Overall, 2 weeks of treatment with Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) Acetate Capsules

667 mg capsule is supplied as a white opaque/blue opaque capsule, imprinted with “54 215” on the cap and body.

NDC 0615-2303-39: Blistercards of 30 Capsules

NDC 0615-2303-30: Unit-dose Boxes of 30 Capsules

STORAGE

Store at 20° to 25°C (68° to 77°F).

17 PATIENT COUNSELING INFORMATION

Inform patients to take Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) supplements including nonprescription antacids. Inform the patients about the symptoms of hypercalcemia [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ].

Advise patients who are taking an oral medication where reduction in the bioavailability of that medication would have clinically significant effect on its safety or efficacy to take the drug one hour before or three hours after Super Multi-Minerals Regular Strength (Calcium (Calcium Citrate)) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Calcium (Calcium Gluconate):


1 INDICATIONS AND USAGE

Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate is a phosphate binder indicated to reduce serum phosphorus in patients with end stage renal disease (ESRD).

- Calcium acetate is a phosphate binder indicated for the reduction of serum phosphorus in patients with end stage renal disease. (1)

2 DOSAGE AND ADMINISTRATION

The recommended initial dose of Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate for the adult dialysis patient is 2 capsules with each meal. Increase the dose gradually to lower serum phosphorus levels to the target range, as long as hypercalcemia does not develop. Most patients require 3 to 4 capsules with each meal.

- Starting dose is 2 capsules with each meal. (2)

- Titrate the dose every 2 to 3 weeks until acceptable serum phosphorus level is reached. Most patients require 3 to 4 capsules with each meal. (2)

3 DOSAGE FORMS AND STRENGTHS

Capsule: 667 mg Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate capsule.

- Capsule: 667 mg Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Super Multi-Minerals Regular Strength ) acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate. (5.1)

- Hypercalcemia may aggravate digitalis toxicity. (5.2)

5.1 Hypercalcemia

Patients with end stage renal disease may develop hypercalcemia when treated with Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)), including Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate. Avoid the use of Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) supplements, including Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) based nonprescription antacids, concurrently with Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate.

An overdose of Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) levels twice weekly. Should hypercalcemia develop, reduce the Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate dosage, or discontinue the treatment, depending on the severity of hypercalcemia

More severe hypercalcemia (Ca >12 mg/dL) is associated with confusion, delirium, stupor and coma. Severe hypercalcemia can be treated by acute hemodialysis and discontinuing Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate therapy.

Mild hypercalcemia (10.5 to 11.9 mg/dL) may be asymptomatic or manifest as constipation, anorexia, nausea, and vomiting. Mild hypercalcemia is usually controlled by reducing the Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate dose or temporarily discontinuing therapy. Decreasing or discontinuing Vitamin D therapy is recommended as well.

Chronic hypercalcemia may lead to vascular calcification and other soft-tissue calcification. Radiographic evaluation of suspected anatomical regions may be helpful in early detection of soft tissue calcification. The long term effect of Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate on the progression of vascular or soft tissue calcification has not been determined.

Hypercalcemia (>11 mg/dL) was reported in 16% of patients in a 3 month study of solid dose formulation of Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate; all cases resolved upon lowering the dose or discontinuing treatment.

Maintain the serum calcium-phosphorus (Ca x P) product below 55 mg2/dL2.

5.2 Concomitant Use with Medications

Hypercalcemia may aggravate digitalis toxicity.

6 ADVERSE REACTIONS

Hypercalcemia is discussed elsewhere [see Warnings and Precautions ].

- The most common (>10%) adverse reactions are hypercalcemia, nausea and vomiting. (6.1)

- In clinical studies, patients have occasionally experienced nausea during Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate therapy. (6)

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical studies, Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate has been generally well tolerated.

Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate was studied in a two week double-blind, placebo-controlled, cross-over study with 69 enrolled ESRD hemodialysis patients. Adverse reactions (>2% on treatment) from these trials are presented in Table 1.


Preferred Term


Total adverse reactions reported for Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate

N=167

N (%)


3 month, open label study of Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate

N=98

N (%)


Double blind, placebo-controlled, cross-over study of liquid Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate

N=69


Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate

N (%)


Placebo

N (%)


Nausea


6 (3.6)


6 (6.1)


0 (0)


0 (0)


Vomiting


4 (2.4)


4 (4.1)


0 (0)


0 (0)


Hypercalcemia


21 (12.6)


16 (16.3)


5 (7.2)


0 (0)


Mild hypercalcemia may be asymptomatic or manifest itself as constipation, anorexia, nausea, and vomiting. More severe hypercalcemia is associated with confusion, delirium, stupor, and coma. Decreasing dialysate Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) concentration could reduce the incidence and severity of Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate-induced hypercalcemia. Isolated cases pruritus have been reported, which may represent allergic reactions.

6.2 Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or to establish a causal relationship to drug exposure.

The following additional adverse reactions have been identified during post-approval of Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of Super Multi-Minerals Regular Strength ) acetate is characterized by the potential of Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate and most concomitant drugs. When administering an oral medication with Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, administer the drug one hour before or three hours after Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate. Monitor blood levels of the concomitant drugs that have a narrow therapeutic range. Patients taking anti-arrhythmic medications for the control of arrhythmias and anti-seizure medications for the control of seizure disorders were excluded from the clinical trials with all forms of Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate.

- Calcium acetate may decrease the bioavailability of tetracyclines or fluoroquinolones. (7)

- When clinically significant drug interactions are expected, administer the drug at least one hour before or at least three hours after Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate or consider monitoring blood levels of the drug. (7)

7.1 Ciprofloxacin

In a study of 15 healthy subjects, a co-administered single dose of 4 Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

Super Multi-Minerals Regular Strength ) acetate capsules contains Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate. Animal reproduction studies have not been conducted with Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate, and there are no adequate and well controlled studies of Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) levels is important for maternal and fetal well being. Hypercalcemia during pregnancy may increase the risk for maternal and neonatal complications such as stillbirth, preterm delivery, and neonatal hypocalcemia and hypoparathyroidism. Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate treatment, as recommended, is not expected to harm a fetus if maternal Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Super Multi-Minerals Regular Strength ) Acetate Capsules contains Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate and is excreted in human milk. Human milk feeding by a mother receiving Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate is not expected to harm an infant, provided maternal serum Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) levels are appropriately monitored.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

Administration of Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate acts as a phosphate binder. Its chemical name is Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate. Its molecular formula is C4H6CaO4, and its molecular weight is 158.17. Its structural formula is:


Each white opaque/blue opaque capsule contains 667 mg of Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate USP (anhydrous; Ca(CH3COO)2; MW=158.17 grams) equal to 169 mg (8.45 mEq) Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)), polyethylene glycol 8000 and magnesium stearate. Each capsule shell contains: black monogramming ink, FD&C Blue #1, FD&C Red #3, gelatin and titanium dioxide. The black monogramming ink contains: ammonium hydroxide, iron oxide black, isopropyl alcohol, n-butyl alcohol, propylene glycol and shellac glaze.

Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) Acetate Capsules are administered orally for the control of hyperphosphatemia in end-stage renal failure.

Chemical Structure

12 CLINICAL PHARMACOLOGY

Patients with ESRD retain phosphorus and can develop hyperphosphatemia. High serum phosphorus can precipitate serum Super Multi-Minerals Regular Strength ) resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate from pharmaceutical dosage forms is systemically absorbed up to approximately 40% under fasting conditions and up to approximately 30% under nonfasting conditions. This range represents data from both healthy subjects and renal dialysis patients under various conditions.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate.

14 CLINICAL STUDIES

Effectiveness of Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate solid oral dosage form.

Ninety-one patients with end-stage renal disease who were undergoing hemodialysis and were hyperphosphatemic (serum phosphorus >5.5 mg/dL) following a 1 week phosphate binder washout period contributed efficacy data to an open-label, non-randomized study.

The patients received Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate 667 mg tablets at each meal for a period of 12 weeks. The initial starting dose was 2 tablets per meal for 3 meals a day, and the dose was adjusted as necessary to control serum phosphorus levels. The average final dose after 12 weeks of treatment was 3.4 tablets per meal. Although there was a decrease in serum phosphorus, in the absence of a control group the true magnitude of effect is uncertain.

The data presented in Table 2 demonstrate the efficacy of Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) levels are also presented.


* Ninety-one patients completed at least 6 weeks of the study.

ANOVA of difference in values at pre-study and study completion.

‡ Values expressed as mean ± SE.


Parameter


Pre-Study


Week 4*


Week 8


Week 12


p-value†


Phosphorus (mg/dL)‡


7.4 ± 0.17


5.9 ± 0.16


5.6 ± 0.17


5.2 ± 0.17


≤0.01


Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) (mg/dL)‡


8.9 ± 0.09


9.5 ± 0.10


9.7 ± 0.10


9.7 ± 0.10


≤0.01


There was a 30% decrease in serum phosphorus levels during the 12 week study period (p<0.01). Two-thirds of the decline occurred in the first month of the study. Serum Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) increased 9% during the study mostly in the first month of the study.

Treatment with the phosphate binder was discontinued for patients from the open-label study, and those patients whose serum phosphorus exceeded 5.5 mg/dL were eligible for entry into a double-blind, placebo-controlled, cross-over study. Patients were randomized to receive Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate or placebo, and each continued to receive the same number of tablets as had been individually established during the previous study. Following 2 weeks of treatment, patients switched to the alternative therapy for an additional 2 weeks.

The phosphate binding effect of Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate is shown in the Table 3.


* ANOVA of Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate vs. placebo after 2 weeks of treatment.

Values expressed as mean ± SEM.


Parameter


Pre-Study


Post-Treatment


p-value*


Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) Acetate


Placebo


Phosphorus (mg/dL)


7.3 ± 0.18


5.9 ± 0.24


7.8 ± 0.22


<0.01


Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) (mg/dL)


8.9 ± 0.11


9.5 ± 0.13


8.8 ± 0.12


<0.01


Overall, 2 weeks of treatment with Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) Acetate Capsules

667 mg capsule is supplied as a white opaque/blue opaque capsule, imprinted with “54 215” on the cap and body.

NDC 0615-2303-39: Blistercards of 30 Capsules

NDC 0615-2303-30: Unit-dose Boxes of 30 Capsules

STORAGE

Store at 20° to 25°C (68° to 77°F).

17 PATIENT COUNSELING INFORMATION

Inform patients to take Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) supplements including nonprescription antacids. Inform the patients about the symptoms of hypercalcemia [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ].

Advise patients who are taking an oral medication where reduction in the bioavailability of that medication would have clinically significant effect on its safety or efficacy to take the drug one hour before or three hours after Super Multi-Minerals Regular Strength (Calcium (Calcium Gluconate)) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Calcium (Calcium HVP Chelate):


1 INDICATIONS AND USAGE

Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate is a phosphate binder indicated to reduce serum phosphorus in patients with end stage renal disease (ESRD).

- Calcium acetate is a phosphate binder indicated for the reduction of serum phosphorus in patients with end stage renal disease. (1)

2 DOSAGE AND ADMINISTRATION

The recommended initial dose of Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate for the adult dialysis patient is 2 capsules with each meal. Increase the dose gradually to lower serum phosphorus levels to the target range, as long as hypercalcemia does not develop. Most patients require 3 to 4 capsules with each meal.

- Starting dose is 2 capsules with each meal. (2)

- Titrate the dose every 2 to 3 weeks until acceptable serum phosphorus level is reached. Most patients require 3 to 4 capsules with each meal. (2)

3 DOSAGE FORMS AND STRENGTHS

Capsule: 667 mg Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate capsule.

- Capsule: 667 mg Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Super Multi-Minerals Regular Strength ) acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate. (5.1)

- Hypercalcemia may aggravate digitalis toxicity. (5.2)

5.1 Hypercalcemia

Patients with end stage renal disease may develop hypercalcemia when treated with Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)), including Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate. Avoid the use of Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) supplements, including Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) based nonprescription antacids, concurrently with Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate.

An overdose of Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) levels twice weekly. Should hypercalcemia develop, reduce the Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate dosage, or discontinue the treatment, depending on the severity of hypercalcemia

More severe hypercalcemia (Ca >12 mg/dL) is associated with confusion, delirium, stupor and coma. Severe hypercalcemia can be treated by acute hemodialysis and discontinuing Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate therapy.

Mild hypercalcemia (10.5 to 11.9 mg/dL) may be asymptomatic or manifest as constipation, anorexia, nausea, and vomiting. Mild hypercalcemia is usually controlled by reducing the Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate dose or temporarily discontinuing therapy. Decreasing or discontinuing Vitamin D therapy is recommended as well.

Chronic hypercalcemia may lead to vascular calcification and other soft-tissue calcification. Radiographic evaluation of suspected anatomical regions may be helpful in early detection of soft tissue calcification. The long term effect of Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate on the progression of vascular or soft tissue calcification has not been determined.

Hypercalcemia (>11 mg/dL) was reported in 16% of patients in a 3 month study of solid dose formulation of Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate; all cases resolved upon lowering the dose or discontinuing treatment.

Maintain the serum calcium-phosphorus (Ca x P) product below 55 mg2/dL2.

5.2 Concomitant Use with Medications

Hypercalcemia may aggravate digitalis toxicity.

6 ADVERSE REACTIONS

Hypercalcemia is discussed elsewhere [see Warnings and Precautions ].

- The most common (>10%) adverse reactions are hypercalcemia, nausea and vomiting. (6.1)

- In clinical studies, patients have occasionally experienced nausea during Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate therapy. (6)

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical studies, Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate has been generally well tolerated.

Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate was studied in a two week double-blind, placebo-controlled, cross-over study with 69 enrolled ESRD hemodialysis patients. Adverse reactions (>2% on treatment) from these trials are presented in Table 1.


Preferred Term


Total adverse reactions reported for Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate

N=167

N (%)


3 month, open label study of Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate

N=98

N (%)


Double blind, placebo-controlled, cross-over study of liquid Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate

N=69


Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate

N (%)


Placebo

N (%)


Nausea


6 (3.6)


6 (6.1)


0 (0)


0 (0)


Vomiting


4 (2.4)


4 (4.1)


0 (0)


0 (0)


Hypercalcemia


21 (12.6)


16 (16.3)


5 (7.2)


0 (0)


Mild hypercalcemia may be asymptomatic or manifest itself as constipation, anorexia, nausea, and vomiting. More severe hypercalcemia is associated with confusion, delirium, stupor, and coma. Decreasing dialysate Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) concentration could reduce the incidence and severity of Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate-induced hypercalcemia. Isolated cases pruritus have been reported, which may represent allergic reactions.

6.2 Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or to establish a causal relationship to drug exposure.

The following additional adverse reactions have been identified during post-approval of Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of Super Multi-Minerals Regular Strength ) acetate is characterized by the potential of Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate and most concomitant drugs. When administering an oral medication with Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, administer the drug one hour before or three hours after Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate. Monitor blood levels of the concomitant drugs that have a narrow therapeutic range. Patients taking anti-arrhythmic medications for the control of arrhythmias and anti-seizure medications for the control of seizure disorders were excluded from the clinical trials with all forms of Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate.

- Calcium acetate may decrease the bioavailability of tetracyclines or fluoroquinolones. (7)

- When clinically significant drug interactions are expected, administer the drug at least one hour before or at least three hours after Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate or consider monitoring blood levels of the drug. (7)

7.1 Ciprofloxacin

In a study of 15 healthy subjects, a co-administered single dose of 4 Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

Super Multi-Minerals Regular Strength ) acetate capsules contains Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate. Animal reproduction studies have not been conducted with Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate, and there are no adequate and well controlled studies of Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) levels is important for maternal and fetal well being. Hypercalcemia during pregnancy may increase the risk for maternal and neonatal complications such as stillbirth, preterm delivery, and neonatal hypocalcemia and hypoparathyroidism. Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate treatment, as recommended, is not expected to harm a fetus if maternal Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Super Multi-Minerals Regular Strength ) Acetate Capsules contains Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate and is excreted in human milk. Human milk feeding by a mother receiving Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate is not expected to harm an infant, provided maternal serum Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) levels are appropriately monitored.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

Administration of Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate acts as a phosphate binder. Its chemical name is Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate. Its molecular formula is C4H6CaO4, and its molecular weight is 158.17. Its structural formula is:


Each white opaque/blue opaque capsule contains 667 mg of Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate USP (anhydrous; Ca(CH3COO)2; MW=158.17 grams) equal to 169 mg (8.45 mEq) Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)), polyethylene glycol 8000 and magnesium stearate. Each capsule shell contains: black monogramming ink, FD&C Blue #1, FD&C Red #3, gelatin and titanium dioxide. The black monogramming ink contains: ammonium hydroxide, iron oxide black, isopropyl alcohol, n-butyl alcohol, propylene glycol and shellac glaze.

Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) Acetate Capsules are administered orally for the control of hyperphosphatemia in end-stage renal failure.

Chemical Structure

12 CLINICAL PHARMACOLOGY

Patients with ESRD retain phosphorus and can develop hyperphosphatemia. High serum phosphorus can precipitate serum Super Multi-Minerals Regular Strength ) resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate from pharmaceutical dosage forms is systemically absorbed up to approximately 40% under fasting conditions and up to approximately 30% under nonfasting conditions. This range represents data from both healthy subjects and renal dialysis patients under various conditions.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate.

14 CLINICAL STUDIES

Effectiveness of Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate solid oral dosage form.

Ninety-one patients with end-stage renal disease who were undergoing hemodialysis and were hyperphosphatemic (serum phosphorus >5.5 mg/dL) following a 1 week phosphate binder washout period contributed efficacy data to an open-label, non-randomized study.

The patients received Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate 667 mg tablets at each meal for a period of 12 weeks. The initial starting dose was 2 tablets per meal for 3 meals a day, and the dose was adjusted as necessary to control serum phosphorus levels. The average final dose after 12 weeks of treatment was 3.4 tablets per meal. Although there was a decrease in serum phosphorus, in the absence of a control group the true magnitude of effect is uncertain.

The data presented in Table 2 demonstrate the efficacy of Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) levels are also presented.


* Ninety-one patients completed at least 6 weeks of the study.

ANOVA of difference in values at pre-study and study completion.

‡ Values expressed as mean ± SE.


Parameter


Pre-Study


Week 4*


Week 8


Week 12


p-value†


Phosphorus (mg/dL)‡


7.4 ± 0.17


5.9 ± 0.16


5.6 ± 0.17


5.2 ± 0.17


≤0.01


Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) (mg/dL)‡


8.9 ± 0.09


9.5 ± 0.10


9.7 ± 0.10


9.7 ± 0.10


≤0.01


There was a 30% decrease in serum phosphorus levels during the 12 week study period (p<0.01). Two-thirds of the decline occurred in the first month of the study. Serum Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) increased 9% during the study mostly in the first month of the study.

Treatment with the phosphate binder was discontinued for patients from the open-label study, and those patients whose serum phosphorus exceeded 5.5 mg/dL were eligible for entry into a double-blind, placebo-controlled, cross-over study. Patients were randomized to receive Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate or placebo, and each continued to receive the same number of tablets as had been individually established during the previous study. Following 2 weeks of treatment, patients switched to the alternative therapy for an additional 2 weeks.

The phosphate binding effect of Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate is shown in the Table 3.


* ANOVA of Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate vs. placebo after 2 weeks of treatment.

Values expressed as mean ± SEM.


Parameter


Pre-Study


Post-Treatment


p-value*


Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) Acetate


Placebo


Phosphorus (mg/dL)


7.3 ± 0.18


5.9 ± 0.24


7.8 ± 0.22


<0.01


Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) (mg/dL)


8.9 ± 0.11


9.5 ± 0.13


8.8 ± 0.12


<0.01


Overall, 2 weeks of treatment with Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) Acetate Capsules

667 mg capsule is supplied as a white opaque/blue opaque capsule, imprinted with “54 215” on the cap and body.

NDC 0615-2303-39: Blistercards of 30 Capsules

NDC 0615-2303-30: Unit-dose Boxes of 30 Capsules

STORAGE

Store at 20° to 25°C (68° to 77°F).

17 PATIENT COUNSELING INFORMATION

Inform patients to take Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) supplements including nonprescription antacids. Inform the patients about the symptoms of hypercalcemia [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ].

Advise patients who are taking an oral medication where reduction in the bioavailability of that medication would have clinically significant effect on its safety or efficacy to take the drug one hour before or three hours after Super Multi-Minerals Regular Strength (Calcium (Calcium HVP Chelate)) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Calcium (Oyster Shells):


1 INDICATIONS AND USAGE

Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate is a phosphate binder indicated to reduce serum phosphorus in patients with end stage renal disease (ESRD).

- Calcium acetate is a phosphate binder indicated for the reduction of serum phosphorus in patients with end stage renal disease. (1)

2 DOSAGE AND ADMINISTRATION

The recommended initial dose of Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate for the adult dialysis patient is 2 capsules with each meal. Increase the dose gradually to lower serum phosphorus levels to the target range, as long as hypercalcemia does not develop. Most patients require 3 to 4 capsules with each meal.

- Starting dose is 2 capsules with each meal. (2)

- Titrate the dose every 2 to 3 weeks until acceptable serum phosphorus level is reached. Most patients require 3 to 4 capsules with each meal. (2)

3 DOSAGE FORMS AND STRENGTHS

Capsule: 667 mg Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate capsule.

- Capsule: 667 mg Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Super Multi-Minerals Regular Strength ) acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate. (5.1)

- Hypercalcemia may aggravate digitalis toxicity. (5.2)

5.1 Hypercalcemia

Patients with end stage renal disease may develop hypercalcemia when treated with Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)), including Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate. Avoid the use of Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) supplements, including Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) based nonprescription antacids, concurrently with Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate.

An overdose of Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) levels twice weekly. Should hypercalcemia develop, reduce the Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate dosage, or discontinue the treatment, depending on the severity of hypercalcemia

More severe hypercalcemia (Ca >12 mg/dL) is associated with confusion, delirium, stupor and coma. Severe hypercalcemia can be treated by acute hemodialysis and discontinuing Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate therapy.

Mild hypercalcemia (10.5 to 11.9 mg/dL) may be asymptomatic or manifest as constipation, anorexia, nausea, and vomiting. Mild hypercalcemia is usually controlled by reducing the Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate dose or temporarily discontinuing therapy. Decreasing or discontinuing Vitamin D therapy is recommended as well.

Chronic hypercalcemia may lead to vascular calcification and other soft-tissue calcification. Radiographic evaluation of suspected anatomical regions may be helpful in early detection of soft tissue calcification. The long term effect of Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate on the progression of vascular or soft tissue calcification has not been determined.

Hypercalcemia (>11 mg/dL) was reported in 16% of patients in a 3 month study of solid dose formulation of Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate; all cases resolved upon lowering the dose or discontinuing treatment.

Maintain the serum calcium-phosphorus (Ca x P) product below 55 mg2/dL2.

5.2 Concomitant Use with Medications

Hypercalcemia may aggravate digitalis toxicity.

6 ADVERSE REACTIONS

Hypercalcemia is discussed elsewhere [see Warnings and Precautions ].

- The most common (>10%) adverse reactions are hypercalcemia, nausea and vomiting. (6.1)

- In clinical studies, patients have occasionally experienced nausea during Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate therapy. (6)

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical studies, Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate has been generally well tolerated.

Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate was studied in a two week double-blind, placebo-controlled, cross-over study with 69 enrolled ESRD hemodialysis patients. Adverse reactions (>2% on treatment) from these trials are presented in Table 1.


Preferred Term


Total adverse reactions reported for Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate

N=167

N (%)


3 month, open label study of Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate

N=98

N (%)


Double blind, placebo-controlled, cross-over study of liquid Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate

N=69


Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate

N (%)


Placebo

N (%)


Nausea


6 (3.6)


6 (6.1)


0 (0)


0 (0)


Vomiting


4 (2.4)


4 (4.1)


0 (0)


0 (0)


Hypercalcemia


21 (12.6)


16 (16.3)


5 (7.2)


0 (0)


Mild hypercalcemia may be asymptomatic or manifest itself as constipation, anorexia, nausea, and vomiting. More severe hypercalcemia is associated with confusion, delirium, stupor, and coma. Decreasing dialysate Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) concentration could reduce the incidence and severity of Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate-induced hypercalcemia. Isolated cases pruritus have been reported, which may represent allergic reactions.

6.2 Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or to establish a causal relationship to drug exposure.

The following additional adverse reactions have been identified during post-approval of Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of Super Multi-Minerals Regular Strength ) acetate is characterized by the potential of Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate and most concomitant drugs. When administering an oral medication with Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, administer the drug one hour before or three hours after Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate. Monitor blood levels of the concomitant drugs that have a narrow therapeutic range. Patients taking anti-arrhythmic medications for the control of arrhythmias and anti-seizure medications for the control of seizure disorders were excluded from the clinical trials with all forms of Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate.

- Calcium acetate may decrease the bioavailability of tetracyclines or fluoroquinolones. (7)

- When clinically significant drug interactions are expected, administer the drug at least one hour before or at least three hours after Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate or consider monitoring blood levels of the drug. (7)

7.1 Ciprofloxacin

In a study of 15 healthy subjects, a co-administered single dose of 4 Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

Super Multi-Minerals Regular Strength ) acetate capsules contains Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate. Animal reproduction studies have not been conducted with Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate, and there are no adequate and well controlled studies of Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) levels is important for maternal and fetal well being. Hypercalcemia during pregnancy may increase the risk for maternal and neonatal complications such as stillbirth, preterm delivery, and neonatal hypocalcemia and hypoparathyroidism. Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate treatment, as recommended, is not expected to harm a fetus if maternal Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Super Multi-Minerals Regular Strength ) Acetate Capsules contains Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate and is excreted in human milk. Human milk feeding by a mother receiving Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate is not expected to harm an infant, provided maternal serum Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) levels are appropriately monitored.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

Administration of Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate acts as a phosphate binder. Its chemical name is Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate. Its molecular formula is C4H6CaO4, and its molecular weight is 158.17. Its structural formula is:


Each white opaque/blue opaque capsule contains 667 mg of Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate USP (anhydrous; Ca(CH3COO)2; MW=158.17 grams) equal to 169 mg (8.45 mEq) Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)), polyethylene glycol 8000 and magnesium stearate. Each capsule shell contains: black monogramming ink, FD&C Blue #1, FD&C Red #3, gelatin and titanium dioxide. The black monogramming ink contains: ammonium hydroxide, iron oxide black, isopropyl alcohol, n-butyl alcohol, propylene glycol and shellac glaze.

Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) Acetate Capsules are administered orally for the control of hyperphosphatemia in end-stage renal failure.

Chemical Structure

12 CLINICAL PHARMACOLOGY

Patients with ESRD retain phosphorus and can develop hyperphosphatemia. High serum phosphorus can precipitate serum Super Multi-Minerals Regular Strength ) resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate from pharmaceutical dosage forms is systemically absorbed up to approximately 40% under fasting conditions and up to approximately 30% under nonfasting conditions. This range represents data from both healthy subjects and renal dialysis patients under various conditions.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate.

14 CLINICAL STUDIES

Effectiveness of Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate solid oral dosage form.

Ninety-one patients with end-stage renal disease who were undergoing hemodialysis and were hyperphosphatemic (serum phosphorus >5.5 mg/dL) following a 1 week phosphate binder washout period contributed efficacy data to an open-label, non-randomized study.

The patients received Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate 667 mg tablets at each meal for a period of 12 weeks. The initial starting dose was 2 tablets per meal for 3 meals a day, and the dose was adjusted as necessary to control serum phosphorus levels. The average final dose after 12 weeks of treatment was 3.4 tablets per meal. Although there was a decrease in serum phosphorus, in the absence of a control group the true magnitude of effect is uncertain.

The data presented in Table 2 demonstrate the efficacy of Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) levels are also presented.


* Ninety-one patients completed at least 6 weeks of the study.

ANOVA of difference in values at pre-study and study completion.

‡ Values expressed as mean ± SE.


Parameter


Pre-Study


Week 4*


Week 8


Week 12


p-value†


Phosphorus (mg/dL)‡


7.4 ± 0.17


5.9 ± 0.16


5.6 ± 0.17


5.2 ± 0.17


≤0.01


Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) (mg/dL)‡


8.9 ± 0.09


9.5 ± 0.10


9.7 ± 0.10


9.7 ± 0.10


≤0.01


There was a 30% decrease in serum phosphorus levels during the 12 week study period (p<0.01). Two-thirds of the decline occurred in the first month of the study. Serum Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) increased 9% during the study mostly in the first month of the study.

Treatment with the phosphate binder was discontinued for patients from the open-label study, and those patients whose serum phosphorus exceeded 5.5 mg/dL were eligible for entry into a double-blind, placebo-controlled, cross-over study. Patients were randomized to receive Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate or placebo, and each continued to receive the same number of tablets as had been individually established during the previous study. Following 2 weeks of treatment, patients switched to the alternative therapy for an additional 2 weeks.

The phosphate binding effect of Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate is shown in the Table 3.


* ANOVA of Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate vs. placebo after 2 weeks of treatment.

Values expressed as mean ± SEM.


Parameter


Pre-Study


Post-Treatment


p-value*


Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) Acetate


Placebo


Phosphorus (mg/dL)


7.3 ± 0.18


5.9 ± 0.24


7.8 ± 0.22


<0.01


Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) (mg/dL)


8.9 ± 0.11


9.5 ± 0.13


8.8 ± 0.12


<0.01


Overall, 2 weeks of treatment with Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) Acetate Capsules

667 mg capsule is supplied as a white opaque/blue opaque capsule, imprinted with “54 215” on the cap and body.

NDC 0615-2303-39: Blistercards of 30 Capsules

NDC 0615-2303-30: Unit-dose Boxes of 30 Capsules

STORAGE

Store at 20° to 25°C (68° to 77°F).

17 PATIENT COUNSELING INFORMATION

Inform patients to take Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) supplements including nonprescription antacids. Inform the patients about the symptoms of hypercalcemia [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ].

Advise patients who are taking an oral medication where reduction in the bioavailability of that medication would have clinically significant effect on its safety or efficacy to take the drug one hour before or three hours after Super Multi-Minerals Regular Strength (Calcium (Oyster Shells)) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Copper (Copper Citrate):



Water-Resistant Protection Without Bandaging

Recommended as an Aid in Treating Horses and Ponies With Thrush Due to Organisms Susceptible to Super Multi-Minerals Regular Strength (Copper (Copper Citrate)) Naphthenate.

For Animal Use Only.

INDICATIONS:

ThrushTox® is indicated in the treatment of thrush in horses and ponies.

GENERAL DIRECTIONS:

Clean the hoof thoroughly, removing debris and necrotic material prior to application of Super Multi-Minerals Regular Strength (Copper (Copper Citrate))®. Apply daily to affected hoofs with a narrow paint brush (about 1”) until fully healed. Caution: Do not allow runoff of excess Super Multi-Minerals Regular Strength (Copper (Copper Citrate))® onto hair since contact with Super Multi-Minerals Regular Strength (Copper (Copper Citrate))® may cause some hair loss. Do not contaminate feed.

NOTE: Super Multi-Minerals Regular Strength (Copper (Copper Citrate))® is easily removed from hands, clothing and surfaces with light grade fuel oil or any type of lighter fluid.

CONTAINS FOIL SEAL – REMOVE BEFORE USE.

SHAKE WELL BEFORE USE.

To report suspected adverse reactions or to obtain technical assistance, call 1-800-650-4899.

ACTIVE INGREDIENT:

Super Multi-Minerals Regular Strength (Copper (Copper Citrate)) Naphthenate...37.5% w/w

INACTIVE INGREDIENTS:

Inert Ingredients...62.5% w/w

Total... 100.0%

CAUTION:

Do not use in horses intended for human consumption.

CAUTION: COMBUSTIBLE MIXTURE.

Use in a well-ventilated place. Avoid fire, flame, sparks or heaters.

If swallowed, do not induce vomiting, call physician immediately. Avoid breathing vapor. Avoid contact with skin and eyes.

KEEP OUT OF REACH OF CHILDREN AND PETS.

STORAGE:

Store at controlled room temperature 15º to 30ºC (59º to 86ºF). Keep container tightly closed when not in use.

Manufactured for:

Aspen Veterinary Resources,® Ltd.

Liberty, MO 64068, USA

FC163FP 11/13

Manufactured by:

First Priority, Inc.

Elgin, IL 60123-1146, USA

NET CONTENTS:

16 OZ (473 mL)

ANADA 200-304, Approved by FDA

Image of 473 mL bottle/case label

Copper (Copper Fumarate):



Water-Resistant Protection Without Bandaging

Recommended as an Aid in Treating Horses and Ponies With Thrush Due to Organisms Susceptible to Super Multi-Minerals Regular Strength (Copper (Copper Fumarate)) Naphthenate.

For Animal Use Only.

INDICATIONS:

ThrushTox® is indicated in the treatment of thrush in horses and ponies.

GENERAL DIRECTIONS:

Clean the hoof thoroughly, removing debris and necrotic material prior to application of Super Multi-Minerals Regular Strength (Copper (Copper Fumarate))®. Apply daily to affected hoofs with a narrow paint brush (about 1”) until fully healed. Caution: Do not allow runoff of excess Super Multi-Minerals Regular Strength (Copper (Copper Fumarate))® onto hair since contact with Super Multi-Minerals Regular Strength (Copper (Copper Fumarate))® may cause some hair loss. Do not contaminate feed.

NOTE: Super Multi-Minerals Regular Strength (Copper (Copper Fumarate))® is easily removed from hands, clothing and surfaces with light grade fuel oil or any type of lighter fluid.

CONTAINS FOIL SEAL – REMOVE BEFORE USE.

SHAKE WELL BEFORE USE.

To report suspected adverse reactions or to obtain technical assistance, call 1-800-650-4899.

ACTIVE INGREDIENT:

Super Multi-Minerals Regular Strength (Copper (Copper Fumarate)) Naphthenate...37.5% w/w

INACTIVE INGREDIENTS:

Inert Ingredients...62.5% w/w

Total... 100.0%

CAUTION:

Do not use in horses intended for human consumption.

CAUTION: COMBUSTIBLE MIXTURE.

Use in a well-ventilated place. Avoid fire, flame, sparks or heaters.

If swallowed, do not induce vomiting, call physician immediately. Avoid breathing vapor. Avoid contact with skin and eyes.

KEEP OUT OF REACH OF CHILDREN AND PETS.

STORAGE:

Store at controlled room temperature 15º to 30ºC (59º to 86ºF). Keep container tightly closed when not in use.

Manufactured for:

Aspen Veterinary Resources,® Ltd.

Liberty, MO 64068, USA

FC163FP 11/13

Manufactured by:

First Priority, Inc.

Elgin, IL 60123-1146, USA

NET CONTENTS:

16 OZ (473 mL)

ANADA 200-304, Approved by FDA

Image of 473 mL bottle/case label

Copper (Copper Gluconate):



Water-Resistant Protection Without Bandaging

Recommended as an Aid in Treating Horses and Ponies With Thrush Due to Organisms Susceptible to Super Multi-Minerals Regular Strength (Copper (Copper Gluconate)) Naphthenate.

For Animal Use Only.

INDICATIONS:

ThrushTox® is indicated in the treatment of thrush in horses and ponies.

GENERAL DIRECTIONS:

Clean the hoof thoroughly, removing debris and necrotic material prior to application of Super Multi-Minerals Regular Strength (Copper (Copper Gluconate))®. Apply daily to affected hoofs with a narrow paint brush (about 1”) until fully healed. Caution: Do not allow runoff of excess Super Multi-Minerals Regular Strength (Copper (Copper Gluconate))® onto hair since contact with Super Multi-Minerals Regular Strength (Copper (Copper Gluconate))® may cause some hair loss. Do not contaminate feed.

NOTE: Super Multi-Minerals Regular Strength (Copper (Copper Gluconate))® is easily removed from hands, clothing and surfaces with light grade fuel oil or any type of lighter fluid.

CONTAINS FOIL SEAL – REMOVE BEFORE USE.

SHAKE WELL BEFORE USE.

To report suspected adverse reactions or to obtain technical assistance, call 1-800-650-4899.

ACTIVE INGREDIENT:

Super Multi-Minerals Regular Strength (Copper (Copper Gluconate)) Naphthenate...37.5% w/w

INACTIVE INGREDIENTS:

Inert Ingredients...62.5% w/w

Total... 100.0%

CAUTION:

Do not use in horses intended for human consumption.

CAUTION: COMBUSTIBLE MIXTURE.

Use in a well-ventilated place. Avoid fire, flame, sparks or heaters.

If swallowed, do not induce vomiting, call physician immediately. Avoid breathing vapor. Avoid contact with skin and eyes.

KEEP OUT OF REACH OF CHILDREN AND PETS.

STORAGE:

Store at controlled room temperature 15º to 30ºC (59º to 86ºF). Keep container tightly closed when not in use.

Manufactured for:

Aspen Veterinary Resources,® Ltd.

Liberty, MO 64068, USA

FC163FP 11/13

Manufactured by:

First Priority, Inc.

Elgin, IL 60123-1146, USA

NET CONTENTS:

16 OZ (473 mL)

ANADA 200-304, Approved by FDA

Image of 473 mL bottle/case label

Copper (Copper Malate):



Water-Resistant Protection Without Bandaging

Recommended as an Aid in Treating Horses and Ponies With Thrush Due to Organisms Susceptible to Super Multi-Minerals Regular Strength (Copper (Copper Malate)) Naphthenate.

For Animal Use Only.

INDICATIONS:

ThrushTox® is indicated in the treatment of thrush in horses and ponies.

GENERAL DIRECTIONS:

Clean the hoof thoroughly, removing debris and necrotic material prior to application of Super Multi-Minerals Regular Strength (Copper (Copper Malate))®. Apply daily to affected hoofs with a narrow paint brush (about 1”) until fully healed. Caution: Do not allow runoff of excess Super Multi-Minerals Regular Strength (Copper (Copper Malate))® onto hair since contact with Super Multi-Minerals Regular Strength (Copper (Copper Malate))® may cause some hair loss. Do not contaminate feed.

NOTE: Super Multi-Minerals Regular Strength (Copper (Copper Malate))® is easily removed from hands, clothing and surfaces with light grade fuel oil or any type of lighter fluid.

CONTAINS FOIL SEAL – REMOVE BEFORE USE.

SHAKE WELL BEFORE USE.

To report suspected adverse reactions or to obtain technical assistance, call 1-800-650-4899.

ACTIVE INGREDIENT:

Super Multi-Minerals Regular Strength (Copper (Copper Malate)) Naphthenate...37.5% w/w

INACTIVE INGREDIENTS:

Inert Ingredients...62.5% w/w

Total... 100.0%

CAUTION:

Do not use in horses intended for human consumption.

CAUTION: COMBUSTIBLE MIXTURE.

Use in a well-ventilated place. Avoid fire, flame, sparks or heaters.

If swallowed, do not induce vomiting, call physician immediately. Avoid breathing vapor. Avoid contact with skin and eyes.

KEEP OUT OF REACH OF CHILDREN AND PETS.

STORAGE:

Store at controlled room temperature 15º to 30ºC (59º to 86ºF). Keep container tightly closed when not in use.

Manufactured for:

Aspen Veterinary Resources,® Ltd.

Liberty, MO 64068, USA

FC163FP 11/13

Manufactured by:

First Priority, Inc.

Elgin, IL 60123-1146, USA

NET CONTENTS:

16 OZ (473 mL)

ANADA 200-304, Approved by FDA

Image of 473 mL bottle/case label

Copper (Copper Succinate):



Water-Resistant Protection Without Bandaging

Recommended as an Aid in Treating Horses and Ponies With Thrush Due to Organisms Susceptible to Super Multi-Minerals Regular Strength (Copper (Copper Succinate)) Naphthenate.

For Animal Use Only.

INDICATIONS:

ThrushTox® is indicated in the treatment of thrush in horses and ponies.

GENERAL DIRECTIONS:

Clean the hoof thoroughly, removing debris and necrotic material prior to application of Super Multi-Minerals Regular Strength (Copper (Copper Succinate))®. Apply daily to affected hoofs with a narrow paint brush (about 1”) until fully healed. Caution: Do not allow runoff of excess Super Multi-Minerals Regular Strength (Copper (Copper Succinate))® onto hair since contact with Super Multi-Minerals Regular Strength (Copper (Copper Succinate))® may cause some hair loss. Do not contaminate feed.

NOTE: Super Multi-Minerals Regular Strength (Copper (Copper Succinate))® is easily removed from hands, clothing and surfaces with light grade fuel oil or any type of lighter fluid.

CONTAINS FOIL SEAL – REMOVE BEFORE USE.

SHAKE WELL BEFORE USE.

To report suspected adverse reactions or to obtain technical assistance, call 1-800-650-4899.

ACTIVE INGREDIENT:

Super Multi-Minerals Regular Strength (Copper (Copper Succinate)) Naphthenate...37.5% w/w

INACTIVE INGREDIENTS:

Inert Ingredients...62.5% w/w

Total... 100.0%

CAUTION:

Do not use in horses intended for human consumption.

CAUTION: COMBUSTIBLE MIXTURE.

Use in a well-ventilated place. Avoid fire, flame, sparks or heaters.

If swallowed, do not induce vomiting, call physician immediately. Avoid breathing vapor. Avoid contact with skin and eyes.

KEEP OUT OF REACH OF CHILDREN AND PETS.

STORAGE:

Store at controlled room temperature 15º to 30ºC (59º to 86ºF). Keep container tightly closed when not in use.

Manufactured for:

Aspen Veterinary Resources,® Ltd.

Liberty, MO 64068, USA

FC163FP 11/13

Manufactured by:

First Priority, Inc.

Elgin, IL 60123-1146, USA

NET CONTENTS:

16 OZ (473 mL)

ANADA 200-304, Approved by FDA

Image of 473 mL bottle/case label

Iodine (Kelp):


Super Multi-Minerals Regular Strength ) Tincture 7%

Directions:


Topical Antiseptic

Use full Strength for superficial cuts, wounds, abrasions, insect bites and bruises on the skin of animals. Apply Super Multi-Minerals Regular Strength (Iodine (Kelp)) with a swab.

If necessary, clip hair around the area being treated and clean with soap and water.

Apply Super Multi-Minerals Regular Strength (Iodine (Kelp)) Tincture 7% only once daily. Dilute product 3 to 1 if repeating application.

Do not apply under bandage.

Irritation may occur if used on tender skin areas. If redness, irritation, or swelling persists or increases, discontinue use and consult a veterinarian.


Storage:

Store at 2-30 degrees C (36-86 degrees F).

Keep container away from heat and out of sunlight. Rinse empty container thoroughly and discard.


DANGER - Poison


Caution:

If swallowed, give starch paste, milk, bread, egg white, or

activated charcoal. A 5% solutions of sodium thiosulfate

(Photographic (“hypc”) may be administered orally at a

rate of 10 ml per kilogram of body weight.


Eye irritant: Use only as directed. Avoid contact with eyes. In case of contact, flush eyes immediately with tepid water for at least 15 minutes. Consult a physician.


Avoid contamination of food.


Not for use on burns, deep cuts, or body cavities.

Super Multi-Minerals Regular Strength ) Tincture 7%

image description

Iodine (Potassium Iodide):


Super Multi-Minerals Regular Strength ) Tincture 7%

Directions:


Topical Antiseptic

Use full Strength for superficial cuts, wounds, abrasions, insect bites and bruises on the skin of animals. Apply Super Multi-Minerals Regular Strength (Iodine (Potassium Iodide)) with a swab.

If necessary, clip hair around the area being treated and clean with soap and water.

Apply Super Multi-Minerals Regular Strength (Iodine (Potassium Iodide)) Tincture 7% only once daily. Dilute product 3 to 1 if repeating application.

Do not apply under bandage.

Irritation may occur if used on tender skin areas. If redness, irritation, or swelling persists or increases, discontinue use and consult a veterinarian.


Storage:

Store at 2-30 degrees C (36-86 degrees F).

Keep container away from heat and out of sunlight. Rinse empty container thoroughly and discard.


DANGER - Poison


Caution:

If swallowed, give starch paste, milk, bread, egg white, or

activated charcoal. A 5% solutions of sodium thiosulfate

(Photographic (“hypc”) may be administered orally at a

rate of 10 ml per kilogram of body weight.


Eye irritant: Use only as directed. Avoid contact with eyes. In case of contact, flush eyes immediately with tepid water for at least 15 minutes. Consult a physician.


Avoid contamination of food.


Not for use on burns, deep cuts, or body cavities.

Super Multi-Minerals Regular Strength ) Tincture 7%

image description

Iron (Ferrous Citrate):


1 INDICATIONS AND USAGE

Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) is indicated for the treatment of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) deficiency anemia in patients with chronic kidney disease (CKD).

Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) is an Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) replacement product indicated for the treatment of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) deficiency anemia in patients with chronic kidney disease (CKD). (1)

2 DOSAGE AND ADMINISTRATION

Super Multi-Minerals Regular Strength ) must only be administered intravenously either by slow injection or by infusion. The dosage of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) is expressed in mg of elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)). Each mL contains 20 mg of elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)).

Population Dose
Adult patients Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD) (2.1) 100 mg slow intravenous injection or infusion
Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) (2.2) 200 mg slow intravenous injection or infusion
Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD) (2.3) 300 mg or 400 mg intravenous infusion
Pediatric patients HDD-CKD (2.4), PDD-CKD or NDD-CKD (2.5) 0.5 mg/kg slow intravenous injection or infusion

2.1 Adult Patients with Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)

Administer Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) 100 mg undiluted as a slow intravenous injection over 2 to 5 minutes, or as an infusion of 100 mg diluted in a maximum of 100 mL of 0.9% NaCl over a period of at least 15 minutes, per consecutive hemodialysis session. Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) should be administered early during the dialysis session. The usual total treatment course of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) is 1000 mg. Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) treatment may be repeated if Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) deficiency reoccurs.

2.2 Adult Patients with Non-Dialysis Dependent-Chronic Kidney Disease

Administer Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) 200 mg undiluted as a slow intravenous injection over 2 to 5 minutes or as an infusion of 200 mg in a maximum of 100 mL of 0.9% NaCl over a period of 15 minutes. Administer on 5 different occasions over a 14 day period. There is limited experience with administration of an infusion of 500 mg of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)), diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5 to 4 hours on Day 1 and Day 14. Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) treatment may be repeated if Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) in 3 divided doses, given by slow intravenous infusion, within a 28 day period: 2 infusions each of 300 mg over 1.5 hours 14 days apart followed by one 400 mg infusion over 2.5 hours 14 days later. Dilute Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) in a maximum of 250 mL of 0.9% NaCl. Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) treatment may be repeated if Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) maintenance treatment

The dosing for Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) replacement treatment in pediatric patients with HDD-CKD has not been established.

For Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) maintenance treatment: Administer Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every two weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) treatment may be repeated if necessary.

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) maintenance treatment

The dosing for Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

For Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) maintenance treatment: Administer Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every four weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

  • 10 mL single-use vial / 200 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) (20 mg/mL)
  • 5 mL single-use vial / 100 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) (20 mg/mL)
  • 2.5 mL single-use vial / 50 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) (20 mg/mL)
  • 10 mL single-use vial / 200 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) (20 mg/mL) (3)
  • 5 mL single-use vial / 100 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) (20 mg/mL) (3)
  • 2.5 mL single-use vial / 50 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) (20 mg/mL) (3)

4 CONTRAINDICATIONS

  • Known hypersensitivity to Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate))
  • Known hypersensitivity to Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) (4)

5 WARNINGS AND PRECAUTIONS

  • Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after Super Multi-Minerals Regular Strength ) administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. (5.1)
  • Hypotension: Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) may cause hypotension. Monitor for signs and symptoms of hypotension during and following each administration of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)). (5.2)
  • Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) Overload: Regularly monitor hematologic responses during Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) therapy. Do not administer Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) to patients with Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) overload. (5.3)

5.1 Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)). Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. If hypersensitivity reactions or signs of intolerance occur during administration, stop Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) preparations occur within 30 minutes of the completion of the infusion .

5.2 Hypotension

Super Multi-Minerals Regular Strength ) may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)). Hypotension following administration of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) may be related to the rate of administration and/or total dose administered .

5.3 Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) Overload

Excessive therapy with parenteral Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) can lead to excess storage of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) with the possibility of iatrogenic hemosiderosis. All adult and pediatric patients receiving Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) require periodic monitoring of hematologic and Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) to patients with evidence of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) overload. Transferrin saturation (TSAT) values increase rapidly after intravenous administration of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) sucrose; do not perform serum Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) measurements for at least 48 hours after intravenous dosing .

6 ADVERSE REACTIONS

The following serious adverse reactions associated with Super Multi-Minerals Regular Strength ) are described in other sections .

  • The most common adverse reactions (≥2%) following the administration of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) are diarrhea, nausea, vomiting, headache, dizziness, hypotension, pruritus, pain in extremity, arthralgia, back pain, muscle cramp, injection site reactions, chest pain, and peripheral edema. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact American Regent, Inc. at 1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Adverse Reactions in Clinical Trials

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in practice.

Adverse Reactions in Adults Patients with CKD

Adverse Reactions in Adult Patients with CKD

The frequency of adverse reactions associated with the use of Super Multi-Minerals Regular Strength ) has been documented in six clinical trials involving 231 patients with HDD-CKD, 139 patients with NDD-CKD and 75 patients with PDD-CKD. Treatment-emergent adverse reactions reported by ≥ 2% of treated patients in the six clinical trials for which the rate for Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) exceeds the rate for comparator are listed by indication in Table 1. Patients with HDD-CKD received 100 mg doses at 10 consecutive dialysis sessions until a cumulative dose of 1000 mg was administered. Patients with NDD-CKD received either 5 doses of 200 mg over 2 weeks or 2 doses of 500 mg separated by fourteen days, and patients with PDD-CKD received 2 doses of 300 mg followed by a dose of 400 mg over a period of 4 weeks.


* EPO=Erythropoietin

Adverse Reactions

(Preferred Term)

HDD-CKD NDD-CKD PDD-CKD
Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) Oral Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) EPO* Only
(N=231) (N=139) (N=139) (N=75) (N=46)
% % % % %
Subjects with any adverse reaction 78.8 76.3 73.4 72.0 65.2
Ear and Labyrinth Disorders
Ear Pain 0 2.2 0.7 0 0
Eye Disorders
Conjunctivitis 0.4 0 0 2.7 0
Gastrointestinal Disorders
Abdominal pain 3.5 1.4 2.9 4.0 6.5
Diarrhea 5.2 7.2 10.1 8.0 4.3
Dysgeusia 0.9 7.9 0 0 0
Nausea 14.7 8.6 12.2 5.3 4.3
Vomiting 9.1 5.0 8.6 8.0 2.2
General Disorders and
Administration Site Conditions
Asthenia 2.2 0.7 2.2 2.7 0
Chest pain 6.1 1.4 0 2.7 0
Feeling abnormal 3.0 0 0 0 0
Infusion site pain or burning 0 5.8 0 0 0
Injection site extravasation 0 2.2 0 0 0
Peripheral edema 2.6 7.2 5.0 5.3 10.9
Pyrexia 3.0 0.7 0.7 1.3 0
Infections and Infestations
Nasopharyngitis, Sinusitis, Upper

respiratory tract infections, Pharyngitis

2.6 2.2 4.3 16.0 4.3
Injury, Poisoning and Procedural
Complications
Graft complication 9.5 1.4 0 0 0
Metabolism and Nutrition Disorders
Fluid overload 3.0 1.4 0.7 1.3 0
Gout 0 2.9 1.4 0 0
Hyperglycemia 0 2.9 0 0 2.2
Hypoglycemia 0.4 0.7 0.7 4.0 0
Musculoskeletal and Connective
Tissue Disorders
Arthralgia 3.5 1.4 2.2 4.0 4.3
Back pain 2.2 2.2 3.6 1.3 4.3
Muscle cramp 29.4 0.7 0.7 2.7 0
Myalgia 0 3.6 0 1.3 0
Pain in extremity 5.6 4.3 0 2.7 6.5
Nervous System Disorders
Dizziness 6.5 6.5 1.4 1.3 4.3
Headache 12.6 2.9 0.7 4.0 0
Respiratory, Thoracic and
Mediastinal Disorders
Cough 3.0 2.2 0.7 1.3 0
Dyspnea 3.5 5.8 1.4 1.3 2.2
Nasal congestion 0 1.4 2.2 1.3 0
Skin and Subcutaneous
Tissue Disorders
Pruritus 3.9 2.2 4.3 2.7 0
Vascular Disorders
Hypertension 6.5 6.5 4.3 8.0 6.5
Hypotension 39.4 2.2 0.7 2.7 2.2

One hundred thirty (11%) of the 1,151 patients evaluated in the 4 U.S. trials in HDD-CKD patients (studies A, B and the two post marketing studies) had prior other intravenous Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) therapy and were reported to be intolerant (defined as precluding further use of that Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) product). When these patients were treated with Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) there were no occurrences of adverse reactions that precluded further use of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) .

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

In a randomized, open-label, dose-ranging trial for Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) maintenance treatment with Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) in pediatric patients with CKD on stable erythropoietin therapy , at least one treatment-emergent adverse reaction was experienced by 57% (27/47) of the patients receiving Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) 0.5 mg/kg, 53% (25/47) of the patients receiving Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) 1.0 mg/kg, and 55% (26/47) of the patients receiving Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) 2.0 mg/kg.

A total of 5 (11%) subjects in the Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) 0.5 mg/kg group, 10 (21%) patients in the Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) 1.0 mg/kg group, and 10 (21%) patients in the Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) 2.0 mg/kg group experienced at least 1 serious adverse reaction during the study. The most common treatment-emergent adverse reactions (> 2% of patients) in all patients were headache (6%), respiratory tract viral infection (4%), peritonitis (4%), vomiting (4%), pyrexia (4%), dizziness (4%), cough (4%), renal transplant (4%), nausea (3%), arteriovenous fistula thrombosis (2%), hypotension (2%), and hypertension (2.1%).

6.2 Adverse Reactions from Post-Marketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In the post-marketing safety studies in 1,051 treated patients with HDD-CKD, the adverse reactions reported by > 1% were: cardiac failure congestive, sepsis and dysgeusia.

The following adverse reactions have been identified during post-approval use of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Anaphylactic-type reactions, shock, loss of consciousness, collapse, bronchospasm, dyspnea, convulsions, light-headedness, confusion, angioedema, swelling of the joints, hyperhidrosis, back pain, bradycardia, and chromaturia.

Symptoms associated with Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) total dosage or infusing too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. These adverse reactions have occurred up to 30 minutes after the administration of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) injection. Reactions have occurred following the first dose or subsequent doses of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)). Symptoms may respond to intravenous fluids, hydrocortisone, and/or antihistamines. Slowing the infusion rate may alleviate symptoms.

Injection site discoloration has been reported following extravasation. Assure stable intravenous access to avoid extravasation.

7 DRUG INTERACTIONS

Drug interactions involving Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) have not been studied. However, Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) may reduce the absorption of concomitantly administered oral Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) preparations.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, Super Multi-Minerals Regular Strength ) sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) (half or equivalent to the maximum recommended human dose based on body surface area, respectively) and revealed no evidence of harm to the fetus due to Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) sucrose. Because animal reproductive studies are not always predictive of human response, Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) sucrose is excreted in human milk. Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) sucrose is secreted into the milk of lactating rats. Because many drugs are excreted in human milk, caution should be exercised when Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of Super Multi-Minerals Regular Strength ) for Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.

Safety and effectiveness of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) for Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) maintenance treatment in pediatric patients 2 years of age and older with dialysis-dependent or non-dialysis-dependent CKD receiving erythropoietin therapy were studied. Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) at doses of 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg was administered. All three doses maintained hemoglobin between 10.5 g/dL and 14.0 g/dL in about 50% of subjects over the 12-week treatment period with stable EPO dosing. [See Clinical Studies (14.6)]

Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) has not been studied in patients younger than 2 years of age.

In a country where Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) is available for use in children, at a single site, five premature infants (weight less than 1,250 g) developed necrotizing enterocolitis and two of the five died during or following a period when they received Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)), several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) or any other drugs could be established.

8.5 Geriatric Use

Clinical studies of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Of the 1,051 patients in two post-marketing safety studies of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)), 40% were 65 years and older. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose administration to an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

No data are available regarding overdosage of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) in humans. Excessive dosages of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) may lead to accumulation of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) in storage sites potentially leading to hemosiderosis. Do not administer Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) to patients with Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) overload.

Toxicities in single-dose studies in mice and rats, at intravenous Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) sucrose doses up to 8 times the maximum recommended human dose based on body surface area, included sedation, hypoactivity, pale eyes, bleeding in the gastrointestinal tract and lungs, and mortality.

11 DESCRIPTION

Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) (iron sucrose injection, USP), an Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) replacement product, is a brown, sterile, aqueous, complex of polynuclear Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) (III)-hydroxide in sucrose for intravenous use. Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) sucrose injection has a molecular weight of approximately 34,000 to 60,000 daltons and a proposed structural formula:

[Na2Fe5O8(OH) ·3(H2O)]n ·m(C12H22O11)

where: n is the degree of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) polymerization and m is the number of sucrose molecules associated with the Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) (III)-hydroxide.

Each mL contains 20 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) as Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) sucrose in water for injection. Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) is available in 10 mL single-use vials (200 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) per 10 mL), 5 mL single-use vials (100 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) per 5 mL), and 2.5 mL single-use vials (50 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) per 2.5 mL). The drug product contains approximately 30% sucrose w/v (300 mg/mL) and has a pH of 10.5 to 11.1. The product contains no preservatives. The osmolarity of the injection is 1,250 mOsmol/L.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Super Multi-Minerals Regular Strength ) is an aqueous complex of poly-nuclear Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) (III)-hydroxide in sucrose. Following intravenous administration, Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) is dissociated into Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) and sucrose and the Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) is transported as a complex with transferrin to target cells including erythroid precursor cells. The Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) in the precursor cells is incorporated into hemoglobin as the cells mature into red blood cells.

12.2 Pharmacodynamics

Following intravenous administration, Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) is dissociated into Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) and sucrose. In 22 patients undergoing hemodialysis and receiving erythropoietin (recombinant human erythropoietin) therapy treated with Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) sucrose containing 100 mg of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)), three times weekly for three weeks, significant increases in serum Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) and serum ferritin and significant decreases in total Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) binding capacity occurred four weeks from the initiation of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) sucrose treatment.

12.3 Pharmacokinetics

In healthy adults administered intravenous doses of Super Multi-Minerals Regular Strength ), its Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) component exhibited first order kinetics with an elimination half-life of 6 h, total clearance of 1.2 L/h, and steady state apparent volume of distribution of 7.9 L. The Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) containing 100 mg of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) labeled with 52Fe/59Fe in patients with Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) deficiency showed that a significant amount of the administered Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) trapping compartment.

Following intravenous administration of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)), Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) sucrose is dissociated into Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) containing 1,510 mg of sucrose and 100 mg of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) in 12 healthy adults (9 female, 3 male: age range 32 to 52), 68.3% of the sucrose was eliminated in urine in 4 h and 75.4% in 24 h. Some Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) was also eliminated in the urine. Neither transferrin nor transferrin receptor levels changed immediately after the dose administration. In this study and another study evaluating a single intravenous dose of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) sucrose containing 500 to 700 mg of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60), approximately 5% of the Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) have not been studied.

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

In a single-dose PK study of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)), patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)), the half-life of total serum Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) was 8 hours. The mean Cmax and AUC values were 8545 μg/dl and 31305 hr-μg/dL, respectively, which were 1.42- and 1.67-fold higher than dose adjusted adult Cmax and AUC values.

Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) sucrose in the dialysate fluid was below the levels of detection of the assay (less than 2 parts per million).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) sucrose.

Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.

Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) sucrose at intravenous doses up to 15 mg/kg/day of elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) (1.2 times the maximum recommended human dose based on body surface area) had no effect on fertility and reproductive function of male and female rats.

14 CLINICAL STUDIES

Five clinical trials involving 647 adult patients and one clinical trial involving 131 pediatric patients were conducted to assess the safety and efficacy of Super Multi-Minerals Regular Strength ).

14.1 Study A: Hemodialysis Dependent-Chronic Kidney Disease (HDD–CKD)

Study A was a multicenter, open-label, historically-controlled study in 101 patients with HDD-CKD (77 patients with Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) treatment and 24 in the historical control group) with Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) deficiency anemia. Eligibility criteria for Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) treatment included patients undergoing chronic hemodialysis, receiving erythropoietin, hemoglobin level between 8.0 and 11.0 g/dL, transferrin saturation < 20%, and serum ferritin < 300 ng/mL. The mean age of the patients was 65 years with the age range of 31 to 85 years. Of the 77 patients, 44 (57%) were male and 33 (43%) were female.

Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) 100 mg was administered at 10 consecutive dialysis sessions either as slow injection or a slow infusion. The historical control population consisted of 24 patients with similar ferritin levels as patients treated with Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)), who were off intravenous Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) for at least 2 weeks and who had received erythropoietin therapy with hematocrit averaging 31 to 36 for at least two months prior to study entry. The mean age of patients in the historical control group was 56 years, with an age range of 29 to 80 years. Patient age and serum ferritin level were similar between treatment and historical control patients.

Patients in the Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) treated population showed a greater increase in hemoglobin and hematocrit than did patients in the historical control population. See Table 2.


**p < 0.01 and *p < 0.05 compared to historical control from ANCOVA analysis with baseline hemoglobin, serum ferritin and erythropoietin dose as covariates.


Efficacy

parameters

End of treatment 2 week follow-up 5 week follow-up
Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) (n=69 Historical Control (n=18) Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate))

(n=73)

Historical Control

(n=18)

Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate))

(n=71)

Historical

Control

(n=15)

Hemoglobin (g/dL) 1.0 ± 0.12** 0.0 ± 0.21 1.3 ± 0.14** -0.6 ± 0.24 1.2 ± 0.17* -0.1 ± 0.23
Hematocrit (%) 3.1 ± 0.37** -0.3 ± 0.65 3.6 ± 0.44** -1.2 ± 0.76 3.3 ± 0.54 0.2 ± 0.86

Serum ferritin increased at endpoint of study from baseline in the Venofer-treated population (165.3 ± 24.2 ng/mL) compared to the historical control population (-27.6 ± 9.5 ng/mL). Transferrin saturation also increased at endpoint of study from baseline in the Venofer-treated population (8.8 ± 1.6%) compared to this historical control population (-5.1 ± 4.3%).

14.2 Study B: Hemodialysis Dependent-Chronic Kidney Disease

Study B was a multicenter, open label study of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) in 23 patients with Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) deficiency and HDD-CKD who had been discontinued from Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) dextran due to intolerance. Eligibility criteria were otherwise identical to Study A. The mean age of the patients in this study was 53 years, with ages ranging from 21 to 79 years. Of the 23 patients enrolled in the study, 10 (44%) were male and 13 (56%) were female.

All 23 enrolled patients were evaluated for efficacy. Increases in mean hemoglobin (1.1 ± 0.2 g/dL), hematocrit (3.6 ± 0.6%), serum ferritin (266.3 ± 30.3 ng/mL) and transferrin saturation (8.7 ± 2.0%) were observed from baseline to end of treatment.

14.3 Study C: Hemodialysis Dependent-Chronic Kidney Disease

Study C was a multicenter, open-label study in patients with HDD-CKD. This study enrolled patients with a hemoglobin ≤ 10 g/dL, a serum transferrin saturation ≤ 20%, and a serum ferritin ≤ 200 ng/mL, who were undergoing maintenance hemodialysis 2 to 3 times weekly. The mean age of the patients enrolled in this study was 41 years, with ages ranging from 16 to 70 years. Of 130 patients evaluated for efficacy in this study, 68 (52%) were male and 62 (48%) were female. Forty-eight percent of the patients had previously been treated with oral Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)). Exclusion criteria were similar to those in studies A and B. Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) was administered. A 50 mg dose (2.5 mL) was given to patients within two weeks of study entry as a test dose. Twenty-seven patients (20%) were receiving erythropoietin treatment at study entry and they continued to receive the same erythropoietin dose for the duration of the study.

The modified intention-to-treat (mITT) population consisted of 131 patients. Increases from baseline in mean hemoglobin (1.7 g/dL), hematocrit (5%), serum ferritin (434.6 ng/mL), and serum transferrin saturation (14%) were observed at week 2 of the observation period and these values remained increased at week 4 of the observation period.

14.4 Study D: Non-Dialysis Dependent-Chronic Kidney Disease

Study D was a randomized, open-label, multicenter, active-controlled study of the safety and efficacy of oral Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) versus Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) in patients with NDD-CKD with or without erythropoietin therapy. Erythropoietin therapy was stable for 8 weeks prior to randomization. In the study 188 patients with NDD-CKD, hemoglobin of ≤ 11.0 g/dL, transferrin saturation ≤ 25%, ferritin ≤ 300 ng/mL were randomized to receive oral Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) (325 mg ferrous sulfate three times daily for 56 days); or Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) (either 200 mg over 2 to 5 minutes 5 times within 14 days or two 500 mg infusions on Day 1 and Day 14, administered over 3.5 to 4 hours). The mean age of the 91 treated patients in the Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) group was 61.6 years (range 25 to 86 years) and 64 years (range 21 to 86 years) for the 91 patients in the oral Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) group.

A statistically significantly greater proportion of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) subjects (35/79; 44.3%) compared to oral Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) subjects (23/82; 28%) had an increase in hemoglobin ≥ 1 g/dL at anytime during the study (p = 0.03).

14.5 Study E: Peritoneal Dialysis Dependent-Chronic Kidney Disease

Study E was a randomized, open-label, multicenter study comparing patients with PDD-CKD receiving an erythropoietin and intravenous Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) to patients with PDD-CKD receiving an erythropoietin alone without Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) supplementation. Patients with PDD-CKD, stable erythropoietin for 8 weeks, hemoglobin of ≤ 11.5 g/dL, TSAT ≤ 25%, ferritin ≤ 500 ng/mL were randomized to receive either no Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) or Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) (300 mg in 250 mL 0.9% NaCl over 1.5 hours on Day 1 and 15 and 400 mg in 250 mL 0.9% NaCl over 2.5 hours on Day 29). The mean age of the 75 treated patients in the Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) / erythropoietin group was 51.9 years (range 21 to 81 years) vs. 52.8 years (range 23 to 77 years) for 46 patients in the erythropoietin alone group.

Patients in the Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) / erythropoietin group had statistically significantly greater mean change from baseline to the highest hemoglobin value (1.3 g/dL), compared to subjects who received erythropoietin alone (0.6 g/dL) (p < 0.01). A greater proportion of subjects treated with Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) / erythropoietin (59.1 %) had an increase in hemoglobin of ≥ 1 g/dL at any time during the study compared to the subjects who received erythropoietin only (33.3%).

14.6 Study F: Super Multi-Minerals Regular Strength ) Maintenance Treatment Dosing in Pediatric Patients Ages 2 years and Older with Chronic Kidney Disease

Study F was a randomized, open-label, dose-ranging study for Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) maintenance treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD on stable erythropoietin therapy. The study randomized patients to one of three doses of Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) (0.5 mg/kg, 1.0 mg/kg or 2.0 mg/kg). The mean age was 13 years (range 2 to 20 years). Over 70% of patients were 12 years or older in all three groups. There were 84 males and 61 females. About 60% of patients underwent hemodialysis and 25% underwent peritoneal dialysis in all three dose groups. At baseline, the mean hemoglobin was 12 g/dL, the mean TSAT was 33% and the mean ferritin was 300 ng/mL. Patients with HDD-CKD received Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) once every 4 weeks for 3 doses. Among 131 evaluable patients with stable erythropoietin dosing, the proportion of patients who maintained hemoglobin between 10.5 g/dL and 14.0 g/dL during the 12-week treatment period was 58.7%, 46.7%, and 45.0% in the Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg groups, respectively. A dose-response relationship was not demonstrated.

16 HOW SUPPLIED/storage and handling

16.1 How Supplied

Super Multi-Minerals Regular Strength ) is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)), each 5 mL vial contains 100 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)), and each 2.5 mL vial contains 50 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) (20 mg/mL).

NDC-0517-2310-05 200 mg/10 mL Single-Use Vial Packages of 5
NDC-0517-2310-10 200 mg/10 mL Single-Use Vial Packages of 10
NDC-0517-2340-01 100 mg/5 mL Single-Use Vial Individually Boxed
NDC-0517-2340-10 100 mg/5 mL Single-Use Vial Packages of 10
NDC-0517-2340-25 100 mg/5 mL Single-Use Vial Packages of 25
NDC-0517-2340-99 100 mg/5 mL Single-Use Vial Packages of 10
NDC-0517-2325-10 50 mg/2.5 mL Single-Use Vial Packages of 10
NDC-0517-2325-25 50 mg/2.5 mL Single-Use Vial Packages of 25

16.2 Stability and Storage

Contains no preservatives. Store in original carton at 20°C to 25°C (68° F to 77° F); excursions permitted to 15° to 30°C (59° to 86°F).. Do not freeze.

Syringe Stability: Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) per mL, or undiluted (20 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) per mL) and stored in a plastic syringe, was found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C) and under refrigeration (4°C ± 2°C).

Intravenous Admixture Stability: Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)), when added to intravenous infusion bags (PVC or non-PVC) containing 0.9% NaCl at concentrations ranging from 1 mg to 2 mg of elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) per mL, has been found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C).

Do not dilute to concentrations below 1 mg/mL.

Do not mix Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) with other medications or add to parenteral nutrition solutions for intravenous infusion.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to infusion.

17 PATIENT COUNSELING INFORMATION

Prior to Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) administration:

  • Question patients regarding any prior history of reactions to parenteral Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) products
  • Advise patients of the risks associated with Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate))
  • Advise patients to report any symptoms of hypersensitivity that may develop during and following Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) administration, such as rash, itching, dizziness, light-headedness, swelling, and breathing problems [see Warnings and Precautions (5)]

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Super Multi-Minerals Regular Strength (Iron (Ferrous Citrate)) is manufactured under license from Vifor (International) Inc., Switzerland.

PremierProRx® is a trademark of Premier, Inc., used under license.

PREMIERProRx®

IN2340

MG #15727

Iron (Ferrous Fumarate):


1 INDICATIONS AND USAGE

Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) is indicated for the treatment of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) deficiency anemia in patients with chronic kidney disease (CKD).

Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) is an Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) replacement product indicated for the treatment of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) deficiency anemia in patients with chronic kidney disease (CKD). (1)

2 DOSAGE AND ADMINISTRATION

Super Multi-Minerals Regular Strength ) must only be administered intravenously either by slow injection or by infusion. The dosage of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) is expressed in mg of elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)). Each mL contains 20 mg of elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)).

Population Dose
Adult patients Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD) (2.1) 100 mg slow intravenous injection or infusion
Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) (2.2) 200 mg slow intravenous injection or infusion
Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD) (2.3) 300 mg or 400 mg intravenous infusion
Pediatric patients HDD-CKD (2.4), PDD-CKD or NDD-CKD (2.5) 0.5 mg/kg slow intravenous injection or infusion

2.1 Adult Patients with Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)

Administer Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) 100 mg undiluted as a slow intravenous injection over 2 to 5 minutes, or as an infusion of 100 mg diluted in a maximum of 100 mL of 0.9% NaCl over a period of at least 15 minutes, per consecutive hemodialysis session. Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) should be administered early during the dialysis session. The usual total treatment course of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) is 1000 mg. Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) treatment may be repeated if Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) deficiency reoccurs.

2.2 Adult Patients with Non-Dialysis Dependent-Chronic Kidney Disease

Administer Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) 200 mg undiluted as a slow intravenous injection over 2 to 5 minutes or as an infusion of 200 mg in a maximum of 100 mL of 0.9% NaCl over a period of 15 minutes. Administer on 5 different occasions over a 14 day period. There is limited experience with administration of an infusion of 500 mg of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)), diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5 to 4 hours on Day 1 and Day 14. Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) treatment may be repeated if Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) in 3 divided doses, given by slow intravenous infusion, within a 28 day period: 2 infusions each of 300 mg over 1.5 hours 14 days apart followed by one 400 mg infusion over 2.5 hours 14 days later. Dilute Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) in a maximum of 250 mL of 0.9% NaCl. Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) treatment may be repeated if Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) maintenance treatment

The dosing for Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) replacement treatment in pediatric patients with HDD-CKD has not been established.

For Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) maintenance treatment: Administer Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every two weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) treatment may be repeated if necessary.

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) maintenance treatment

The dosing for Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

For Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) maintenance treatment: Administer Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every four weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

  • 10 mL single-use vial / 200 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) (20 mg/mL)
  • 5 mL single-use vial / 100 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) (20 mg/mL)
  • 2.5 mL single-use vial / 50 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) (20 mg/mL)
  • 10 mL single-use vial / 200 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) (20 mg/mL) (3)
  • 5 mL single-use vial / 100 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) (20 mg/mL) (3)
  • 2.5 mL single-use vial / 50 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) (20 mg/mL) (3)

4 CONTRAINDICATIONS

  • Known hypersensitivity to Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate))
  • Known hypersensitivity to Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) (4)

5 WARNINGS AND PRECAUTIONS

  • Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after Super Multi-Minerals Regular Strength ) administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. (5.1)
  • Hypotension: Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) may cause hypotension. Monitor for signs and symptoms of hypotension during and following each administration of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)). (5.2)
  • Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) Overload: Regularly monitor hematologic responses during Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) therapy. Do not administer Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) to patients with Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) overload. (5.3)

5.1 Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)). Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. If hypersensitivity reactions or signs of intolerance occur during administration, stop Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) preparations occur within 30 minutes of the completion of the infusion .

5.2 Hypotension

Super Multi-Minerals Regular Strength ) may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)). Hypotension following administration of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) may be related to the rate of administration and/or total dose administered .

5.3 Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) Overload

Excessive therapy with parenteral Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) can lead to excess storage of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) with the possibility of iatrogenic hemosiderosis. All adult and pediatric patients receiving Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) require periodic monitoring of hematologic and Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) to patients with evidence of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) overload. Transferrin saturation (TSAT) values increase rapidly after intravenous administration of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) sucrose; do not perform serum Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) measurements for at least 48 hours after intravenous dosing .

6 ADVERSE REACTIONS

The following serious adverse reactions associated with Super Multi-Minerals Regular Strength ) are described in other sections .

  • The most common adverse reactions (≥2%) following the administration of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) are diarrhea, nausea, vomiting, headache, dizziness, hypotension, pruritus, pain in extremity, arthralgia, back pain, muscle cramp, injection site reactions, chest pain, and peripheral edema. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact American Regent, Inc. at 1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Adverse Reactions in Clinical Trials

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in practice.

Adverse Reactions in Adults Patients with CKD

Adverse Reactions in Adult Patients with CKD

The frequency of adverse reactions associated with the use of Super Multi-Minerals Regular Strength ) has been documented in six clinical trials involving 231 patients with HDD-CKD, 139 patients with NDD-CKD and 75 patients with PDD-CKD. Treatment-emergent adverse reactions reported by ≥ 2% of treated patients in the six clinical trials for which the rate for Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) exceeds the rate for comparator are listed by indication in Table 1. Patients with HDD-CKD received 100 mg doses at 10 consecutive dialysis sessions until a cumulative dose of 1000 mg was administered. Patients with NDD-CKD received either 5 doses of 200 mg over 2 weeks or 2 doses of 500 mg separated by fourteen days, and patients with PDD-CKD received 2 doses of 300 mg followed by a dose of 400 mg over a period of 4 weeks.


* EPO=Erythropoietin

Adverse Reactions

(Preferred Term)

HDD-CKD NDD-CKD PDD-CKD
Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) Oral Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) EPO* Only
(N=231) (N=139) (N=139) (N=75) (N=46)
% % % % %
Subjects with any adverse reaction 78.8 76.3 73.4 72.0 65.2
Ear and Labyrinth Disorders
Ear Pain 0 2.2 0.7 0 0
Eye Disorders
Conjunctivitis 0.4 0 0 2.7 0
Gastrointestinal Disorders
Abdominal pain 3.5 1.4 2.9 4.0 6.5
Diarrhea 5.2 7.2 10.1 8.0 4.3
Dysgeusia 0.9 7.9 0 0 0
Nausea 14.7 8.6 12.2 5.3 4.3
Vomiting 9.1 5.0 8.6 8.0 2.2
General Disorders and
Administration Site Conditions
Asthenia 2.2 0.7 2.2 2.7 0
Chest pain 6.1 1.4 0 2.7 0
Feeling abnormal 3.0 0 0 0 0
Infusion site pain or burning 0 5.8 0 0 0
Injection site extravasation 0 2.2 0 0 0
Peripheral edema 2.6 7.2 5.0 5.3 10.9
Pyrexia 3.0 0.7 0.7 1.3 0
Infections and Infestations
Nasopharyngitis, Sinusitis, Upper

respiratory tract infections, Pharyngitis

2.6 2.2 4.3 16.0 4.3
Injury, Poisoning and Procedural
Complications
Graft complication 9.5 1.4 0 0 0
Metabolism and Nutrition Disorders
Fluid overload 3.0 1.4 0.7 1.3 0
Gout 0 2.9 1.4 0 0
Hyperglycemia 0 2.9 0 0 2.2
Hypoglycemia 0.4 0.7 0.7 4.0 0
Musculoskeletal and Connective
Tissue Disorders
Arthralgia 3.5 1.4 2.2 4.0 4.3
Back pain 2.2 2.2 3.6 1.3 4.3
Muscle cramp 29.4 0.7 0.7 2.7 0
Myalgia 0 3.6 0 1.3 0
Pain in extremity 5.6 4.3 0 2.7 6.5
Nervous System Disorders
Dizziness 6.5 6.5 1.4 1.3 4.3
Headache 12.6 2.9 0.7 4.0 0
Respiratory, Thoracic and
Mediastinal Disorders
Cough 3.0 2.2 0.7 1.3 0
Dyspnea 3.5 5.8 1.4 1.3 2.2
Nasal congestion 0 1.4 2.2 1.3 0
Skin and Subcutaneous
Tissue Disorders
Pruritus 3.9 2.2 4.3 2.7 0
Vascular Disorders
Hypertension 6.5 6.5 4.3 8.0 6.5
Hypotension 39.4 2.2 0.7 2.7 2.2

One hundred thirty (11%) of the 1,151 patients evaluated in the 4 U.S. trials in HDD-CKD patients (studies A, B and the two post marketing studies) had prior other intravenous Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) therapy and were reported to be intolerant (defined as precluding further use of that Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) product). When these patients were treated with Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) there were no occurrences of adverse reactions that precluded further use of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) .

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

In a randomized, open-label, dose-ranging trial for Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) maintenance treatment with Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) in pediatric patients with CKD on stable erythropoietin therapy , at least one treatment-emergent adverse reaction was experienced by 57% (27/47) of the patients receiving Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) 0.5 mg/kg, 53% (25/47) of the patients receiving Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) 1.0 mg/kg, and 55% (26/47) of the patients receiving Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) 2.0 mg/kg.

A total of 5 (11%) subjects in the Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) 0.5 mg/kg group, 10 (21%) patients in the Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) 1.0 mg/kg group, and 10 (21%) patients in the Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) 2.0 mg/kg group experienced at least 1 serious adverse reaction during the study. The most common treatment-emergent adverse reactions (> 2% of patients) in all patients were headache (6%), respiratory tract viral infection (4%), peritonitis (4%), vomiting (4%), pyrexia (4%), dizziness (4%), cough (4%), renal transplant (4%), nausea (3%), arteriovenous fistula thrombosis (2%), hypotension (2%), and hypertension (2.1%).

6.2 Adverse Reactions from Post-Marketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In the post-marketing safety studies in 1,051 treated patients with HDD-CKD, the adverse reactions reported by > 1% were: cardiac failure congestive, sepsis and dysgeusia.

The following adverse reactions have been identified during post-approval use of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Anaphylactic-type reactions, shock, loss of consciousness, collapse, bronchospasm, dyspnea, convulsions, light-headedness, confusion, angioedema, swelling of the joints, hyperhidrosis, back pain, bradycardia, and chromaturia.

Symptoms associated with Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) total dosage or infusing too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. These adverse reactions have occurred up to 30 minutes after the administration of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) injection. Reactions have occurred following the first dose or subsequent doses of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)). Symptoms may respond to intravenous fluids, hydrocortisone, and/or antihistamines. Slowing the infusion rate may alleviate symptoms.

Injection site discoloration has been reported following extravasation. Assure stable intravenous access to avoid extravasation.

7 DRUG INTERACTIONS

Drug interactions involving Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) have not been studied. However, Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) may reduce the absorption of concomitantly administered oral Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) preparations.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, Super Multi-Minerals Regular Strength ) sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) (half or equivalent to the maximum recommended human dose based on body surface area, respectively) and revealed no evidence of harm to the fetus due to Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) sucrose. Because animal reproductive studies are not always predictive of human response, Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) sucrose is excreted in human milk. Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) sucrose is secreted into the milk of lactating rats. Because many drugs are excreted in human milk, caution should be exercised when Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of Super Multi-Minerals Regular Strength ) for Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.

Safety and effectiveness of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) for Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) maintenance treatment in pediatric patients 2 years of age and older with dialysis-dependent or non-dialysis-dependent CKD receiving erythropoietin therapy were studied. Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) at doses of 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg was administered. All three doses maintained hemoglobin between 10.5 g/dL and 14.0 g/dL in about 50% of subjects over the 12-week treatment period with stable EPO dosing. [See Clinical Studies (14.6)]

Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) has not been studied in patients younger than 2 years of age.

In a country where Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) is available for use in children, at a single site, five premature infants (weight less than 1,250 g) developed necrotizing enterocolitis and two of the five died during or following a period when they received Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)), several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) or any other drugs could be established.

8.5 Geriatric Use

Clinical studies of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Of the 1,051 patients in two post-marketing safety studies of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)), 40% were 65 years and older. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose administration to an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

No data are available regarding overdosage of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) in humans. Excessive dosages of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) may lead to accumulation of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) in storage sites potentially leading to hemosiderosis. Do not administer Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) to patients with Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) overload.

Toxicities in single-dose studies in mice and rats, at intravenous Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) sucrose doses up to 8 times the maximum recommended human dose based on body surface area, included sedation, hypoactivity, pale eyes, bleeding in the gastrointestinal tract and lungs, and mortality.

11 DESCRIPTION

Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) (iron sucrose injection, USP), an Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) replacement product, is a brown, sterile, aqueous, complex of polynuclear Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) (III)-hydroxide in sucrose for intravenous use. Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) sucrose injection has a molecular weight of approximately 34,000 to 60,000 daltons and a proposed structural formula:

[Na2Fe5O8(OH) ·3(H2O)]n ·m(C12H22O11)

where: n is the degree of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) polymerization and m is the number of sucrose molecules associated with the Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) (III)-hydroxide.

Each mL contains 20 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) as Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) sucrose in water for injection. Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) is available in 10 mL single-use vials (200 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) per 10 mL), 5 mL single-use vials (100 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) per 5 mL), and 2.5 mL single-use vials (50 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) per 2.5 mL). The drug product contains approximately 30% sucrose w/v (300 mg/mL) and has a pH of 10.5 to 11.1. The product contains no preservatives. The osmolarity of the injection is 1,250 mOsmol/L.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Super Multi-Minerals Regular Strength ) is an aqueous complex of poly-nuclear Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) (III)-hydroxide in sucrose. Following intravenous administration, Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) is dissociated into Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) and sucrose and the Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) is transported as a complex with transferrin to target cells including erythroid precursor cells. The Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) in the precursor cells is incorporated into hemoglobin as the cells mature into red blood cells.

12.2 Pharmacodynamics

Following intravenous administration, Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) is dissociated into Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) and sucrose. In 22 patients undergoing hemodialysis and receiving erythropoietin (recombinant human erythropoietin) therapy treated with Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) sucrose containing 100 mg of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)), three times weekly for three weeks, significant increases in serum Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) and serum ferritin and significant decreases in total Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) binding capacity occurred four weeks from the initiation of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) sucrose treatment.

12.3 Pharmacokinetics

In healthy adults administered intravenous doses of Super Multi-Minerals Regular Strength ), its Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) component exhibited first order kinetics with an elimination half-life of 6 h, total clearance of 1.2 L/h, and steady state apparent volume of distribution of 7.9 L. The Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) containing 100 mg of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) labeled with 52Fe/59Fe in patients with Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) deficiency showed that a significant amount of the administered Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) trapping compartment.

Following intravenous administration of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)), Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) sucrose is dissociated into Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) containing 1,510 mg of sucrose and 100 mg of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) in 12 healthy adults (9 female, 3 male: age range 32 to 52), 68.3% of the sucrose was eliminated in urine in 4 h and 75.4% in 24 h. Some Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) was also eliminated in the urine. Neither transferrin nor transferrin receptor levels changed immediately after the dose administration. In this study and another study evaluating a single intravenous dose of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) sucrose containing 500 to 700 mg of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60), approximately 5% of the Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) have not been studied.

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

In a single-dose PK study of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)), patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)), the half-life of total serum Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) was 8 hours. The mean Cmax and AUC values were 8545 μg/dl and 31305 hr-μg/dL, respectively, which were 1.42- and 1.67-fold higher than dose adjusted adult Cmax and AUC values.

Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) sucrose in the dialysate fluid was below the levels of detection of the assay (less than 2 parts per million).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) sucrose.

Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.

Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) sucrose at intravenous doses up to 15 mg/kg/day of elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) (1.2 times the maximum recommended human dose based on body surface area) had no effect on fertility and reproductive function of male and female rats.

14 CLINICAL STUDIES

Five clinical trials involving 647 adult patients and one clinical trial involving 131 pediatric patients were conducted to assess the safety and efficacy of Super Multi-Minerals Regular Strength ).

14.1 Study A: Hemodialysis Dependent-Chronic Kidney Disease (HDD–CKD)

Study A was a multicenter, open-label, historically-controlled study in 101 patients with HDD-CKD (77 patients with Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) treatment and 24 in the historical control group) with Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) deficiency anemia. Eligibility criteria for Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) treatment included patients undergoing chronic hemodialysis, receiving erythropoietin, hemoglobin level between 8.0 and 11.0 g/dL, transferrin saturation < 20%, and serum ferritin < 300 ng/mL. The mean age of the patients was 65 years with the age range of 31 to 85 years. Of the 77 patients, 44 (57%) were male and 33 (43%) were female.

Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) 100 mg was administered at 10 consecutive dialysis sessions either as slow injection or a slow infusion. The historical control population consisted of 24 patients with similar ferritin levels as patients treated with Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)), who were off intravenous Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) for at least 2 weeks and who had received erythropoietin therapy with hematocrit averaging 31 to 36 for at least two months prior to study entry. The mean age of patients in the historical control group was 56 years, with an age range of 29 to 80 years. Patient age and serum ferritin level were similar between treatment and historical control patients.

Patients in the Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) treated population showed a greater increase in hemoglobin and hematocrit than did patients in the historical control population. See Table 2.


**p < 0.01 and *p < 0.05 compared to historical control from ANCOVA analysis with baseline hemoglobin, serum ferritin and erythropoietin dose as covariates.


Efficacy

parameters

End of treatment 2 week follow-up 5 week follow-up
Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) (n=69 Historical Control (n=18) Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate))

(n=73)

Historical Control

(n=18)

Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate))

(n=71)

Historical

Control

(n=15)

Hemoglobin (g/dL) 1.0 ± 0.12** 0.0 ± 0.21 1.3 ± 0.14** -0.6 ± 0.24 1.2 ± 0.17* -0.1 ± 0.23
Hematocrit (%) 3.1 ± 0.37** -0.3 ± 0.65 3.6 ± 0.44** -1.2 ± 0.76 3.3 ± 0.54 0.2 ± 0.86

Serum ferritin increased at endpoint of study from baseline in the Venofer-treated population (165.3 ± 24.2 ng/mL) compared to the historical control population (-27.6 ± 9.5 ng/mL). Transferrin saturation also increased at endpoint of study from baseline in the Venofer-treated population (8.8 ± 1.6%) compared to this historical control population (-5.1 ± 4.3%).

14.2 Study B: Hemodialysis Dependent-Chronic Kidney Disease

Study B was a multicenter, open label study of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) in 23 patients with Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) deficiency and HDD-CKD who had been discontinued from Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) dextran due to intolerance. Eligibility criteria were otherwise identical to Study A. The mean age of the patients in this study was 53 years, with ages ranging from 21 to 79 years. Of the 23 patients enrolled in the study, 10 (44%) were male and 13 (56%) were female.

All 23 enrolled patients were evaluated for efficacy. Increases in mean hemoglobin (1.1 ± 0.2 g/dL), hematocrit (3.6 ± 0.6%), serum ferritin (266.3 ± 30.3 ng/mL) and transferrin saturation (8.7 ± 2.0%) were observed from baseline to end of treatment.

14.3 Study C: Hemodialysis Dependent-Chronic Kidney Disease

Study C was a multicenter, open-label study in patients with HDD-CKD. This study enrolled patients with a hemoglobin ≤ 10 g/dL, a serum transferrin saturation ≤ 20%, and a serum ferritin ≤ 200 ng/mL, who were undergoing maintenance hemodialysis 2 to 3 times weekly. The mean age of the patients enrolled in this study was 41 years, with ages ranging from 16 to 70 years. Of 130 patients evaluated for efficacy in this study, 68 (52%) were male and 62 (48%) were female. Forty-eight percent of the patients had previously been treated with oral Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)). Exclusion criteria were similar to those in studies A and B. Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) was administered. A 50 mg dose (2.5 mL) was given to patients within two weeks of study entry as a test dose. Twenty-seven patients (20%) were receiving erythropoietin treatment at study entry and they continued to receive the same erythropoietin dose for the duration of the study.

The modified intention-to-treat (mITT) population consisted of 131 patients. Increases from baseline in mean hemoglobin (1.7 g/dL), hematocrit (5%), serum ferritin (434.6 ng/mL), and serum transferrin saturation (14%) were observed at week 2 of the observation period and these values remained increased at week 4 of the observation period.

14.4 Study D: Non-Dialysis Dependent-Chronic Kidney Disease

Study D was a randomized, open-label, multicenter, active-controlled study of the safety and efficacy of oral Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) versus Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) in patients with NDD-CKD with or without erythropoietin therapy. Erythropoietin therapy was stable for 8 weeks prior to randomization. In the study 188 patients with NDD-CKD, hemoglobin of ≤ 11.0 g/dL, transferrin saturation ≤ 25%, ferritin ≤ 300 ng/mL were randomized to receive oral Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) (325 mg ferrous sulfate three times daily for 56 days); or Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) (either 200 mg over 2 to 5 minutes 5 times within 14 days or two 500 mg infusions on Day 1 and Day 14, administered over 3.5 to 4 hours). The mean age of the 91 treated patients in the Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) group was 61.6 years (range 25 to 86 years) and 64 years (range 21 to 86 years) for the 91 patients in the oral Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) group.

A statistically significantly greater proportion of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) subjects (35/79; 44.3%) compared to oral Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) subjects (23/82; 28%) had an increase in hemoglobin ≥ 1 g/dL at anytime during the study (p = 0.03).

14.5 Study E: Peritoneal Dialysis Dependent-Chronic Kidney Disease

Study E was a randomized, open-label, multicenter study comparing patients with PDD-CKD receiving an erythropoietin and intravenous Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) to patients with PDD-CKD receiving an erythropoietin alone without Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) supplementation. Patients with PDD-CKD, stable erythropoietin for 8 weeks, hemoglobin of ≤ 11.5 g/dL, TSAT ≤ 25%, ferritin ≤ 500 ng/mL were randomized to receive either no Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) or Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) (300 mg in 250 mL 0.9% NaCl over 1.5 hours on Day 1 and 15 and 400 mg in 250 mL 0.9% NaCl over 2.5 hours on Day 29). The mean age of the 75 treated patients in the Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) / erythropoietin group was 51.9 years (range 21 to 81 years) vs. 52.8 years (range 23 to 77 years) for 46 patients in the erythropoietin alone group.

Patients in the Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) / erythropoietin group had statistically significantly greater mean change from baseline to the highest hemoglobin value (1.3 g/dL), compared to subjects who received erythropoietin alone (0.6 g/dL) (p < 0.01). A greater proportion of subjects treated with Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) / erythropoietin (59.1 %) had an increase in hemoglobin of ≥ 1 g/dL at any time during the study compared to the subjects who received erythropoietin only (33.3%).

14.6 Study F: Super Multi-Minerals Regular Strength ) Maintenance Treatment Dosing in Pediatric Patients Ages 2 years and Older with Chronic Kidney Disease

Study F was a randomized, open-label, dose-ranging study for Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) maintenance treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD on stable erythropoietin therapy. The study randomized patients to one of three doses of Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) (0.5 mg/kg, 1.0 mg/kg or 2.0 mg/kg). The mean age was 13 years (range 2 to 20 years). Over 70% of patients were 12 years or older in all three groups. There were 84 males and 61 females. About 60% of patients underwent hemodialysis and 25% underwent peritoneal dialysis in all three dose groups. At baseline, the mean hemoglobin was 12 g/dL, the mean TSAT was 33% and the mean ferritin was 300 ng/mL. Patients with HDD-CKD received Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) once every 4 weeks for 3 doses. Among 131 evaluable patients with stable erythropoietin dosing, the proportion of patients who maintained hemoglobin between 10.5 g/dL and 14.0 g/dL during the 12-week treatment period was 58.7%, 46.7%, and 45.0% in the Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg groups, respectively. A dose-response relationship was not demonstrated.

16 HOW SUPPLIED/storage and handling

16.1 How Supplied

Super Multi-Minerals Regular Strength ) is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)), each 5 mL vial contains 100 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)), and each 2.5 mL vial contains 50 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) (20 mg/mL).

NDC-0517-2310-05 200 mg/10 mL Single-Use Vial Packages of 5
NDC-0517-2310-10 200 mg/10 mL Single-Use Vial Packages of 10
NDC-0517-2340-01 100 mg/5 mL Single-Use Vial Individually Boxed
NDC-0517-2340-10 100 mg/5 mL Single-Use Vial Packages of 10
NDC-0517-2340-25 100 mg/5 mL Single-Use Vial Packages of 25
NDC-0517-2340-99 100 mg/5 mL Single-Use Vial Packages of 10
NDC-0517-2325-10 50 mg/2.5 mL Single-Use Vial Packages of 10
NDC-0517-2325-25 50 mg/2.5 mL Single-Use Vial Packages of 25

16.2 Stability and Storage

Contains no preservatives. Store in original carton at 20°C to 25°C (68° F to 77° F); excursions permitted to 15° to 30°C (59° to 86°F).. Do not freeze.

Syringe Stability: Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) per mL, or undiluted (20 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) per mL) and stored in a plastic syringe, was found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C) and under refrigeration (4°C ± 2°C).

Intravenous Admixture Stability: Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)), when added to intravenous infusion bags (PVC or non-PVC) containing 0.9% NaCl at concentrations ranging from 1 mg to 2 mg of elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) per mL, has been found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C).

Do not dilute to concentrations below 1 mg/mL.

Do not mix Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) with other medications or add to parenteral nutrition solutions for intravenous infusion.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to infusion.

17 PATIENT COUNSELING INFORMATION

Prior to Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) administration:

  • Question patients regarding any prior history of reactions to parenteral Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) products
  • Advise patients of the risks associated with Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate))
  • Advise patients to report any symptoms of hypersensitivity that may develop during and following Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) administration, such as rash, itching, dizziness, light-headedness, swelling, and breathing problems [see Warnings and Precautions (5)]

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Super Multi-Minerals Regular Strength (Iron (Ferrous Fumarate)) is manufactured under license from Vifor (International) Inc., Switzerland.

PremierProRx® is a trademark of Premier, Inc., used under license.

PREMIERProRx®

IN2340

MG #15727

Iron (Ferrous Gluconate):


1 INDICATIONS AND USAGE

Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) is indicated for the treatment of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) deficiency anemia in patients with chronic kidney disease (CKD).

Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) is an Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) replacement product indicated for the treatment of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) deficiency anemia in patients with chronic kidney disease (CKD). (1)

2 DOSAGE AND ADMINISTRATION

Super Multi-Minerals Regular Strength ) must only be administered intravenously either by slow injection or by infusion. The dosage of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) is expressed in mg of elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)). Each mL contains 20 mg of elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)).

Population Dose
Adult patients Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD) (2.1) 100 mg slow intravenous injection or infusion
Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) (2.2) 200 mg slow intravenous injection or infusion
Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD) (2.3) 300 mg or 400 mg intravenous infusion
Pediatric patients HDD-CKD (2.4), PDD-CKD or NDD-CKD (2.5) 0.5 mg/kg slow intravenous injection or infusion

2.1 Adult Patients with Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)

Administer Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) 100 mg undiluted as a slow intravenous injection over 2 to 5 minutes, or as an infusion of 100 mg diluted in a maximum of 100 mL of 0.9% NaCl over a period of at least 15 minutes, per consecutive hemodialysis session. Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) should be administered early during the dialysis session. The usual total treatment course of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) is 1000 mg. Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) treatment may be repeated if Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) deficiency reoccurs.

2.2 Adult Patients with Non-Dialysis Dependent-Chronic Kidney Disease

Administer Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) 200 mg undiluted as a slow intravenous injection over 2 to 5 minutes or as an infusion of 200 mg in a maximum of 100 mL of 0.9% NaCl over a period of 15 minutes. Administer on 5 different occasions over a 14 day period. There is limited experience with administration of an infusion of 500 mg of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)), diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5 to 4 hours on Day 1 and Day 14. Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) treatment may be repeated if Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) in 3 divided doses, given by slow intravenous infusion, within a 28 day period: 2 infusions each of 300 mg over 1.5 hours 14 days apart followed by one 400 mg infusion over 2.5 hours 14 days later. Dilute Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) in a maximum of 250 mL of 0.9% NaCl. Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) treatment may be repeated if Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) maintenance treatment

The dosing for Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) replacement treatment in pediatric patients with HDD-CKD has not been established.

For Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) maintenance treatment: Administer Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every two weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) treatment may be repeated if necessary.

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) maintenance treatment

The dosing for Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

For Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) maintenance treatment: Administer Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every four weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

  • 10 mL single-use vial / 200 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) (20 mg/mL)
  • 5 mL single-use vial / 100 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) (20 mg/mL)
  • 2.5 mL single-use vial / 50 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) (20 mg/mL)
  • 10 mL single-use vial / 200 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) (20 mg/mL) (3)
  • 5 mL single-use vial / 100 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) (20 mg/mL) (3)
  • 2.5 mL single-use vial / 50 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) (20 mg/mL) (3)

4 CONTRAINDICATIONS

  • Known hypersensitivity to Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate))
  • Known hypersensitivity to Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) (4)

5 WARNINGS AND PRECAUTIONS

  • Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after Super Multi-Minerals Regular Strength ) administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. (5.1)
  • Hypotension: Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) may cause hypotension. Monitor for signs and symptoms of hypotension during and following each administration of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)). (5.2)
  • Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) Overload: Regularly monitor hematologic responses during Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) therapy. Do not administer Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) to patients with Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) overload. (5.3)

5.1 Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)). Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. If hypersensitivity reactions or signs of intolerance occur during administration, stop Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) preparations occur within 30 minutes of the completion of the infusion .

5.2 Hypotension

Super Multi-Minerals Regular Strength ) may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)). Hypotension following administration of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) may be related to the rate of administration and/or total dose administered .

5.3 Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) Overload

Excessive therapy with parenteral Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) can lead to excess storage of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) with the possibility of iatrogenic hemosiderosis. All adult and pediatric patients receiving Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) require periodic monitoring of hematologic and Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) to patients with evidence of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) overload. Transferrin saturation (TSAT) values increase rapidly after intravenous administration of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) sucrose; do not perform serum Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) measurements for at least 48 hours after intravenous dosing .

6 ADVERSE REACTIONS

The following serious adverse reactions associated with Super Multi-Minerals Regular Strength ) are described in other sections .

  • The most common adverse reactions (≥2%) following the administration of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) are diarrhea, nausea, vomiting, headache, dizziness, hypotension, pruritus, pain in extremity, arthralgia, back pain, muscle cramp, injection site reactions, chest pain, and peripheral edema. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact American Regent, Inc. at 1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Adverse Reactions in Clinical Trials

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in practice.

Adverse Reactions in Adults Patients with CKD

Adverse Reactions in Adult Patients with CKD

The frequency of adverse reactions associated with the use of Super Multi-Minerals Regular Strength ) has been documented in six clinical trials involving 231 patients with HDD-CKD, 139 patients with NDD-CKD and 75 patients with PDD-CKD. Treatment-emergent adverse reactions reported by ≥ 2% of treated patients in the six clinical trials for which the rate for Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) exceeds the rate for comparator are listed by indication in Table 1. Patients with HDD-CKD received 100 mg doses at 10 consecutive dialysis sessions until a cumulative dose of 1000 mg was administered. Patients with NDD-CKD received either 5 doses of 200 mg over 2 weeks or 2 doses of 500 mg separated by fourteen days, and patients with PDD-CKD received 2 doses of 300 mg followed by a dose of 400 mg over a period of 4 weeks.


* EPO=Erythropoietin

Adverse Reactions

(Preferred Term)

HDD-CKD NDD-CKD PDD-CKD
Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) Oral Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) EPO* Only
(N=231) (N=139) (N=139) (N=75) (N=46)
% % % % %
Subjects with any adverse reaction 78.8 76.3 73.4 72.0 65.2
Ear and Labyrinth Disorders
Ear Pain 0 2.2 0.7 0 0
Eye Disorders
Conjunctivitis 0.4 0 0 2.7 0
Gastrointestinal Disorders
Abdominal pain 3.5 1.4 2.9 4.0 6.5
Diarrhea 5.2 7.2 10.1 8.0 4.3
Dysgeusia 0.9 7.9 0 0 0
Nausea 14.7 8.6 12.2 5.3 4.3
Vomiting 9.1 5.0 8.6 8.0 2.2
General Disorders and
Administration Site Conditions
Asthenia 2.2 0.7 2.2 2.7 0
Chest pain 6.1 1.4 0 2.7 0
Feeling abnormal 3.0 0 0 0 0
Infusion site pain or burning 0 5.8 0 0 0
Injection site extravasation 0 2.2 0 0 0
Peripheral edema 2.6 7.2 5.0 5.3 10.9
Pyrexia 3.0 0.7 0.7 1.3 0
Infections and Infestations
Nasopharyngitis, Sinusitis, Upper

respiratory tract infections, Pharyngitis

2.6 2.2 4.3 16.0 4.3
Injury, Poisoning and Procedural
Complications
Graft complication 9.5 1.4 0 0 0
Metabolism and Nutrition Disorders
Fluid overload 3.0 1.4 0.7 1.3 0
Gout 0 2.9 1.4 0 0
Hyperglycemia 0 2.9 0 0 2.2
Hypoglycemia 0.4 0.7 0.7 4.0 0
Musculoskeletal and Connective
Tissue Disorders
Arthralgia 3.5 1.4 2.2 4.0 4.3
Back pain 2.2 2.2 3.6 1.3 4.3
Muscle cramp 29.4 0.7 0.7 2.7 0
Myalgia 0 3.6 0 1.3 0
Pain in extremity 5.6 4.3 0 2.7 6.5
Nervous System Disorders
Dizziness 6.5 6.5 1.4 1.3 4.3
Headache 12.6 2.9 0.7 4.0 0
Respiratory, Thoracic and
Mediastinal Disorders
Cough 3.0 2.2 0.7 1.3 0
Dyspnea 3.5 5.8 1.4 1.3 2.2
Nasal congestion 0 1.4 2.2 1.3 0
Skin and Subcutaneous
Tissue Disorders
Pruritus 3.9 2.2 4.3 2.7 0
Vascular Disorders
Hypertension 6.5 6.5 4.3 8.0 6.5
Hypotension 39.4 2.2 0.7 2.7 2.2

One hundred thirty (11%) of the 1,151 patients evaluated in the 4 U.S. trials in HDD-CKD patients (studies A, B and the two post marketing studies) had prior other intravenous Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) therapy and were reported to be intolerant (defined as precluding further use of that Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) product). When these patients were treated with Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) there were no occurrences of adverse reactions that precluded further use of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) .

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

In a randomized, open-label, dose-ranging trial for Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) maintenance treatment with Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) in pediatric patients with CKD on stable erythropoietin therapy , at least one treatment-emergent adverse reaction was experienced by 57% (27/47) of the patients receiving Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) 0.5 mg/kg, 53% (25/47) of the patients receiving Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) 1.0 mg/kg, and 55% (26/47) of the patients receiving Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) 2.0 mg/kg.

A total of 5 (11%) subjects in the Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) 0.5 mg/kg group, 10 (21%) patients in the Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) 1.0 mg/kg group, and 10 (21%) patients in the Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) 2.0 mg/kg group experienced at least 1 serious adverse reaction during the study. The most common treatment-emergent adverse reactions (> 2% of patients) in all patients were headache (6%), respiratory tract viral infection (4%), peritonitis (4%), vomiting (4%), pyrexia (4%), dizziness (4%), cough (4%), renal transplant (4%), nausea (3%), arteriovenous fistula thrombosis (2%), hypotension (2%), and hypertension (2.1%).

6.2 Adverse Reactions from Post-Marketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In the post-marketing safety studies in 1,051 treated patients with HDD-CKD, the adverse reactions reported by > 1% were: cardiac failure congestive, sepsis and dysgeusia.

The following adverse reactions have been identified during post-approval use of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Anaphylactic-type reactions, shock, loss of consciousness, collapse, bronchospasm, dyspnea, convulsions, light-headedness, confusion, angioedema, swelling of the joints, hyperhidrosis, back pain, bradycardia, and chromaturia.

Symptoms associated with Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) total dosage or infusing too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. These adverse reactions have occurred up to 30 minutes after the administration of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) injection. Reactions have occurred following the first dose or subsequent doses of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)). Symptoms may respond to intravenous fluids, hydrocortisone, and/or antihistamines. Slowing the infusion rate may alleviate symptoms.

Injection site discoloration has been reported following extravasation. Assure stable intravenous access to avoid extravasation.

7 DRUG INTERACTIONS

Drug interactions involving Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) have not been studied. However, Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) may reduce the absorption of concomitantly administered oral Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) preparations.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, Super Multi-Minerals Regular Strength ) sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) (half or equivalent to the maximum recommended human dose based on body surface area, respectively) and revealed no evidence of harm to the fetus due to Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) sucrose. Because animal reproductive studies are not always predictive of human response, Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) sucrose is excreted in human milk. Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) sucrose is secreted into the milk of lactating rats. Because many drugs are excreted in human milk, caution should be exercised when Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of Super Multi-Minerals Regular Strength ) for Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.

Safety and effectiveness of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) for Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) maintenance treatment in pediatric patients 2 years of age and older with dialysis-dependent or non-dialysis-dependent CKD receiving erythropoietin therapy were studied. Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) at doses of 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg was administered. All three doses maintained hemoglobin between 10.5 g/dL and 14.0 g/dL in about 50% of subjects over the 12-week treatment period with stable EPO dosing. [See Clinical Studies (14.6)]

Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) has not been studied in patients younger than 2 years of age.

In a country where Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) is available for use in children, at a single site, five premature infants (weight less than 1,250 g) developed necrotizing enterocolitis and two of the five died during or following a period when they received Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)), several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) or any other drugs could be established.

8.5 Geriatric Use

Clinical studies of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Of the 1,051 patients in two post-marketing safety studies of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)), 40% were 65 years and older. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose administration to an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

No data are available regarding overdosage of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) in humans. Excessive dosages of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) may lead to accumulation of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) in storage sites potentially leading to hemosiderosis. Do not administer Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) to patients with Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) overload.

Toxicities in single-dose studies in mice and rats, at intravenous Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) sucrose doses up to 8 times the maximum recommended human dose based on body surface area, included sedation, hypoactivity, pale eyes, bleeding in the gastrointestinal tract and lungs, and mortality.

11 DESCRIPTION

Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) (iron sucrose injection, USP), an Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) replacement product, is a brown, sterile, aqueous, complex of polynuclear Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) (III)-hydroxide in sucrose for intravenous use. Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) sucrose injection has a molecular weight of approximately 34,000 to 60,000 daltons and a proposed structural formula:

[Na2Fe5O8(OH) ·3(H2O)]n ·m(C12H22O11)

where: n is the degree of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) polymerization and m is the number of sucrose molecules associated with the Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) (III)-hydroxide.

Each mL contains 20 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) as Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) sucrose in water for injection. Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) is available in 10 mL single-use vials (200 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) per 10 mL), 5 mL single-use vials (100 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) per 5 mL), and 2.5 mL single-use vials (50 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) per 2.5 mL). The drug product contains approximately 30% sucrose w/v (300 mg/mL) and has a pH of 10.5 to 11.1. The product contains no preservatives. The osmolarity of the injection is 1,250 mOsmol/L.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Super Multi-Minerals Regular Strength ) is an aqueous complex of poly-nuclear Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) (III)-hydroxide in sucrose. Following intravenous administration, Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) is dissociated into Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) and sucrose and the Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) is transported as a complex with transferrin to target cells including erythroid precursor cells. The Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) in the precursor cells is incorporated into hemoglobin as the cells mature into red blood cells.

12.2 Pharmacodynamics

Following intravenous administration, Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) is dissociated into Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) and sucrose. In 22 patients undergoing hemodialysis and receiving erythropoietin (recombinant human erythropoietin) therapy treated with Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) sucrose containing 100 mg of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)), three times weekly for three weeks, significant increases in serum Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) and serum ferritin and significant decreases in total Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) binding capacity occurred four weeks from the initiation of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) sucrose treatment.

12.3 Pharmacokinetics

In healthy adults administered intravenous doses of Super Multi-Minerals Regular Strength ), its Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) component exhibited first order kinetics with an elimination half-life of 6 h, total clearance of 1.2 L/h, and steady state apparent volume of distribution of 7.9 L. The Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) containing 100 mg of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) labeled with 52Fe/59Fe in patients with Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) deficiency showed that a significant amount of the administered Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) trapping compartment.

Following intravenous administration of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)), Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) sucrose is dissociated into Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) containing 1,510 mg of sucrose and 100 mg of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) in 12 healthy adults (9 female, 3 male: age range 32 to 52), 68.3% of the sucrose was eliminated in urine in 4 h and 75.4% in 24 h. Some Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) was also eliminated in the urine. Neither transferrin nor transferrin receptor levels changed immediately after the dose administration. In this study and another study evaluating a single intravenous dose of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) sucrose containing 500 to 700 mg of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60), approximately 5% of the Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) have not been studied.

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

In a single-dose PK study of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)), patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)), the half-life of total serum Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) was 8 hours. The mean Cmax and AUC values were 8545 μg/dl and 31305 hr-μg/dL, respectively, which were 1.42- and 1.67-fold higher than dose adjusted adult Cmax and AUC values.

Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) sucrose in the dialysate fluid was below the levels of detection of the assay (less than 2 parts per million).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) sucrose.

Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.

Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) sucrose at intravenous doses up to 15 mg/kg/day of elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) (1.2 times the maximum recommended human dose based on body surface area) had no effect on fertility and reproductive function of male and female rats.

14 CLINICAL STUDIES

Five clinical trials involving 647 adult patients and one clinical trial involving 131 pediatric patients were conducted to assess the safety and efficacy of Super Multi-Minerals Regular Strength ).

14.1 Study A: Hemodialysis Dependent-Chronic Kidney Disease (HDD–CKD)

Study A was a multicenter, open-label, historically-controlled study in 101 patients with HDD-CKD (77 patients with Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) treatment and 24 in the historical control group) with Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) deficiency anemia. Eligibility criteria for Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) treatment included patients undergoing chronic hemodialysis, receiving erythropoietin, hemoglobin level between 8.0 and 11.0 g/dL, transferrin saturation < 20%, and serum ferritin < 300 ng/mL. The mean age of the patients was 65 years with the age range of 31 to 85 years. Of the 77 patients, 44 (57%) were male and 33 (43%) were female.

Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) 100 mg was administered at 10 consecutive dialysis sessions either as slow injection or a slow infusion. The historical control population consisted of 24 patients with similar ferritin levels as patients treated with Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)), who were off intravenous Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) for at least 2 weeks and who had received erythropoietin therapy with hematocrit averaging 31 to 36 for at least two months prior to study entry. The mean age of patients in the historical control group was 56 years, with an age range of 29 to 80 years. Patient age and serum ferritin level were similar between treatment and historical control patients.

Patients in the Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) treated population showed a greater increase in hemoglobin and hematocrit than did patients in the historical control population. See Table 2.


**p < 0.01 and *p < 0.05 compared to historical control from ANCOVA analysis with baseline hemoglobin, serum ferritin and erythropoietin dose as covariates.


Efficacy

parameters

End of treatment 2 week follow-up 5 week follow-up
Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) (n=69 Historical Control (n=18) Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate))

(n=73)

Historical Control

(n=18)

Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate))

(n=71)

Historical

Control

(n=15)

Hemoglobin (g/dL) 1.0 ± 0.12** 0.0 ± 0.21 1.3 ± 0.14** -0.6 ± 0.24 1.2 ± 0.17* -0.1 ± 0.23
Hematocrit (%) 3.1 ± 0.37** -0.3 ± 0.65 3.6 ± 0.44** -1.2 ± 0.76 3.3 ± 0.54 0.2 ± 0.86

Serum ferritin increased at endpoint of study from baseline in the Venofer-treated population (165.3 ± 24.2 ng/mL) compared to the historical control population (-27.6 ± 9.5 ng/mL). Transferrin saturation also increased at endpoint of study from baseline in the Venofer-treated population (8.8 ± 1.6%) compared to this historical control population (-5.1 ± 4.3%).

14.2 Study B: Hemodialysis Dependent-Chronic Kidney Disease

Study B was a multicenter, open label study of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) in 23 patients with Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) deficiency and HDD-CKD who had been discontinued from Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) dextran due to intolerance. Eligibility criteria were otherwise identical to Study A. The mean age of the patients in this study was 53 years, with ages ranging from 21 to 79 years. Of the 23 patients enrolled in the study, 10 (44%) were male and 13 (56%) were female.

All 23 enrolled patients were evaluated for efficacy. Increases in mean hemoglobin (1.1 ± 0.2 g/dL), hematocrit (3.6 ± 0.6%), serum ferritin (266.3 ± 30.3 ng/mL) and transferrin saturation (8.7 ± 2.0%) were observed from baseline to end of treatment.

14.3 Study C: Hemodialysis Dependent-Chronic Kidney Disease

Study C was a multicenter, open-label study in patients with HDD-CKD. This study enrolled patients with a hemoglobin ≤ 10 g/dL, a serum transferrin saturation ≤ 20%, and a serum ferritin ≤ 200 ng/mL, who were undergoing maintenance hemodialysis 2 to 3 times weekly. The mean age of the patients enrolled in this study was 41 years, with ages ranging from 16 to 70 years. Of 130 patients evaluated for efficacy in this study, 68 (52%) were male and 62 (48%) were female. Forty-eight percent of the patients had previously been treated with oral Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)). Exclusion criteria were similar to those in studies A and B. Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) was administered. A 50 mg dose (2.5 mL) was given to patients within two weeks of study entry as a test dose. Twenty-seven patients (20%) were receiving erythropoietin treatment at study entry and they continued to receive the same erythropoietin dose for the duration of the study.

The modified intention-to-treat (mITT) population consisted of 131 patients. Increases from baseline in mean hemoglobin (1.7 g/dL), hematocrit (5%), serum ferritin (434.6 ng/mL), and serum transferrin saturation (14%) were observed at week 2 of the observation period and these values remained increased at week 4 of the observation period.

14.4 Study D: Non-Dialysis Dependent-Chronic Kidney Disease

Study D was a randomized, open-label, multicenter, active-controlled study of the safety and efficacy of oral Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) versus Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) in patients with NDD-CKD with or without erythropoietin therapy. Erythropoietin therapy was stable for 8 weeks prior to randomization. In the study 188 patients with NDD-CKD, hemoglobin of ≤ 11.0 g/dL, transferrin saturation ≤ 25%, ferritin ≤ 300 ng/mL were randomized to receive oral Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) (325 mg ferrous sulfate three times daily for 56 days); or Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) (either 200 mg over 2 to 5 minutes 5 times within 14 days or two 500 mg infusions on Day 1 and Day 14, administered over 3.5 to 4 hours). The mean age of the 91 treated patients in the Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) group was 61.6 years (range 25 to 86 years) and 64 years (range 21 to 86 years) for the 91 patients in the oral Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) group.

A statistically significantly greater proportion of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) subjects (35/79; 44.3%) compared to oral Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) subjects (23/82; 28%) had an increase in hemoglobin ≥ 1 g/dL at anytime during the study (p = 0.03).

14.5 Study E: Peritoneal Dialysis Dependent-Chronic Kidney Disease

Study E was a randomized, open-label, multicenter study comparing patients with PDD-CKD receiving an erythropoietin and intravenous Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) to patients with PDD-CKD receiving an erythropoietin alone without Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) supplementation. Patients with PDD-CKD, stable erythropoietin for 8 weeks, hemoglobin of ≤ 11.5 g/dL, TSAT ≤ 25%, ferritin ≤ 500 ng/mL were randomized to receive either no Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) or Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) (300 mg in 250 mL 0.9% NaCl over 1.5 hours on Day 1 and 15 and 400 mg in 250 mL 0.9% NaCl over 2.5 hours on Day 29). The mean age of the 75 treated patients in the Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) / erythropoietin group was 51.9 years (range 21 to 81 years) vs. 52.8 years (range 23 to 77 years) for 46 patients in the erythropoietin alone group.

Patients in the Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) / erythropoietin group had statistically significantly greater mean change from baseline to the highest hemoglobin value (1.3 g/dL), compared to subjects who received erythropoietin alone (0.6 g/dL) (p < 0.01). A greater proportion of subjects treated with Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) / erythropoietin (59.1 %) had an increase in hemoglobin of ≥ 1 g/dL at any time during the study compared to the subjects who received erythropoietin only (33.3%).

14.6 Study F: Super Multi-Minerals Regular Strength ) Maintenance Treatment Dosing in Pediatric Patients Ages 2 years and Older with Chronic Kidney Disease

Study F was a randomized, open-label, dose-ranging study for Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) maintenance treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD on stable erythropoietin therapy. The study randomized patients to one of three doses of Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) (0.5 mg/kg, 1.0 mg/kg or 2.0 mg/kg). The mean age was 13 years (range 2 to 20 years). Over 70% of patients were 12 years or older in all three groups. There were 84 males and 61 females. About 60% of patients underwent hemodialysis and 25% underwent peritoneal dialysis in all three dose groups. At baseline, the mean hemoglobin was 12 g/dL, the mean TSAT was 33% and the mean ferritin was 300 ng/mL. Patients with HDD-CKD received Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) once every 4 weeks for 3 doses. Among 131 evaluable patients with stable erythropoietin dosing, the proportion of patients who maintained hemoglobin between 10.5 g/dL and 14.0 g/dL during the 12-week treatment period was 58.7%, 46.7%, and 45.0% in the Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg groups, respectively. A dose-response relationship was not demonstrated.

16 HOW SUPPLIED/storage and handling

16.1 How Supplied

Super Multi-Minerals Regular Strength ) is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)), each 5 mL vial contains 100 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)), and each 2.5 mL vial contains 50 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) (20 mg/mL).

NDC-0517-2310-05 200 mg/10 mL Single-Use Vial Packages of 5
NDC-0517-2310-10 200 mg/10 mL Single-Use Vial Packages of 10
NDC-0517-2340-01 100 mg/5 mL Single-Use Vial Individually Boxed
NDC-0517-2340-10 100 mg/5 mL Single-Use Vial Packages of 10
NDC-0517-2340-25 100 mg/5 mL Single-Use Vial Packages of 25
NDC-0517-2340-99 100 mg/5 mL Single-Use Vial Packages of 10
NDC-0517-2325-10 50 mg/2.5 mL Single-Use Vial Packages of 10
NDC-0517-2325-25 50 mg/2.5 mL Single-Use Vial Packages of 25

16.2 Stability and Storage

Contains no preservatives. Store in original carton at 20°C to 25°C (68° F to 77° F); excursions permitted to 15° to 30°C (59° to 86°F).. Do not freeze.

Syringe Stability: Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) per mL, or undiluted (20 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) per mL) and stored in a plastic syringe, was found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C) and under refrigeration (4°C ± 2°C).

Intravenous Admixture Stability: Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)), when added to intravenous infusion bags (PVC or non-PVC) containing 0.9% NaCl at concentrations ranging from 1 mg to 2 mg of elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) per mL, has been found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C).

Do not dilute to concentrations below 1 mg/mL.

Do not mix Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) with other medications or add to parenteral nutrition solutions for intravenous infusion.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to infusion.

17 PATIENT COUNSELING INFORMATION

Prior to Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) administration:

  • Question patients regarding any prior history of reactions to parenteral Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) products
  • Advise patients of the risks associated with Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate))
  • Advise patients to report any symptoms of hypersensitivity that may develop during and following Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) administration, such as rash, itching, dizziness, light-headedness, swelling, and breathing problems [see Warnings and Precautions (5)]

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Super Multi-Minerals Regular Strength (Iron (Ferrous Gluconate)) is manufactured under license from Vifor (International) Inc., Switzerland.

PremierProRx® is a trademark of Premier, Inc., used under license.

PREMIERProRx®

IN2340

MG #15727

Iron (Ferrous HVP Chelate):


1 INDICATIONS AND USAGE

Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) is indicated for the treatment of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) deficiency anemia in patients with chronic kidney disease (CKD).

Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) is an Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) replacement product indicated for the treatment of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) deficiency anemia in patients with chronic kidney disease (CKD). (1)

2 DOSAGE AND ADMINISTRATION

Super Multi-Minerals Regular Strength ) must only be administered intravenously either by slow injection or by infusion. The dosage of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) is expressed in mg of elemental Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)). Each mL contains 20 mg of elemental Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)).

Population Dose
Adult patients Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD) (2.1) 100 mg slow intravenous injection or infusion
Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) (2.2) 200 mg slow intravenous injection or infusion
Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD) (2.3) 300 mg or 400 mg intravenous infusion
Pediatric patients HDD-CKD (2.4), PDD-CKD or NDD-CKD (2.5) 0.5 mg/kg slow intravenous injection or infusion

2.1 Adult Patients with Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)

Administer Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) 100 mg undiluted as a slow intravenous injection over 2 to 5 minutes, or as an infusion of 100 mg diluted in a maximum of 100 mL of 0.9% NaCl over a period of at least 15 minutes, per consecutive hemodialysis session. Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) should be administered early during the dialysis session. The usual total treatment course of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) is 1000 mg. Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) treatment may be repeated if Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) deficiency reoccurs.

2.2 Adult Patients with Non-Dialysis Dependent-Chronic Kidney Disease

Administer Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) 200 mg undiluted as a slow intravenous injection over 2 to 5 minutes or as an infusion of 200 mg in a maximum of 100 mL of 0.9% NaCl over a period of 15 minutes. Administer on 5 different occasions over a 14 day period. There is limited experience with administration of an infusion of 500 mg of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)), diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5 to 4 hours on Day 1 and Day 14. Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) treatment may be repeated if Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) in 3 divided doses, given by slow intravenous infusion, within a 28 day period: 2 infusions each of 300 mg over 1.5 hours 14 days apart followed by one 400 mg infusion over 2.5 hours 14 days later. Dilute Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) in a maximum of 250 mL of 0.9% NaCl. Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) treatment may be repeated if Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) maintenance treatment

The dosing for Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) replacement treatment in pediatric patients with HDD-CKD has not been established.

For Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) maintenance treatment: Administer Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every two weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) treatment may be repeated if necessary.

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) maintenance treatment

The dosing for Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

For Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) maintenance treatment: Administer Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every four weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

  • 10 mL single-use vial / 200 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) (20 mg/mL)
  • 5 mL single-use vial / 100 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) (20 mg/mL)
  • 2.5 mL single-use vial / 50 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) (20 mg/mL)
  • 10 mL single-use vial / 200 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) (20 mg/mL) (3)
  • 5 mL single-use vial / 100 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) (20 mg/mL) (3)
  • 2.5 mL single-use vial / 50 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) (20 mg/mL) (3)

4 CONTRAINDICATIONS

  • Known hypersensitivity to Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate))
  • Known hypersensitivity to Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) (4)

5 WARNINGS AND PRECAUTIONS

  • Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after Super Multi-Minerals Regular Strength ) administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. (5.1)
  • Hypotension: Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) may cause hypotension. Monitor for signs and symptoms of hypotension during and following each administration of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)). (5.2)
  • Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) Overload: Regularly monitor hematologic responses during Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) therapy. Do not administer Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) to patients with Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) overload. (5.3)

5.1 Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)). Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. If hypersensitivity reactions or signs of intolerance occur during administration, stop Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) preparations occur within 30 minutes of the completion of the infusion .

5.2 Hypotension

Super Multi-Minerals Regular Strength ) may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)). Hypotension following administration of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) may be related to the rate of administration and/or total dose administered .

5.3 Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) Overload

Excessive therapy with parenteral Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) can lead to excess storage of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) with the possibility of iatrogenic hemosiderosis. All adult and pediatric patients receiving Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) require periodic monitoring of hematologic and Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) to patients with evidence of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) overload. Transferrin saturation (TSAT) values increase rapidly after intravenous administration of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) sucrose; do not perform serum Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) measurements for at least 48 hours after intravenous dosing .

6 ADVERSE REACTIONS

The following serious adverse reactions associated with Super Multi-Minerals Regular Strength ) are described in other sections .

  • The most common adverse reactions (≥2%) following the administration of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) are diarrhea, nausea, vomiting, headache, dizziness, hypotension, pruritus, pain in extremity, arthralgia, back pain, muscle cramp, injection site reactions, chest pain, and peripheral edema. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact American Regent, Inc. at 1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Adverse Reactions in Clinical Trials

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in practice.

Adverse Reactions in Adults Patients with CKD

Adverse Reactions in Adult Patients with CKD

The frequency of adverse reactions associated with the use of Super Multi-Minerals Regular Strength ) has been documented in six clinical trials involving 231 patients with HDD-CKD, 139 patients with NDD-CKD and 75 patients with PDD-CKD. Treatment-emergent adverse reactions reported by ≥ 2% of treated patients in the six clinical trials for which the rate for Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) exceeds the rate for comparator are listed by indication in Table 1. Patients with HDD-CKD received 100 mg doses at 10 consecutive dialysis sessions until a cumulative dose of 1000 mg was administered. Patients with NDD-CKD received either 5 doses of 200 mg over 2 weeks or 2 doses of 500 mg separated by fourteen days, and patients with PDD-CKD received 2 doses of 300 mg followed by a dose of 400 mg over a period of 4 weeks.


* EPO=Erythropoietin

Adverse Reactions

(Preferred Term)

HDD-CKD NDD-CKD PDD-CKD
Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) Oral Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) EPO* Only
(N=231) (N=139) (N=139) (N=75) (N=46)
% % % % %
Subjects with any adverse reaction 78.8 76.3 73.4 72.0 65.2
Ear and Labyrinth Disorders
Ear Pain 0 2.2 0.7 0 0
Eye Disorders
Conjunctivitis 0.4 0 0 2.7 0
Gastrointestinal Disorders
Abdominal pain 3.5 1.4 2.9 4.0 6.5
Diarrhea 5.2 7.2 10.1 8.0 4.3
Dysgeusia 0.9 7.9 0 0 0
Nausea 14.7 8.6 12.2 5.3 4.3
Vomiting 9.1 5.0 8.6 8.0 2.2
General Disorders and
Administration Site Conditions
Asthenia 2.2 0.7 2.2 2.7 0
Chest pain 6.1 1.4 0 2.7 0
Feeling abnormal 3.0 0 0 0 0
Infusion site pain or burning 0 5.8 0 0 0
Injection site extravasation 0 2.2 0 0 0
Peripheral edema 2.6 7.2 5.0 5.3 10.9
Pyrexia 3.0 0.7 0.7 1.3 0
Infections and Infestations
Nasopharyngitis, Sinusitis, Upper

respiratory tract infections, Pharyngitis

2.6 2.2 4.3 16.0 4.3
Injury, Poisoning and Procedural
Complications
Graft complication 9.5 1.4 0 0 0
Metabolism and Nutrition Disorders
Fluid overload 3.0 1.4 0.7 1.3 0
Gout 0 2.9 1.4 0 0
Hyperglycemia 0 2.9 0 0 2.2
Hypoglycemia 0.4 0.7 0.7 4.0 0
Musculoskeletal and Connective
Tissue Disorders
Arthralgia 3.5 1.4 2.2 4.0 4.3
Back pain 2.2 2.2 3.6 1.3 4.3
Muscle cramp 29.4 0.7 0.7 2.7 0
Myalgia 0 3.6 0 1.3 0
Pain in extremity 5.6 4.3 0 2.7 6.5
Nervous System Disorders
Dizziness 6.5 6.5 1.4 1.3 4.3
Headache 12.6 2.9 0.7 4.0 0
Respiratory, Thoracic and
Mediastinal Disorders
Cough 3.0 2.2 0.7 1.3 0
Dyspnea 3.5 5.8 1.4 1.3 2.2
Nasal congestion 0 1.4 2.2 1.3 0
Skin and Subcutaneous
Tissue Disorders
Pruritus 3.9 2.2 4.3 2.7 0
Vascular Disorders
Hypertension 6.5 6.5 4.3 8.0 6.5
Hypotension 39.4 2.2 0.7 2.7 2.2

One hundred thirty (11%) of the 1,151 patients evaluated in the 4 U.S. trials in HDD-CKD patients (studies A, B and the two post marketing studies) had prior other intravenous Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) therapy and were reported to be intolerant (defined as precluding further use of that Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) product). When these patients were treated with Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) there were no occurrences of adverse reactions that precluded further use of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) .

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

In a randomized, open-label, dose-ranging trial for Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) maintenance treatment with Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) in pediatric patients with CKD on stable erythropoietin therapy , at least one treatment-emergent adverse reaction was experienced by 57% (27/47) of the patients receiving Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) 0.5 mg/kg, 53% (25/47) of the patients receiving Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) 1.0 mg/kg, and 55% (26/47) of the patients receiving Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) 2.0 mg/kg.

A total of 5 (11%) subjects in the Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) 0.5 mg/kg group, 10 (21%) patients in the Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) 1.0 mg/kg group, and 10 (21%) patients in the Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) 2.0 mg/kg group experienced at least 1 serious adverse reaction during the study. The most common treatment-emergent adverse reactions (> 2% of patients) in all patients were headache (6%), respiratory tract viral infection (4%), peritonitis (4%), vomiting (4%), pyrexia (4%), dizziness (4%), cough (4%), renal transplant (4%), nausea (3%), arteriovenous fistula thrombosis (2%), hypotension (2%), and hypertension (2.1%).

6.2 Adverse Reactions from Post-Marketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In the post-marketing safety studies in 1,051 treated patients with HDD-CKD, the adverse reactions reported by > 1% were: cardiac failure congestive, sepsis and dysgeusia.

The following adverse reactions have been identified during post-approval use of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Anaphylactic-type reactions, shock, loss of consciousness, collapse, bronchospasm, dyspnea, convulsions, light-headedness, confusion, angioedema, swelling of the joints, hyperhidrosis, back pain, bradycardia, and chromaturia.

Symptoms associated with Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) total dosage or infusing too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. These adverse reactions have occurred up to 30 minutes after the administration of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) injection. Reactions have occurred following the first dose or subsequent doses of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)). Symptoms may respond to intravenous fluids, hydrocortisone, and/or antihistamines. Slowing the infusion rate may alleviate symptoms.

Injection site discoloration has been reported following extravasation. Assure stable intravenous access to avoid extravasation.

7 DRUG INTERACTIONS

Drug interactions involving Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) have not been studied. However, Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) may reduce the absorption of concomitantly administered oral Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) preparations.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, Super Multi-Minerals Regular Strength ) sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) (half or equivalent to the maximum recommended human dose based on body surface area, respectively) and revealed no evidence of harm to the fetus due to Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) sucrose. Because animal reproductive studies are not always predictive of human response, Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) sucrose is excreted in human milk. Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) sucrose is secreted into the milk of lactating rats. Because many drugs are excreted in human milk, caution should be exercised when Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of Super Multi-Minerals Regular Strength ) for Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.

Safety and effectiveness of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) for Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) maintenance treatment in pediatric patients 2 years of age and older with dialysis-dependent or non-dialysis-dependent CKD receiving erythropoietin therapy were studied. Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) at doses of 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg was administered. All three doses maintained hemoglobin between 10.5 g/dL and 14.0 g/dL in about 50% of subjects over the 12-week treatment period with stable EPO dosing. [See Clinical Studies (14.6)]

Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) has not been studied in patients younger than 2 years of age.

In a country where Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) is available for use in children, at a single site, five premature infants (weight less than 1,250 g) developed necrotizing enterocolitis and two of the five died during or following a period when they received Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)), several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) or any other drugs could be established.

8.5 Geriatric Use

Clinical studies of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Of the 1,051 patients in two post-marketing safety studies of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)), 40% were 65 years and older. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose administration to an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

No data are available regarding overdosage of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) in humans. Excessive dosages of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) may lead to accumulation of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) in storage sites potentially leading to hemosiderosis. Do not administer Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) to patients with Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) overload.

Toxicities in single-dose studies in mice and rats, at intravenous Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) sucrose doses up to 8 times the maximum recommended human dose based on body surface area, included sedation, hypoactivity, pale eyes, bleeding in the gastrointestinal tract and lungs, and mortality.

11 DESCRIPTION

Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) (iron sucrose injection, USP), an Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) replacement product, is a brown, sterile, aqueous, complex of polynuclear Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) (III)-hydroxide in sucrose for intravenous use. Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) sucrose injection has a molecular weight of approximately 34,000 to 60,000 daltons and a proposed structural formula:

[Na2Fe5O8(OH) ·3(H2O)]n ·m(C12H22O11)

where: n is the degree of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) polymerization and m is the number of sucrose molecules associated with the Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) (III)-hydroxide.

Each mL contains 20 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) as Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) sucrose in water for injection. Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) is available in 10 mL single-use vials (200 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) per 10 mL), 5 mL single-use vials (100 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) per 5 mL), and 2.5 mL single-use vials (50 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) per 2.5 mL). The drug product contains approximately 30% sucrose w/v (300 mg/mL) and has a pH of 10.5 to 11.1. The product contains no preservatives. The osmolarity of the injection is 1,250 mOsmol/L.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Super Multi-Minerals Regular Strength ) is an aqueous complex of poly-nuclear Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) (III)-hydroxide in sucrose. Following intravenous administration, Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) is dissociated into Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) and sucrose and the Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) is transported as a complex with transferrin to target cells including erythroid precursor cells. The Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) in the precursor cells is incorporated into hemoglobin as the cells mature into red blood cells.

12.2 Pharmacodynamics

Following intravenous administration, Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) is dissociated into Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) and sucrose. In 22 patients undergoing hemodialysis and receiving erythropoietin (recombinant human erythropoietin) therapy treated with Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) sucrose containing 100 mg of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)), three times weekly for three weeks, significant increases in serum Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) and serum ferritin and significant decreases in total Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) binding capacity occurred four weeks from the initiation of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) sucrose treatment.

12.3 Pharmacokinetics

In healthy adults administered intravenous doses of Super Multi-Minerals Regular Strength ), its Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) component exhibited first order kinetics with an elimination half-life of 6 h, total clearance of 1.2 L/h, and steady state apparent volume of distribution of 7.9 L. The Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) containing 100 mg of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) labeled with 52Fe/59Fe in patients with Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) deficiency showed that a significant amount of the administered Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) trapping compartment.

Following intravenous administration of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)), Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) sucrose is dissociated into Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) containing 1,510 mg of sucrose and 100 mg of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) in 12 healthy adults (9 female, 3 male: age range 32 to 52), 68.3% of the sucrose was eliminated in urine in 4 h and 75.4% in 24 h. Some Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) was also eliminated in the urine. Neither transferrin nor transferrin receptor levels changed immediately after the dose administration. In this study and another study evaluating a single intravenous dose of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) sucrose containing 500 to 700 mg of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60), approximately 5% of the Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) have not been studied.

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

In a single-dose PK study of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)), patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)), the half-life of total serum Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) was 8 hours. The mean Cmax and AUC values were 8545 μg/dl and 31305 hr-μg/dL, respectively, which were 1.42- and 1.67-fold higher than dose adjusted adult Cmax and AUC values.

Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) sucrose in the dialysate fluid was below the levels of detection of the assay (less than 2 parts per million).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) sucrose.

Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.

Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) sucrose at intravenous doses up to 15 mg/kg/day of elemental Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) (1.2 times the maximum recommended human dose based on body surface area) had no effect on fertility and reproductive function of male and female rats.

14 CLINICAL STUDIES

Five clinical trials involving 647 adult patients and one clinical trial involving 131 pediatric patients were conducted to assess the safety and efficacy of Super Multi-Minerals Regular Strength ).

14.1 Study A: Hemodialysis Dependent-Chronic Kidney Disease (HDD–CKD)

Study A was a multicenter, open-label, historically-controlled study in 101 patients with HDD-CKD (77 patients with Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) treatment and 24 in the historical control group) with Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) deficiency anemia. Eligibility criteria for Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) treatment included patients undergoing chronic hemodialysis, receiving erythropoietin, hemoglobin level between 8.0 and 11.0 g/dL, transferrin saturation < 20%, and serum ferritin < 300 ng/mL. The mean age of the patients was 65 years with the age range of 31 to 85 years. Of the 77 patients, 44 (57%) were male and 33 (43%) were female.

Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) 100 mg was administered at 10 consecutive dialysis sessions either as slow injection or a slow infusion. The historical control population consisted of 24 patients with similar ferritin levels as patients treated with Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)), who were off intravenous Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) for at least 2 weeks and who had received erythropoietin therapy with hematocrit averaging 31 to 36 for at least two months prior to study entry. The mean age of patients in the historical control group was 56 years, with an age range of 29 to 80 years. Patient age and serum ferritin level were similar between treatment and historical control patients.

Patients in the Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) treated population showed a greater increase in hemoglobin and hematocrit than did patients in the historical control population. See Table 2.


**p < 0.01 and *p < 0.05 compared to historical control from ANCOVA analysis with baseline hemoglobin, serum ferritin and erythropoietin dose as covariates.


Efficacy

parameters

End of treatment 2 week follow-up 5 week follow-up
Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) (n=69 Historical Control (n=18) Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate))

(n=73)

Historical Control

(n=18)

Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate))

(n=71)

Historical

Control

(n=15)

Hemoglobin (g/dL) 1.0 ± 0.12** 0.0 ± 0.21 1.3 ± 0.14** -0.6 ± 0.24 1.2 ± 0.17* -0.1 ± 0.23
Hematocrit (%) 3.1 ± 0.37** -0.3 ± 0.65 3.6 ± 0.44** -1.2 ± 0.76 3.3 ± 0.54 0.2 ± 0.86

Serum ferritin increased at endpoint of study from baseline in the Venofer-treated population (165.3 ± 24.2 ng/mL) compared to the historical control population (-27.6 ± 9.5 ng/mL). Transferrin saturation also increased at endpoint of study from baseline in the Venofer-treated population (8.8 ± 1.6%) compared to this historical control population (-5.1 ± 4.3%).

14.2 Study B: Hemodialysis Dependent-Chronic Kidney Disease

Study B was a multicenter, open label study of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) in 23 patients with Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) deficiency and HDD-CKD who had been discontinued from Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) dextran due to intolerance. Eligibility criteria were otherwise identical to Study A. The mean age of the patients in this study was 53 years, with ages ranging from 21 to 79 years. Of the 23 patients enrolled in the study, 10 (44%) were male and 13 (56%) were female.

All 23 enrolled patients were evaluated for efficacy. Increases in mean hemoglobin (1.1 ± 0.2 g/dL), hematocrit (3.6 ± 0.6%), serum ferritin (266.3 ± 30.3 ng/mL) and transferrin saturation (8.7 ± 2.0%) were observed from baseline to end of treatment.

14.3 Study C: Hemodialysis Dependent-Chronic Kidney Disease

Study C was a multicenter, open-label study in patients with HDD-CKD. This study enrolled patients with a hemoglobin ≤ 10 g/dL, a serum transferrin saturation ≤ 20%, and a serum ferritin ≤ 200 ng/mL, who were undergoing maintenance hemodialysis 2 to 3 times weekly. The mean age of the patients enrolled in this study was 41 years, with ages ranging from 16 to 70 years. Of 130 patients evaluated for efficacy in this study, 68 (52%) were male and 62 (48%) were female. Forty-eight percent of the patients had previously been treated with oral Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)). Exclusion criteria were similar to those in studies A and B. Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) was administered. A 50 mg dose (2.5 mL) was given to patients within two weeks of study entry as a test dose. Twenty-seven patients (20%) were receiving erythropoietin treatment at study entry and they continued to receive the same erythropoietin dose for the duration of the study.

The modified intention-to-treat (mITT) population consisted of 131 patients. Increases from baseline in mean hemoglobin (1.7 g/dL), hematocrit (5%), serum ferritin (434.6 ng/mL), and serum transferrin saturation (14%) were observed at week 2 of the observation period and these values remained increased at week 4 of the observation period.

14.4 Study D: Non-Dialysis Dependent-Chronic Kidney Disease

Study D was a randomized, open-label, multicenter, active-controlled study of the safety and efficacy of oral Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) versus Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) in patients with NDD-CKD with or without erythropoietin therapy. Erythropoietin therapy was stable for 8 weeks prior to randomization. In the study 188 patients with NDD-CKD, hemoglobin of ≤ 11.0 g/dL, transferrin saturation ≤ 25%, ferritin ≤ 300 ng/mL were randomized to receive oral Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) (325 mg ferrous sulfate three times daily for 56 days); or Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) (either 200 mg over 2 to 5 minutes 5 times within 14 days or two 500 mg infusions on Day 1 and Day 14, administered over 3.5 to 4 hours). The mean age of the 91 treated patients in the Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) group was 61.6 years (range 25 to 86 years) and 64 years (range 21 to 86 years) for the 91 patients in the oral Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) group.

A statistically significantly greater proportion of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) subjects (35/79; 44.3%) compared to oral Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) subjects (23/82; 28%) had an increase in hemoglobin ≥ 1 g/dL at anytime during the study (p = 0.03).

14.5 Study E: Peritoneal Dialysis Dependent-Chronic Kidney Disease

Study E was a randomized, open-label, multicenter study comparing patients with PDD-CKD receiving an erythropoietin and intravenous Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) to patients with PDD-CKD receiving an erythropoietin alone without Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) supplementation. Patients with PDD-CKD, stable erythropoietin for 8 weeks, hemoglobin of ≤ 11.5 g/dL, TSAT ≤ 25%, ferritin ≤ 500 ng/mL were randomized to receive either no Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) or Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) (300 mg in 250 mL 0.9% NaCl over 1.5 hours on Day 1 and 15 and 400 mg in 250 mL 0.9% NaCl over 2.5 hours on Day 29). The mean age of the 75 treated patients in the Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) / erythropoietin group was 51.9 years (range 21 to 81 years) vs. 52.8 years (range 23 to 77 years) for 46 patients in the erythropoietin alone group.

Patients in the Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) / erythropoietin group had statistically significantly greater mean change from baseline to the highest hemoglobin value (1.3 g/dL), compared to subjects who received erythropoietin alone (0.6 g/dL) (p < 0.01). A greater proportion of subjects treated with Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) / erythropoietin (59.1 %) had an increase in hemoglobin of ≥ 1 g/dL at any time during the study compared to the subjects who received erythropoietin only (33.3%).

14.6 Study F: Super Multi-Minerals Regular Strength ) Maintenance Treatment Dosing in Pediatric Patients Ages 2 years and Older with Chronic Kidney Disease

Study F was a randomized, open-label, dose-ranging study for Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) maintenance treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD on stable erythropoietin therapy. The study randomized patients to one of three doses of Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) (0.5 mg/kg, 1.0 mg/kg or 2.0 mg/kg). The mean age was 13 years (range 2 to 20 years). Over 70% of patients were 12 years or older in all three groups. There were 84 males and 61 females. About 60% of patients underwent hemodialysis and 25% underwent peritoneal dialysis in all three dose groups. At baseline, the mean hemoglobin was 12 g/dL, the mean TSAT was 33% and the mean ferritin was 300 ng/mL. Patients with HDD-CKD received Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) once every 4 weeks for 3 doses. Among 131 evaluable patients with stable erythropoietin dosing, the proportion of patients who maintained hemoglobin between 10.5 g/dL and 14.0 g/dL during the 12-week treatment period was 58.7%, 46.7%, and 45.0% in the Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg groups, respectively. A dose-response relationship was not demonstrated.

16 HOW SUPPLIED/storage and handling

16.1 How Supplied

Super Multi-Minerals Regular Strength ) is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)), each 5 mL vial contains 100 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)), and each 2.5 mL vial contains 50 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) (20 mg/mL).

NDC-0517-2310-05 200 mg/10 mL Single-Use Vial Packages of 5
NDC-0517-2310-10 200 mg/10 mL Single-Use Vial Packages of 10
NDC-0517-2340-01 100 mg/5 mL Single-Use Vial Individually Boxed
NDC-0517-2340-10 100 mg/5 mL Single-Use Vial Packages of 10
NDC-0517-2340-25 100 mg/5 mL Single-Use Vial Packages of 25
NDC-0517-2340-99 100 mg/5 mL Single-Use Vial Packages of 10
NDC-0517-2325-10 50 mg/2.5 mL Single-Use Vial Packages of 10
NDC-0517-2325-25 50 mg/2.5 mL Single-Use Vial Packages of 25

16.2 Stability and Storage

Contains no preservatives. Store in original carton at 20°C to 25°C (68° F to 77° F); excursions permitted to 15° to 30°C (59° to 86°F).. Do not freeze.

Syringe Stability: Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) per mL, or undiluted (20 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) per mL) and stored in a plastic syringe, was found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C) and under refrigeration (4°C ± 2°C).

Intravenous Admixture Stability: Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)), when added to intravenous infusion bags (PVC or non-PVC) containing 0.9% NaCl at concentrations ranging from 1 mg to 2 mg of elemental Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) per mL, has been found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C).

Do not dilute to concentrations below 1 mg/mL.

Do not mix Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) with other medications or add to parenteral nutrition solutions for intravenous infusion.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to infusion.

17 PATIENT COUNSELING INFORMATION

Prior to Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) administration:

  • Question patients regarding any prior history of reactions to parenteral Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) products
  • Advise patients of the risks associated with Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate))
  • Advise patients to report any symptoms of hypersensitivity that may develop during and following Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) administration, such as rash, itching, dizziness, light-headedness, swelling, and breathing problems [see Warnings and Precautions (5)]

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Super Multi-Minerals Regular Strength (Iron (Ferrous HVP Chelate)) is manufactured under license from Vifor (International) Inc., Switzerland.

PremierProRx® is a trademark of Premier, Inc., used under license.

PREMIERProRx®

IN2340

MG #15727

Iron (Ferrous Malate):


1 INDICATIONS AND USAGE

Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) is indicated for the treatment of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) deficiency anemia in patients with chronic kidney disease (CKD).

Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) is an Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) replacement product indicated for the treatment of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) deficiency anemia in patients with chronic kidney disease (CKD). (1)

2 DOSAGE AND ADMINISTRATION

Super Multi-Minerals Regular Strength ) must only be administered intravenously either by slow injection or by infusion. The dosage of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) is expressed in mg of elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)). Each mL contains 20 mg of elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)).

Population Dose
Adult patients Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD) (2.1) 100 mg slow intravenous injection or infusion
Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) (2.2) 200 mg slow intravenous injection or infusion
Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD) (2.3) 300 mg or 400 mg intravenous infusion
Pediatric patients HDD-CKD (2.4), PDD-CKD or NDD-CKD (2.5) 0.5 mg/kg slow intravenous injection or infusion

2.1 Adult Patients with Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)

Administer Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) 100 mg undiluted as a slow intravenous injection over 2 to 5 minutes, or as an infusion of 100 mg diluted in a maximum of 100 mL of 0.9% NaCl over a period of at least 15 minutes, per consecutive hemodialysis session. Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) should be administered early during the dialysis session. The usual total treatment course of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) is 1000 mg. Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) treatment may be repeated if Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) deficiency reoccurs.

2.2 Adult Patients with Non-Dialysis Dependent-Chronic Kidney Disease

Administer Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) 200 mg undiluted as a slow intravenous injection over 2 to 5 minutes or as an infusion of 200 mg in a maximum of 100 mL of 0.9% NaCl over a period of 15 minutes. Administer on 5 different occasions over a 14 day period. There is limited experience with administration of an infusion of 500 mg of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)), diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5 to 4 hours on Day 1 and Day 14. Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) treatment may be repeated if Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) in 3 divided doses, given by slow intravenous infusion, within a 28 day period: 2 infusions each of 300 mg over 1.5 hours 14 days apart followed by one 400 mg infusion over 2.5 hours 14 days later. Dilute Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) in a maximum of 250 mL of 0.9% NaCl. Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) treatment may be repeated if Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) maintenance treatment

The dosing for Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) replacement treatment in pediatric patients with HDD-CKD has not been established.

For Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) maintenance treatment: Administer Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every two weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) treatment may be repeated if necessary.

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) maintenance treatment

The dosing for Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

For Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) maintenance treatment: Administer Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every four weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

  • 10 mL single-use vial / 200 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) (20 mg/mL)
  • 5 mL single-use vial / 100 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) (20 mg/mL)
  • 2.5 mL single-use vial / 50 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) (20 mg/mL)
  • 10 mL single-use vial / 200 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) (20 mg/mL) (3)
  • 5 mL single-use vial / 100 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) (20 mg/mL) (3)
  • 2.5 mL single-use vial / 50 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) (20 mg/mL) (3)

4 CONTRAINDICATIONS

  • Known hypersensitivity to Super Multi-Minerals Regular Strength (Iron (Ferrous Malate))
  • Known hypersensitivity to Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) (4)

5 WARNINGS AND PRECAUTIONS

  • Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after Super Multi-Minerals Regular Strength ) administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. (5.1)
  • Hypotension: Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) may cause hypotension. Monitor for signs and symptoms of hypotension during and following each administration of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)). (5.2)
  • Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) Overload: Regularly monitor hematologic responses during Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) therapy. Do not administer Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) to patients with Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) overload. (5.3)

5.1 Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)). Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. If hypersensitivity reactions or signs of intolerance occur during administration, stop Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) preparations occur within 30 minutes of the completion of the infusion .

5.2 Hypotension

Super Multi-Minerals Regular Strength ) may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)). Hypotension following administration of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) may be related to the rate of administration and/or total dose administered .

5.3 Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) Overload

Excessive therapy with parenteral Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) can lead to excess storage of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) with the possibility of iatrogenic hemosiderosis. All adult and pediatric patients receiving Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) require periodic monitoring of hematologic and Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) to patients with evidence of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) overload. Transferrin saturation (TSAT) values increase rapidly after intravenous administration of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) sucrose; do not perform serum Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) measurements for at least 48 hours after intravenous dosing .

6 ADVERSE REACTIONS

The following serious adverse reactions associated with Super Multi-Minerals Regular Strength ) are described in other sections .

  • The most common adverse reactions (≥2%) following the administration of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) are diarrhea, nausea, vomiting, headache, dizziness, hypotension, pruritus, pain in extremity, arthralgia, back pain, muscle cramp, injection site reactions, chest pain, and peripheral edema. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact American Regent, Inc. at 1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Adverse Reactions in Clinical Trials

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in practice.

Adverse Reactions in Adults Patients with CKD

Adverse Reactions in Adult Patients with CKD

The frequency of adverse reactions associated with the use of Super Multi-Minerals Regular Strength ) has been documented in six clinical trials involving 231 patients with HDD-CKD, 139 patients with NDD-CKD and 75 patients with PDD-CKD. Treatment-emergent adverse reactions reported by ≥ 2% of treated patients in the six clinical trials for which the rate for Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) exceeds the rate for comparator are listed by indication in Table 1. Patients with HDD-CKD received 100 mg doses at 10 consecutive dialysis sessions until a cumulative dose of 1000 mg was administered. Patients with NDD-CKD received either 5 doses of 200 mg over 2 weeks or 2 doses of 500 mg separated by fourteen days, and patients with PDD-CKD received 2 doses of 300 mg followed by a dose of 400 mg over a period of 4 weeks.


* EPO=Erythropoietin

Adverse Reactions

(Preferred Term)

HDD-CKD NDD-CKD PDD-CKD
Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) Oral Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) EPO* Only
(N=231) (N=139) (N=139) (N=75) (N=46)
% % % % %
Subjects with any adverse reaction 78.8 76.3 73.4 72.0 65.2
Ear and Labyrinth Disorders
Ear Pain 0 2.2 0.7 0 0
Eye Disorders
Conjunctivitis 0.4 0 0 2.7 0
Gastrointestinal Disorders
Abdominal pain 3.5 1.4 2.9 4.0 6.5
Diarrhea 5.2 7.2 10.1 8.0 4.3
Dysgeusia 0.9 7.9 0 0 0
Nausea 14.7 8.6 12.2 5.3 4.3
Vomiting 9.1 5.0 8.6 8.0 2.2
General Disorders and
Administration Site Conditions
Asthenia 2.2 0.7 2.2 2.7 0
Chest pain 6.1 1.4 0 2.7 0
Feeling abnormal 3.0 0 0 0 0
Infusion site pain or burning 0 5.8 0 0 0
Injection site extravasation 0 2.2 0 0 0
Peripheral edema 2.6 7.2 5.0 5.3 10.9
Pyrexia 3.0 0.7 0.7 1.3 0
Infections and Infestations
Nasopharyngitis, Sinusitis, Upper

respiratory tract infections, Pharyngitis

2.6 2.2 4.3 16.0 4.3
Injury, Poisoning and Procedural
Complications
Graft complication 9.5 1.4 0 0 0
Metabolism and Nutrition Disorders
Fluid overload 3.0 1.4 0.7 1.3 0
Gout 0 2.9 1.4 0 0
Hyperglycemia 0 2.9 0 0 2.2
Hypoglycemia 0.4 0.7 0.7 4.0 0
Musculoskeletal and Connective
Tissue Disorders
Arthralgia 3.5 1.4 2.2 4.0 4.3
Back pain 2.2 2.2 3.6 1.3 4.3
Muscle cramp 29.4 0.7 0.7 2.7 0
Myalgia 0 3.6 0 1.3 0
Pain in extremity 5.6 4.3 0 2.7 6.5
Nervous System Disorders
Dizziness 6.5 6.5 1.4 1.3 4.3
Headache 12.6 2.9 0.7 4.0 0
Respiratory, Thoracic and
Mediastinal Disorders
Cough 3.0 2.2 0.7 1.3 0
Dyspnea 3.5 5.8 1.4 1.3 2.2
Nasal congestion 0 1.4 2.2 1.3 0
Skin and Subcutaneous
Tissue Disorders
Pruritus 3.9 2.2 4.3 2.7 0
Vascular Disorders
Hypertension 6.5 6.5 4.3 8.0 6.5
Hypotension 39.4 2.2 0.7 2.7 2.2

One hundred thirty (11%) of the 1,151 patients evaluated in the 4 U.S. trials in HDD-CKD patients (studies A, B and the two post marketing studies) had prior other intravenous Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) therapy and were reported to be intolerant (defined as precluding further use of that Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) product). When these patients were treated with Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) there were no occurrences of adverse reactions that precluded further use of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) .

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

In a randomized, open-label, dose-ranging trial for Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) maintenance treatment with Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) in pediatric patients with CKD on stable erythropoietin therapy , at least one treatment-emergent adverse reaction was experienced by 57% (27/47) of the patients receiving Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) 0.5 mg/kg, 53% (25/47) of the patients receiving Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) 1.0 mg/kg, and 55% (26/47) of the patients receiving Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) 2.0 mg/kg.

A total of 5 (11%) subjects in the Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) 0.5 mg/kg group, 10 (21%) patients in the Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) 1.0 mg/kg group, and 10 (21%) patients in the Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) 2.0 mg/kg group experienced at least 1 serious adverse reaction during the study. The most common treatment-emergent adverse reactions (> 2% of patients) in all patients were headache (6%), respiratory tract viral infection (4%), peritonitis (4%), vomiting (4%), pyrexia (4%), dizziness (4%), cough (4%), renal transplant (4%), nausea (3%), arteriovenous fistula thrombosis (2%), hypotension (2%), and hypertension (2.1%).

6.2 Adverse Reactions from Post-Marketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In the post-marketing safety studies in 1,051 treated patients with HDD-CKD, the adverse reactions reported by > 1% were: cardiac failure congestive, sepsis and dysgeusia.

The following adverse reactions have been identified during post-approval use of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Anaphylactic-type reactions, shock, loss of consciousness, collapse, bronchospasm, dyspnea, convulsions, light-headedness, confusion, angioedema, swelling of the joints, hyperhidrosis, back pain, bradycardia, and chromaturia.

Symptoms associated with Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) total dosage or infusing too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. These adverse reactions have occurred up to 30 minutes after the administration of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) injection. Reactions have occurred following the first dose or subsequent doses of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)). Symptoms may respond to intravenous fluids, hydrocortisone, and/or antihistamines. Slowing the infusion rate may alleviate symptoms.

Injection site discoloration has been reported following extravasation. Assure stable intravenous access to avoid extravasation.

7 DRUG INTERACTIONS

Drug interactions involving Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) have not been studied. However, Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) may reduce the absorption of concomitantly administered oral Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) preparations.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, Super Multi-Minerals Regular Strength ) sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) (half or equivalent to the maximum recommended human dose based on body surface area, respectively) and revealed no evidence of harm to the fetus due to Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) sucrose. Because animal reproductive studies are not always predictive of human response, Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) sucrose is excreted in human milk. Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) sucrose is secreted into the milk of lactating rats. Because many drugs are excreted in human milk, caution should be exercised when Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of Super Multi-Minerals Regular Strength ) for Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.

Safety and effectiveness of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) for Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) maintenance treatment in pediatric patients 2 years of age and older with dialysis-dependent or non-dialysis-dependent CKD receiving erythropoietin therapy were studied. Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) at doses of 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg was administered. All three doses maintained hemoglobin between 10.5 g/dL and 14.0 g/dL in about 50% of subjects over the 12-week treatment period with stable EPO dosing. [See Clinical Studies (14.6)]

Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) has not been studied in patients younger than 2 years of age.

In a country where Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) is available for use in children, at a single site, five premature infants (weight less than 1,250 g) developed necrotizing enterocolitis and two of the five died during or following a period when they received Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)), several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) or any other drugs could be established.

8.5 Geriatric Use

Clinical studies of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Of the 1,051 patients in two post-marketing safety studies of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)), 40% were 65 years and older. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose administration to an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

No data are available regarding overdosage of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) in humans. Excessive dosages of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) may lead to accumulation of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) in storage sites potentially leading to hemosiderosis. Do not administer Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) to patients with Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) overload.

Toxicities in single-dose studies in mice and rats, at intravenous Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) sucrose doses up to 8 times the maximum recommended human dose based on body surface area, included sedation, hypoactivity, pale eyes, bleeding in the gastrointestinal tract and lungs, and mortality.

11 DESCRIPTION

Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) (iron sucrose injection, USP), an Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) replacement product, is a brown, sterile, aqueous, complex of polynuclear Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) (III)-hydroxide in sucrose for intravenous use. Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) sucrose injection has a molecular weight of approximately 34,000 to 60,000 daltons and a proposed structural formula:

[Na2Fe5O8(OH) ·3(H2O)]n ·m(C12H22O11)

where: n is the degree of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) polymerization and m is the number of sucrose molecules associated with the Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) (III)-hydroxide.

Each mL contains 20 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) as Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) sucrose in water for injection. Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) is available in 10 mL single-use vials (200 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) per 10 mL), 5 mL single-use vials (100 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) per 5 mL), and 2.5 mL single-use vials (50 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) per 2.5 mL). The drug product contains approximately 30% sucrose w/v (300 mg/mL) and has a pH of 10.5 to 11.1. The product contains no preservatives. The osmolarity of the injection is 1,250 mOsmol/L.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Super Multi-Minerals Regular Strength ) is an aqueous complex of poly-nuclear Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) (III)-hydroxide in sucrose. Following intravenous administration, Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) is dissociated into Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) and sucrose and the Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) is transported as a complex with transferrin to target cells including erythroid precursor cells. The Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) in the precursor cells is incorporated into hemoglobin as the cells mature into red blood cells.

12.2 Pharmacodynamics

Following intravenous administration, Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) is dissociated into Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) and sucrose. In 22 patients undergoing hemodialysis and receiving erythropoietin (recombinant human erythropoietin) therapy treated with Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) sucrose containing 100 mg of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)), three times weekly for three weeks, significant increases in serum Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) and serum ferritin and significant decreases in total Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) binding capacity occurred four weeks from the initiation of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) sucrose treatment.

12.3 Pharmacokinetics

In healthy adults administered intravenous doses of Super Multi-Minerals Regular Strength ), its Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) component exhibited first order kinetics with an elimination half-life of 6 h, total clearance of 1.2 L/h, and steady state apparent volume of distribution of 7.9 L. The Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) containing 100 mg of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) labeled with 52Fe/59Fe in patients with Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) deficiency showed that a significant amount of the administered Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) trapping compartment.

Following intravenous administration of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)), Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) sucrose is dissociated into Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) containing 1,510 mg of sucrose and 100 mg of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) in 12 healthy adults (9 female, 3 male: age range 32 to 52), 68.3% of the sucrose was eliminated in urine in 4 h and 75.4% in 24 h. Some Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) was also eliminated in the urine. Neither transferrin nor transferrin receptor levels changed immediately after the dose administration. In this study and another study evaluating a single intravenous dose of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) sucrose containing 500 to 700 mg of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60), approximately 5% of the Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) have not been studied.

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

In a single-dose PK study of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)), patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)), the half-life of total serum Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) was 8 hours. The mean Cmax and AUC values were 8545 μg/dl and 31305 hr-μg/dL, respectively, which were 1.42- and 1.67-fold higher than dose adjusted adult Cmax and AUC values.

Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) sucrose in the dialysate fluid was below the levels of detection of the assay (less than 2 parts per million).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) sucrose.

Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.

Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) sucrose at intravenous doses up to 15 mg/kg/day of elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) (1.2 times the maximum recommended human dose based on body surface area) had no effect on fertility and reproductive function of male and female rats.

14 CLINICAL STUDIES

Five clinical trials involving 647 adult patients and one clinical trial involving 131 pediatric patients were conducted to assess the safety and efficacy of Super Multi-Minerals Regular Strength ).

14.1 Study A: Hemodialysis Dependent-Chronic Kidney Disease (HDD–CKD)

Study A was a multicenter, open-label, historically-controlled study in 101 patients with HDD-CKD (77 patients with Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) treatment and 24 in the historical control group) with Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) deficiency anemia. Eligibility criteria for Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) treatment included patients undergoing chronic hemodialysis, receiving erythropoietin, hemoglobin level between 8.0 and 11.0 g/dL, transferrin saturation < 20%, and serum ferritin < 300 ng/mL. The mean age of the patients was 65 years with the age range of 31 to 85 years. Of the 77 patients, 44 (57%) were male and 33 (43%) were female.

Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) 100 mg was administered at 10 consecutive dialysis sessions either as slow injection or a slow infusion. The historical control population consisted of 24 patients with similar ferritin levels as patients treated with Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)), who were off intravenous Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) for at least 2 weeks and who had received erythropoietin therapy with hematocrit averaging 31 to 36 for at least two months prior to study entry. The mean age of patients in the historical control group was 56 years, with an age range of 29 to 80 years. Patient age and serum ferritin level were similar between treatment and historical control patients.

Patients in the Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) treated population showed a greater increase in hemoglobin and hematocrit than did patients in the historical control population. See Table 2.


**p < 0.01 and *p < 0.05 compared to historical control from ANCOVA analysis with baseline hemoglobin, serum ferritin and erythropoietin dose as covariates.


Efficacy

parameters

End of treatment 2 week follow-up 5 week follow-up
Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) (n=69 Historical Control (n=18) Super Multi-Minerals Regular Strength (Iron (Ferrous Malate))

(n=73)

Historical Control

(n=18)

Super Multi-Minerals Regular Strength (Iron (Ferrous Malate))

(n=71)

Historical

Control

(n=15)

Hemoglobin (g/dL) 1.0 ± 0.12** 0.0 ± 0.21 1.3 ± 0.14** -0.6 ± 0.24 1.2 ± 0.17* -0.1 ± 0.23
Hematocrit (%) 3.1 ± 0.37** -0.3 ± 0.65 3.6 ± 0.44** -1.2 ± 0.76 3.3 ± 0.54 0.2 ± 0.86

Serum ferritin increased at endpoint of study from baseline in the Venofer-treated population (165.3 ± 24.2 ng/mL) compared to the historical control population (-27.6 ± 9.5 ng/mL). Transferrin saturation also increased at endpoint of study from baseline in the Venofer-treated population (8.8 ± 1.6%) compared to this historical control population (-5.1 ± 4.3%).

14.2 Study B: Hemodialysis Dependent-Chronic Kidney Disease

Study B was a multicenter, open label study of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) in 23 patients with Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) deficiency and HDD-CKD who had been discontinued from Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) dextran due to intolerance. Eligibility criteria were otherwise identical to Study A. The mean age of the patients in this study was 53 years, with ages ranging from 21 to 79 years. Of the 23 patients enrolled in the study, 10 (44%) were male and 13 (56%) were female.

All 23 enrolled patients were evaluated for efficacy. Increases in mean hemoglobin (1.1 ± 0.2 g/dL), hematocrit (3.6 ± 0.6%), serum ferritin (266.3 ± 30.3 ng/mL) and transferrin saturation (8.7 ± 2.0%) were observed from baseline to end of treatment.

14.3 Study C: Hemodialysis Dependent-Chronic Kidney Disease

Study C was a multicenter, open-label study in patients with HDD-CKD. This study enrolled patients with a hemoglobin ≤ 10 g/dL, a serum transferrin saturation ≤ 20%, and a serum ferritin ≤ 200 ng/mL, who were undergoing maintenance hemodialysis 2 to 3 times weekly. The mean age of the patients enrolled in this study was 41 years, with ages ranging from 16 to 70 years. Of 130 patients evaluated for efficacy in this study, 68 (52%) were male and 62 (48%) were female. Forty-eight percent of the patients had previously been treated with oral Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)). Exclusion criteria were similar to those in studies A and B. Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) was administered. A 50 mg dose (2.5 mL) was given to patients within two weeks of study entry as a test dose. Twenty-seven patients (20%) were receiving erythropoietin treatment at study entry and they continued to receive the same erythropoietin dose for the duration of the study.

The modified intention-to-treat (mITT) population consisted of 131 patients. Increases from baseline in mean hemoglobin (1.7 g/dL), hematocrit (5%), serum ferritin (434.6 ng/mL), and serum transferrin saturation (14%) were observed at week 2 of the observation period and these values remained increased at week 4 of the observation period.

14.4 Study D: Non-Dialysis Dependent-Chronic Kidney Disease

Study D was a randomized, open-label, multicenter, active-controlled study of the safety and efficacy of oral Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) versus Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) in patients with NDD-CKD with or without erythropoietin therapy. Erythropoietin therapy was stable for 8 weeks prior to randomization. In the study 188 patients with NDD-CKD, hemoglobin of ≤ 11.0 g/dL, transferrin saturation ≤ 25%, ferritin ≤ 300 ng/mL were randomized to receive oral Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) (325 mg ferrous sulfate three times daily for 56 days); or Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) (either 200 mg over 2 to 5 minutes 5 times within 14 days or two 500 mg infusions on Day 1 and Day 14, administered over 3.5 to 4 hours). The mean age of the 91 treated patients in the Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) group was 61.6 years (range 25 to 86 years) and 64 years (range 21 to 86 years) for the 91 patients in the oral Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) group.

A statistically significantly greater proportion of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) subjects (35/79; 44.3%) compared to oral Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) subjects (23/82; 28%) had an increase in hemoglobin ≥ 1 g/dL at anytime during the study (p = 0.03).

14.5 Study E: Peritoneal Dialysis Dependent-Chronic Kidney Disease

Study E was a randomized, open-label, multicenter study comparing patients with PDD-CKD receiving an erythropoietin and intravenous Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) to patients with PDD-CKD receiving an erythropoietin alone without Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) supplementation. Patients with PDD-CKD, stable erythropoietin for 8 weeks, hemoglobin of ≤ 11.5 g/dL, TSAT ≤ 25%, ferritin ≤ 500 ng/mL were randomized to receive either no Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) or Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) (300 mg in 250 mL 0.9% NaCl over 1.5 hours on Day 1 and 15 and 400 mg in 250 mL 0.9% NaCl over 2.5 hours on Day 29). The mean age of the 75 treated patients in the Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) / erythropoietin group was 51.9 years (range 21 to 81 years) vs. 52.8 years (range 23 to 77 years) for 46 patients in the erythropoietin alone group.

Patients in the Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) / erythropoietin group had statistically significantly greater mean change from baseline to the highest hemoglobin value (1.3 g/dL), compared to subjects who received erythropoietin alone (0.6 g/dL) (p < 0.01). A greater proportion of subjects treated with Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) / erythropoietin (59.1 %) had an increase in hemoglobin of ≥ 1 g/dL at any time during the study compared to the subjects who received erythropoietin only (33.3%).

14.6 Study F: Super Multi-Minerals Regular Strength ) Maintenance Treatment Dosing in Pediatric Patients Ages 2 years and Older with Chronic Kidney Disease

Study F was a randomized, open-label, dose-ranging study for Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) maintenance treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD on stable erythropoietin therapy. The study randomized patients to one of three doses of Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) (0.5 mg/kg, 1.0 mg/kg or 2.0 mg/kg). The mean age was 13 years (range 2 to 20 years). Over 70% of patients were 12 years or older in all three groups. There were 84 males and 61 females. About 60% of patients underwent hemodialysis and 25% underwent peritoneal dialysis in all three dose groups. At baseline, the mean hemoglobin was 12 g/dL, the mean TSAT was 33% and the mean ferritin was 300 ng/mL. Patients with HDD-CKD received Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) once every 4 weeks for 3 doses. Among 131 evaluable patients with stable erythropoietin dosing, the proportion of patients who maintained hemoglobin between 10.5 g/dL and 14.0 g/dL during the 12-week treatment period was 58.7%, 46.7%, and 45.0% in the Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg groups, respectively. A dose-response relationship was not demonstrated.

16 HOW SUPPLIED/storage and handling

16.1 How Supplied

Super Multi-Minerals Regular Strength ) is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)), each 5 mL vial contains 100 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)), and each 2.5 mL vial contains 50 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) (20 mg/mL).

NDC-0517-2310-05 200 mg/10 mL Single-Use Vial Packages of 5
NDC-0517-2310-10 200 mg/10 mL Single-Use Vial Packages of 10
NDC-0517-2340-01 100 mg/5 mL Single-Use Vial Individually Boxed
NDC-0517-2340-10 100 mg/5 mL Single-Use Vial Packages of 10
NDC-0517-2340-25 100 mg/5 mL Single-Use Vial Packages of 25
NDC-0517-2340-99 100 mg/5 mL Single-Use Vial Packages of 10
NDC-0517-2325-10 50 mg/2.5 mL Single-Use Vial Packages of 10
NDC-0517-2325-25 50 mg/2.5 mL Single-Use Vial Packages of 25

16.2 Stability and Storage

Contains no preservatives. Store in original carton at 20°C to 25°C (68° F to 77° F); excursions permitted to 15° to 30°C (59° to 86°F).. Do not freeze.

Syringe Stability: Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) per mL, or undiluted (20 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) per mL) and stored in a plastic syringe, was found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C) and under refrigeration (4°C ± 2°C).

Intravenous Admixture Stability: Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)), when added to intravenous infusion bags (PVC or non-PVC) containing 0.9% NaCl at concentrations ranging from 1 mg to 2 mg of elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) per mL, has been found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C).

Do not dilute to concentrations below 1 mg/mL.

Do not mix Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) with other medications or add to parenteral nutrition solutions for intravenous infusion.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to infusion.

17 PATIENT COUNSELING INFORMATION

Prior to Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) administration:

  • Question patients regarding any prior history of reactions to parenteral Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) products
  • Advise patients of the risks associated with Super Multi-Minerals Regular Strength (Iron (Ferrous Malate))
  • Advise patients to report any symptoms of hypersensitivity that may develop during and following Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) administration, such as rash, itching, dizziness, light-headedness, swelling, and breathing problems [see Warnings and Precautions (5)]

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Super Multi-Minerals Regular Strength (Iron (Ferrous Malate)) is manufactured under license from Vifor (International) Inc., Switzerland.

PremierProRx® is a trademark of Premier, Inc., used under license.

PREMIERProRx®

IN2340

MG #15727

Iron (Ferrous Succinate):


1 INDICATIONS AND USAGE

Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) is indicated for the treatment of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) deficiency anemia in patients with chronic kidney disease (CKD).

Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) is an Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) replacement product indicated for the treatment of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) deficiency anemia in patients with chronic kidney disease (CKD). (1)

2 DOSAGE AND ADMINISTRATION

Super Multi-Minerals Regular Strength ) must only be administered intravenously either by slow injection or by infusion. The dosage of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) is expressed in mg of elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)). Each mL contains 20 mg of elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)).

Population Dose
Adult patients Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD) (2.1) 100 mg slow intravenous injection or infusion
Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) (2.2) 200 mg slow intravenous injection or infusion
Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD) (2.3) 300 mg or 400 mg intravenous infusion
Pediatric patients HDD-CKD (2.4), PDD-CKD or NDD-CKD (2.5) 0.5 mg/kg slow intravenous injection or infusion

2.1 Adult Patients with Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)

Administer Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) 100 mg undiluted as a slow intravenous injection over 2 to 5 minutes, or as an infusion of 100 mg diluted in a maximum of 100 mL of 0.9% NaCl over a period of at least 15 minutes, per consecutive hemodialysis session. Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) should be administered early during the dialysis session. The usual total treatment course of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) is 1000 mg. Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) treatment may be repeated if Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) deficiency reoccurs.

2.2 Adult Patients with Non-Dialysis Dependent-Chronic Kidney Disease

Administer Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) 200 mg undiluted as a slow intravenous injection over 2 to 5 minutes or as an infusion of 200 mg in a maximum of 100 mL of 0.9% NaCl over a period of 15 minutes. Administer on 5 different occasions over a 14 day period. There is limited experience with administration of an infusion of 500 mg of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)), diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5 to 4 hours on Day 1 and Day 14. Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) treatment may be repeated if Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) in 3 divided doses, given by slow intravenous infusion, within a 28 day period: 2 infusions each of 300 mg over 1.5 hours 14 days apart followed by one 400 mg infusion over 2.5 hours 14 days later. Dilute Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) in a maximum of 250 mL of 0.9% NaCl. Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) treatment may be repeated if Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) maintenance treatment

The dosing for Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) replacement treatment in pediatric patients with HDD-CKD has not been established.

For Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) maintenance treatment: Administer Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every two weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) treatment may be repeated if necessary.

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) maintenance treatment

The dosing for Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

For Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) maintenance treatment: Administer Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every four weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

  • 10 mL single-use vial / 200 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) (20 mg/mL)
  • 5 mL single-use vial / 100 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) (20 mg/mL)
  • 2.5 mL single-use vial / 50 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) (20 mg/mL)
  • 10 mL single-use vial / 200 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) (20 mg/mL) (3)
  • 5 mL single-use vial / 100 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) (20 mg/mL) (3)
  • 2.5 mL single-use vial / 50 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) (20 mg/mL) (3)

4 CONTRAINDICATIONS

  • Known hypersensitivity to Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate))
  • Known hypersensitivity to Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) (4)

5 WARNINGS AND PRECAUTIONS

  • Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after Super Multi-Minerals Regular Strength ) administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. (5.1)
  • Hypotension: Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) may cause hypotension. Monitor for signs and symptoms of hypotension during and following each administration of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)). (5.2)
  • Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) Overload: Regularly monitor hematologic responses during Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) therapy. Do not administer Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) to patients with Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) overload. (5.3)

5.1 Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)). Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. If hypersensitivity reactions or signs of intolerance occur during administration, stop Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) preparations occur within 30 minutes of the completion of the infusion .

5.2 Hypotension

Super Multi-Minerals Regular Strength ) may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)). Hypotension following administration of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) may be related to the rate of administration and/or total dose administered .

5.3 Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) Overload

Excessive therapy with parenteral Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) can lead to excess storage of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) with the possibility of iatrogenic hemosiderosis. All adult and pediatric patients receiving Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) require periodic monitoring of hematologic and Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) to patients with evidence of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) overload. Transferrin saturation (TSAT) values increase rapidly after intravenous administration of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) sucrose; do not perform serum Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) measurements for at least 48 hours after intravenous dosing .

6 ADVERSE REACTIONS

The following serious adverse reactions associated with Super Multi-Minerals Regular Strength ) are described in other sections .

  • The most common adverse reactions (≥2%) following the administration of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) are diarrhea, nausea, vomiting, headache, dizziness, hypotension, pruritus, pain in extremity, arthralgia, back pain, muscle cramp, injection site reactions, chest pain, and peripheral edema. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact American Regent, Inc. at 1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Adverse Reactions in Clinical Trials

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in practice.

Adverse Reactions in Adults Patients with CKD

Adverse Reactions in Adult Patients with CKD

The frequency of adverse reactions associated with the use of Super Multi-Minerals Regular Strength ) has been documented in six clinical trials involving 231 patients with HDD-CKD, 139 patients with NDD-CKD and 75 patients with PDD-CKD. Treatment-emergent adverse reactions reported by ≥ 2% of treated patients in the six clinical trials for which the rate for Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) exceeds the rate for comparator are listed by indication in Table 1. Patients with HDD-CKD received 100 mg doses at 10 consecutive dialysis sessions until a cumulative dose of 1000 mg was administered. Patients with NDD-CKD received either 5 doses of 200 mg over 2 weeks or 2 doses of 500 mg separated by fourteen days, and patients with PDD-CKD received 2 doses of 300 mg followed by a dose of 400 mg over a period of 4 weeks.


* EPO=Erythropoietin

Adverse Reactions

(Preferred Term)

HDD-CKD NDD-CKD PDD-CKD
Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) Oral Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) EPO* Only
(N=231) (N=139) (N=139) (N=75) (N=46)
% % % % %
Subjects with any adverse reaction 78.8 76.3 73.4 72.0 65.2
Ear and Labyrinth Disorders
Ear Pain 0 2.2 0.7 0 0
Eye Disorders
Conjunctivitis 0.4 0 0 2.7 0
Gastrointestinal Disorders
Abdominal pain 3.5 1.4 2.9 4.0 6.5
Diarrhea 5.2 7.2 10.1 8.0 4.3
Dysgeusia 0.9 7.9 0 0 0
Nausea 14.7 8.6 12.2 5.3 4.3
Vomiting 9.1 5.0 8.6 8.0 2.2
General Disorders and
Administration Site Conditions
Asthenia 2.2 0.7 2.2 2.7 0
Chest pain 6.1 1.4 0 2.7 0
Feeling abnormal 3.0 0 0 0 0
Infusion site pain or burning 0 5.8 0 0 0
Injection site extravasation 0 2.2 0 0 0
Peripheral edema 2.6 7.2 5.0 5.3 10.9
Pyrexia 3.0 0.7 0.7 1.3 0
Infections and Infestations
Nasopharyngitis, Sinusitis, Upper

respiratory tract infections, Pharyngitis

2.6 2.2 4.3 16.0 4.3
Injury, Poisoning and Procedural
Complications
Graft complication 9.5 1.4 0 0 0
Metabolism and Nutrition Disorders
Fluid overload 3.0 1.4 0.7 1.3 0
Gout 0 2.9 1.4 0 0
Hyperglycemia 0 2.9 0 0 2.2
Hypoglycemia 0.4 0.7 0.7 4.0 0
Musculoskeletal and Connective
Tissue Disorders
Arthralgia 3.5 1.4 2.2 4.0 4.3
Back pain 2.2 2.2 3.6 1.3 4.3
Muscle cramp 29.4 0.7 0.7 2.7 0
Myalgia 0 3.6 0 1.3 0
Pain in extremity 5.6 4.3 0 2.7 6.5
Nervous System Disorders
Dizziness 6.5 6.5 1.4 1.3 4.3
Headache 12.6 2.9 0.7 4.0 0
Respiratory, Thoracic and
Mediastinal Disorders
Cough 3.0 2.2 0.7 1.3 0
Dyspnea 3.5 5.8 1.4 1.3 2.2
Nasal congestion 0 1.4 2.2 1.3 0
Skin and Subcutaneous
Tissue Disorders
Pruritus 3.9 2.2 4.3 2.7 0
Vascular Disorders
Hypertension 6.5 6.5 4.3 8.0 6.5
Hypotension 39.4 2.2 0.7 2.7 2.2

One hundred thirty (11%) of the 1,151 patients evaluated in the 4 U.S. trials in HDD-CKD patients (studies A, B and the two post marketing studies) had prior other intravenous Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) therapy and were reported to be intolerant (defined as precluding further use of that Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) product). When these patients were treated with Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) there were no occurrences of adverse reactions that precluded further use of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) .

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

In a randomized, open-label, dose-ranging trial for Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) maintenance treatment with Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) in pediatric patients with CKD on stable erythropoietin therapy , at least one treatment-emergent adverse reaction was experienced by 57% (27/47) of the patients receiving Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) 0.5 mg/kg, 53% (25/47) of the patients receiving Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) 1.0 mg/kg, and 55% (26/47) of the patients receiving Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) 2.0 mg/kg.

A total of 5 (11%) subjects in the Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) 0.5 mg/kg group, 10 (21%) patients in the Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) 1.0 mg/kg group, and 10 (21%) patients in the Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) 2.0 mg/kg group experienced at least 1 serious adverse reaction during the study. The most common treatment-emergent adverse reactions (> 2% of patients) in all patients were headache (6%), respiratory tract viral infection (4%), peritonitis (4%), vomiting (4%), pyrexia (4%), dizziness (4%), cough (4%), renal transplant (4%), nausea (3%), arteriovenous fistula thrombosis (2%), hypotension (2%), and hypertension (2.1%).

6.2 Adverse Reactions from Post-Marketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In the post-marketing safety studies in 1,051 treated patients with HDD-CKD, the adverse reactions reported by > 1% were: cardiac failure congestive, sepsis and dysgeusia.

The following adverse reactions have been identified during post-approval use of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Anaphylactic-type reactions, shock, loss of consciousness, collapse, bronchospasm, dyspnea, convulsions, light-headedness, confusion, angioedema, swelling of the joints, hyperhidrosis, back pain, bradycardia, and chromaturia.

Symptoms associated with Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) total dosage or infusing too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. These adverse reactions have occurred up to 30 minutes after the administration of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) injection. Reactions have occurred following the first dose or subsequent doses of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)). Symptoms may respond to intravenous fluids, hydrocortisone, and/or antihistamines. Slowing the infusion rate may alleviate symptoms.

Injection site discoloration has been reported following extravasation. Assure stable intravenous access to avoid extravasation.

7 DRUG INTERACTIONS

Drug interactions involving Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) have not been studied. However, Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) may reduce the absorption of concomitantly administered oral Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) preparations.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, Super Multi-Minerals Regular Strength ) sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) (half or equivalent to the maximum recommended human dose based on body surface area, respectively) and revealed no evidence of harm to the fetus due to Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) sucrose. Because animal reproductive studies are not always predictive of human response, Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) sucrose is excreted in human milk. Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) sucrose is secreted into the milk of lactating rats. Because many drugs are excreted in human milk, caution should be exercised when Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of Super Multi-Minerals Regular Strength ) for Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.

Safety and effectiveness of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) for Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) maintenance treatment in pediatric patients 2 years of age and older with dialysis-dependent or non-dialysis-dependent CKD receiving erythropoietin therapy were studied. Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) at doses of 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg was administered. All three doses maintained hemoglobin between 10.5 g/dL and 14.0 g/dL in about 50% of subjects over the 12-week treatment period with stable EPO dosing. [See Clinical Studies (14.6)]

Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) has not been studied in patients younger than 2 years of age.

In a country where Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) is available for use in children, at a single site, five premature infants (weight less than 1,250 g) developed necrotizing enterocolitis and two of the five died during or following a period when they received Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)), several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) or any other drugs could be established.

8.5 Geriatric Use

Clinical studies of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Of the 1,051 patients in two post-marketing safety studies of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)), 40% were 65 years and older. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose administration to an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

No data are available regarding overdosage of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) in humans. Excessive dosages of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) may lead to accumulation of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) in storage sites potentially leading to hemosiderosis. Do not administer Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) to patients with Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) overload.

Toxicities in single-dose studies in mice and rats, at intravenous Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) sucrose doses up to 8 times the maximum recommended human dose based on body surface area, included sedation, hypoactivity, pale eyes, bleeding in the gastrointestinal tract and lungs, and mortality.

11 DESCRIPTION

Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) (iron sucrose injection, USP), an Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) replacement product, is a brown, sterile, aqueous, complex of polynuclear Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) (III)-hydroxide in sucrose for intravenous use. Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) sucrose injection has a molecular weight of approximately 34,000 to 60,000 daltons and a proposed structural formula:

[Na2Fe5O8(OH) ·3(H2O)]n ·m(C12H22O11)

where: n is the degree of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) polymerization and m is the number of sucrose molecules associated with the Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) (III)-hydroxide.

Each mL contains 20 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) as Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) sucrose in water for injection. Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) is available in 10 mL single-use vials (200 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) per 10 mL), 5 mL single-use vials (100 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) per 5 mL), and 2.5 mL single-use vials (50 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) per 2.5 mL). The drug product contains approximately 30% sucrose w/v (300 mg/mL) and has a pH of 10.5 to 11.1. The product contains no preservatives. The osmolarity of the injection is 1,250 mOsmol/L.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Super Multi-Minerals Regular Strength ) is an aqueous complex of poly-nuclear Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) (III)-hydroxide in sucrose. Following intravenous administration, Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) is dissociated into Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) and sucrose and the Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) is transported as a complex with transferrin to target cells including erythroid precursor cells. The Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) in the precursor cells is incorporated into hemoglobin as the cells mature into red blood cells.

12.2 Pharmacodynamics

Following intravenous administration, Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) is dissociated into Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) and sucrose. In 22 patients undergoing hemodialysis and receiving erythropoietin (recombinant human erythropoietin) therapy treated with Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) sucrose containing 100 mg of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)), three times weekly for three weeks, significant increases in serum Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) and serum ferritin and significant decreases in total Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) binding capacity occurred four weeks from the initiation of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) sucrose treatment.

12.3 Pharmacokinetics

In healthy adults administered intravenous doses of Super Multi-Minerals Regular Strength ), its Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) component exhibited first order kinetics with an elimination half-life of 6 h, total clearance of 1.2 L/h, and steady state apparent volume of distribution of 7.9 L. The Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) containing 100 mg of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) labeled with 52Fe/59Fe in patients with Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) deficiency showed that a significant amount of the administered Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) trapping compartment.

Following intravenous administration of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)), Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) sucrose is dissociated into Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) containing 1,510 mg of sucrose and 100 mg of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) in 12 healthy adults (9 female, 3 male: age range 32 to 52), 68.3% of the sucrose was eliminated in urine in 4 h and 75.4% in 24 h. Some Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) was also eliminated in the urine. Neither transferrin nor transferrin receptor levels changed immediately after the dose administration. In this study and another study evaluating a single intravenous dose of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) sucrose containing 500 to 700 mg of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60), approximately 5% of the Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) have not been studied.

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

In a single-dose PK study of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)), patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)), the half-life of total serum Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) was 8 hours. The mean Cmax and AUC values were 8545 μg/dl and 31305 hr-μg/dL, respectively, which were 1.42- and 1.67-fold higher than dose adjusted adult Cmax and AUC values.

Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) sucrose in the dialysate fluid was below the levels of detection of the assay (less than 2 parts per million).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) sucrose.

Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.

Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) sucrose at intravenous doses up to 15 mg/kg/day of elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) (1.2 times the maximum recommended human dose based on body surface area) had no effect on fertility and reproductive function of male and female rats.

14 CLINICAL STUDIES

Five clinical trials involving 647 adult patients and one clinical trial involving 131 pediatric patients were conducted to assess the safety and efficacy of Super Multi-Minerals Regular Strength ).

14.1 Study A: Hemodialysis Dependent-Chronic Kidney Disease (HDD–CKD)

Study A was a multicenter, open-label, historically-controlled study in 101 patients with HDD-CKD (77 patients with Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) treatment and 24 in the historical control group) with Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) deficiency anemia. Eligibility criteria for Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) treatment included patients undergoing chronic hemodialysis, receiving erythropoietin, hemoglobin level between 8.0 and 11.0 g/dL, transferrin saturation < 20%, and serum ferritin < 300 ng/mL. The mean age of the patients was 65 years with the age range of 31 to 85 years. Of the 77 patients, 44 (57%) were male and 33 (43%) were female.

Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) 100 mg was administered at 10 consecutive dialysis sessions either as slow injection or a slow infusion. The historical control population consisted of 24 patients with similar ferritin levels as patients treated with Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)), who were off intravenous Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) for at least 2 weeks and who had received erythropoietin therapy with hematocrit averaging 31 to 36 for at least two months prior to study entry. The mean age of patients in the historical control group was 56 years, with an age range of 29 to 80 years. Patient age and serum ferritin level were similar between treatment and historical control patients.

Patients in the Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) treated population showed a greater increase in hemoglobin and hematocrit than did patients in the historical control population. See Table 2.


**p < 0.01 and *p < 0.05 compared to historical control from ANCOVA analysis with baseline hemoglobin, serum ferritin and erythropoietin dose as covariates.


Efficacy

parameters

End of treatment 2 week follow-up 5 week follow-up
Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) (n=69 Historical Control (n=18) Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate))

(n=73)

Historical Control

(n=18)

Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate))

(n=71)

Historical

Control

(n=15)

Hemoglobin (g/dL) 1.0 ± 0.12** 0.0 ± 0.21 1.3 ± 0.14** -0.6 ± 0.24 1.2 ± 0.17* -0.1 ± 0.23
Hematocrit (%) 3.1 ± 0.37** -0.3 ± 0.65 3.6 ± 0.44** -1.2 ± 0.76 3.3 ± 0.54 0.2 ± 0.86

Serum ferritin increased at endpoint of study from baseline in the Venofer-treated population (165.3 ± 24.2 ng/mL) compared to the historical control population (-27.6 ± 9.5 ng/mL). Transferrin saturation also increased at endpoint of study from baseline in the Venofer-treated population (8.8 ± 1.6%) compared to this historical control population (-5.1 ± 4.3%).

14.2 Study B: Hemodialysis Dependent-Chronic Kidney Disease

Study B was a multicenter, open label study of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) in 23 patients with Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) deficiency and HDD-CKD who had been discontinued from Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) dextran due to intolerance. Eligibility criteria were otherwise identical to Study A. The mean age of the patients in this study was 53 years, with ages ranging from 21 to 79 years. Of the 23 patients enrolled in the study, 10 (44%) were male and 13 (56%) were female.

All 23 enrolled patients were evaluated for efficacy. Increases in mean hemoglobin (1.1 ± 0.2 g/dL), hematocrit (3.6 ± 0.6%), serum ferritin (266.3 ± 30.3 ng/mL) and transferrin saturation (8.7 ± 2.0%) were observed from baseline to end of treatment.

14.3 Study C: Hemodialysis Dependent-Chronic Kidney Disease

Study C was a multicenter, open-label study in patients with HDD-CKD. This study enrolled patients with a hemoglobin ≤ 10 g/dL, a serum transferrin saturation ≤ 20%, and a serum ferritin ≤ 200 ng/mL, who were undergoing maintenance hemodialysis 2 to 3 times weekly. The mean age of the patients enrolled in this study was 41 years, with ages ranging from 16 to 70 years. Of 130 patients evaluated for efficacy in this study, 68 (52%) were male and 62 (48%) were female. Forty-eight percent of the patients had previously been treated with oral Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)). Exclusion criteria were similar to those in studies A and B. Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) was administered. A 50 mg dose (2.5 mL) was given to patients within two weeks of study entry as a test dose. Twenty-seven patients (20%) were receiving erythropoietin treatment at study entry and they continued to receive the same erythropoietin dose for the duration of the study.

The modified intention-to-treat (mITT) population consisted of 131 patients. Increases from baseline in mean hemoglobin (1.7 g/dL), hematocrit (5%), serum ferritin (434.6 ng/mL), and serum transferrin saturation (14%) were observed at week 2 of the observation period and these values remained increased at week 4 of the observation period.

14.4 Study D: Non-Dialysis Dependent-Chronic Kidney Disease

Study D was a randomized, open-label, multicenter, active-controlled study of the safety and efficacy of oral Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) versus Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) in patients with NDD-CKD with or without erythropoietin therapy. Erythropoietin therapy was stable for 8 weeks prior to randomization. In the study 188 patients with NDD-CKD, hemoglobin of ≤ 11.0 g/dL, transferrin saturation ≤ 25%, ferritin ≤ 300 ng/mL were randomized to receive oral Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) (325 mg ferrous sulfate three times daily for 56 days); or Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) (either 200 mg over 2 to 5 minutes 5 times within 14 days or two 500 mg infusions on Day 1 and Day 14, administered over 3.5 to 4 hours). The mean age of the 91 treated patients in the Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) group was 61.6 years (range 25 to 86 years) and 64 years (range 21 to 86 years) for the 91 patients in the oral Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) group.

A statistically significantly greater proportion of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) subjects (35/79; 44.3%) compared to oral Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) subjects (23/82; 28%) had an increase in hemoglobin ≥ 1 g/dL at anytime during the study (p = 0.03).

14.5 Study E: Peritoneal Dialysis Dependent-Chronic Kidney Disease

Study E was a randomized, open-label, multicenter study comparing patients with PDD-CKD receiving an erythropoietin and intravenous Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) to patients with PDD-CKD receiving an erythropoietin alone without Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) supplementation. Patients with PDD-CKD, stable erythropoietin for 8 weeks, hemoglobin of ≤ 11.5 g/dL, TSAT ≤ 25%, ferritin ≤ 500 ng/mL were randomized to receive either no Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) or Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) (300 mg in 250 mL 0.9% NaCl over 1.5 hours on Day 1 and 15 and 400 mg in 250 mL 0.9% NaCl over 2.5 hours on Day 29). The mean age of the 75 treated patients in the Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) / erythropoietin group was 51.9 years (range 21 to 81 years) vs. 52.8 years (range 23 to 77 years) for 46 patients in the erythropoietin alone group.

Patients in the Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) / erythropoietin group had statistically significantly greater mean change from baseline to the highest hemoglobin value (1.3 g/dL), compared to subjects who received erythropoietin alone (0.6 g/dL) (p < 0.01). A greater proportion of subjects treated with Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) / erythropoietin (59.1 %) had an increase in hemoglobin of ≥ 1 g/dL at any time during the study compared to the subjects who received erythropoietin only (33.3%).

14.6 Study F: Super Multi-Minerals Regular Strength ) Maintenance Treatment Dosing in Pediatric Patients Ages 2 years and Older with Chronic Kidney Disease

Study F was a randomized, open-label, dose-ranging study for Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) maintenance treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD on stable erythropoietin therapy. The study randomized patients to one of three doses of Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) (0.5 mg/kg, 1.0 mg/kg or 2.0 mg/kg). The mean age was 13 years (range 2 to 20 years). Over 70% of patients were 12 years or older in all three groups. There were 84 males and 61 females. About 60% of patients underwent hemodialysis and 25% underwent peritoneal dialysis in all three dose groups. At baseline, the mean hemoglobin was 12 g/dL, the mean TSAT was 33% and the mean ferritin was 300 ng/mL. Patients with HDD-CKD received Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) once every 4 weeks for 3 doses. Among 131 evaluable patients with stable erythropoietin dosing, the proportion of patients who maintained hemoglobin between 10.5 g/dL and 14.0 g/dL during the 12-week treatment period was 58.7%, 46.7%, and 45.0% in the Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg groups, respectively. A dose-response relationship was not demonstrated.

16 HOW SUPPLIED/storage and handling

16.1 How Supplied

Super Multi-Minerals Regular Strength ) is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)), each 5 mL vial contains 100 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)), and each 2.5 mL vial contains 50 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) (20 mg/mL).

NDC-0517-2310-05 200 mg/10 mL Single-Use Vial Packages of 5
NDC-0517-2310-10 200 mg/10 mL Single-Use Vial Packages of 10
NDC-0517-2340-01 100 mg/5 mL Single-Use Vial Individually Boxed
NDC-0517-2340-10 100 mg/5 mL Single-Use Vial Packages of 10
NDC-0517-2340-25 100 mg/5 mL Single-Use Vial Packages of 25
NDC-0517-2340-99 100 mg/5 mL Single-Use Vial Packages of 10
NDC-0517-2325-10 50 mg/2.5 mL Single-Use Vial Packages of 10
NDC-0517-2325-25 50 mg/2.5 mL Single-Use Vial Packages of 25

16.2 Stability and Storage

Contains no preservatives. Store in original carton at 20°C to 25°C (68° F to 77° F); excursions permitted to 15° to 30°C (59° to 86°F).. Do not freeze.

Syringe Stability: Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) per mL, or undiluted (20 mg elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) per mL) and stored in a plastic syringe, was found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C) and under refrigeration (4°C ± 2°C).

Intravenous Admixture Stability: Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)), when added to intravenous infusion bags (PVC or non-PVC) containing 0.9% NaCl at concentrations ranging from 1 mg to 2 mg of elemental Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) per mL, has been found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C).

Do not dilute to concentrations below 1 mg/mL.

Do not mix Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) with other medications or add to parenteral nutrition solutions for intravenous infusion.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to infusion.

17 PATIENT COUNSELING INFORMATION

Prior to Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) administration:

  • Question patients regarding any prior history of reactions to parenteral Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) products
  • Advise patients of the risks associated with Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate))
  • Advise patients to report any symptoms of hypersensitivity that may develop during and following Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) administration, such as rash, itching, dizziness, light-headedness, swelling, and breathing problems [see Warnings and Precautions (5)]

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Super Multi-Minerals Regular Strength (Iron (Ferrous Succinate)) is manufactured under license from Vifor (International) Inc., Switzerland.

PremierProRx® is a trademark of Premier, Inc., used under license.

PREMIERProRx®

IN2340

MG #15727

Magnesium (Magnesium Ascorbate):



Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) Sulfate

Injection, USP

Ansyr Plastic Syringe

Rx only

Hospira Logo

DESCRIPTION

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) Sulfate Injection, USP is a sterile solution of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) sulfate heptahydrate in Water for Injection, USP administered by the intravenous or intramuscular routes as an electrolyte replenisher or anticonvulsant. Must be diluted before intravenous use. May contain sulfuric acid and/or sodium hydroxide for pH adjustment. The pH is 5.5 to 7.0. The 50% concentration has an osmolarity of 4.06 mOsmol/mL (calc.).

The solution contains no bacteriostat, antimicrobial agent or added buffer (except for pH adjustment) and is intended only for use as a single-dose injection. When smaller doses are required the unused portion should be discarded with the entire unit.

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) Sulfate, USP heptahydrate is chemically designated MgSO4 - 7H2O with molecular weight of 246.48 and occurs as colorless crystals or white powder freely soluble in water.

The plastic syringe is molded from a specially formulated polypropylene. Water permeates from inside the container at an extremely slow rate which will have an insignificant effect on solution concentration over the expected shelf life. Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the syringe material.

CLINICAL PHARMACOLOGY

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) (Mg++) is an important cofactor for enzymatic reactions and plays an important role in neurochemical transmission and muscular excitability.

As a nutritional adjunct in hyperalimentation, the precise mechanism of action for Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) is uncertain. Early symptoms of hypomagnesemia (less than 1.5 mEq/liter) may develop as early as three to four days or within weeks.

Predominant deficiency effects are neurological, e.g., muscle irritability, clonic twitching and tremors. Hypocalcemia and hypokalemia often follow low serum levels of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)). While there are large stores of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) present intracellularly and in the bones of adults, these stores often are not mobilized sufficiently to maintain plasma levels. Parenteral Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) therapy repairs the plasma deficit and causes deficiency symptoms and signs to cease.

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) prevents or controls convulsions by blocking neuromuscular transmission and decreasing the amount of acetylcholine liberated at the end plate by the motor nerve impulse. Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) is said to have a depressant effect on the central nervous system (CNS), but it does not adversely affect the woman, fetus or neonate when used as directed in eclampsia or pre-eclampsia. Normal plasma Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) levels range from 1.5 to 2.5 mEq/liter.

As plasma Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) rises above 4 mEq/liter, the deep tendon reflexes are first decreased and then disappear as the plasma level approaches 10 mEq/liter. At this level respiratory paralysis may occur. Heart block also may occur at this or lower plasma levels of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)). Serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) concentrations in excess of 12 mEq/L may be fatal.

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) acts peripherally to produce vasodilation. With low doses only flushing and sweating occur, but larger doses cause lowering of blood pressure. The central and peripheral effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) poisoning are antagonized to some extent by intravenous administration of calcium.

Pharmacokinetics

With intravenous administration the onset of anticonvulsant action is immediate and lasts about 30 minutes. Following intramuscular administration the onset of action occurs in about one hour and persists for three to four hours. Effective anticonvulsant serum levels range from 2.5 to 7.5 mEq/liter. Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) is excreted solely by the kidneys at a rate proportional to the plasma concentration and glomerular filtration.

INDICATIONS AND USAGE

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) Sulfate Injection, USP is suitable for replacement therapy in Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) deficiency, especially in acute hypomagnesemia accompanied by signs of tetany similar to those observed in hypocalcemia. In such cases, the serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) (Mg++) level is usually below the lower limit of normal (1.5 to 2.5 mEq/liter) and the serum calcium (Ca++) level is normal (4.3 to 5.3 mEq/liter) or elevated.

In total parenteral nutrition (TPN), Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) sulfate may be added to the nutrient admixture to correct or prevent hypomagnesemia which can arise during the course of therapy.

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) Sulfate Injection, USP is also indicated for the prevention and control of seizures (convulsions) in pre-eclampsia and eclampsia, respectively.

CONTRAINDICATIONS

Parenteral administration of the drug is contraindicated in patients with heart block or myocardial damage.

WARNINGS

FETAL HARM: Continuous administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) sulfate beyond 5 to 7 days to pregnant women can lead to hypocalcemia and bone abnormalities in the developing fetus. These bone abnormalities include skeletal demineralization and osteopenia. In addition, cases of neonatal fracture have been reported. The shortest duration of treatment that can lead to fetal harm is not known. Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) sulfate should be used during pregnancy only if clearly needed. If Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) sulfate is given for treatment of preterm labor, the woman should be informed that the efficacy and safety of such use have not been established and that use of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) sulfate beyond 5 to 7 days may cause fetal abnormalities.

ALUMINUM TOXICITY: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

Parenteral use in the presence of renal insufficiency may lead to Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) intoxication. Intravenous use in the eclampsia should be reserved for immediate control of life-threatening convulsions.

PRECAUTIONS

General

Administer with caution if flushing and sweating occurs. When barbiturates, narcotics or other hypnotics (or systemic anesthetics) are to be given in conjunction with Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)), their dosage should be adjusted with caution because of additive CNS depressant effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)).

Because Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) is removed from the body solely by the kidneys, the drug should be used with caution in patients with renal impairment. Urine output should be maintained at a level of 100 mL or more during the four hours preceding each dose. Monitoring serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) levels and the patient's clinical status is essential to avoid the consequences of overdosage in toxemia. Clinical indications of a safe dosage regimen include the presence of the patellar reflex (knee jerk) and absence of respiratory depression (approximately 16 breaths or more/minute). When repeated doses of the drug are given parenterally, knee jerk reflexes should be tested before each dose and if they are absent, no additional Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) should be given until they return. Serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) levels usually sufficient to control convulsions range from 3 to 6 mg/100 mL (2.5 to 5 mEq/liter). The strength of the deep tendon reflexes begins to diminish when Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) levels exceed 4 mEq/liter. Reflexes may be absent at 10 mEq magnesium/liter, where respiratory paralysis is a potential hazard. An injectable calcium salt should be immediately available to counteract the potential hazards of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) intoxication in eclampsia.

50% Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) Sulfate Injection, USP must be diluted to a concentration of 20% or less prior to intravenous infusion. Rate of administration should be slow and cautious, to avoid producing hypermagnesemia. The 50% solution also should be diluted to 20% or less for intramuscular injection in infants and children.

Laboratory Tests

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) sulfate injection should not be given unless hypomagnesemia has been confirmed and the serum concentration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) is monitored. The normal serum level is 1.5 to 2.5 mEq/L.

Drug Interactions

CNS Depressants - When barbiturates, narcotics or other hypnotics (or systemic anesthetics), or other CNS depressants are to be given in conjunction with Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)), their dosage should be adjusted with caution because of additive CNS depressant effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)). CNS depression and peripheral transmission defects produced by Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) may be antagonized by calcium.

Neuromuscular Blocking Agents - Excessive neuromuscular block has occurred in patients receiving parenteral Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) sulfate and a neuromuscular blocking agent; these drugs should be administered concomitantly with caution.

Cardiac Glycosides - Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) sulfate should be administered with extreme caution in digitalized patients, because serious changes in cardiac conduction which can result in heart block may occur if administration of calcium is required to treat Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) toxicity.

Pregnancy

Teratogenic Effects

Pregnancy Category D (See WARNINGS and PRECAUTIONS )

See WARNINGS and PRECAUTIONS .

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) sulfate can cause fetal abnormalities when administered beyond 5 to 7 days to pregnant women. There are retrospective epidemiological studies and case reports documenting fetal abnormalities such as hypocalcemia, skeletal demineralization, osteopenia and other skeletal abnormalities with continuous maternal administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) sulfate for more than 5 to 7 days.1-10 Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) sulfate injection should be used during pregnancy only if clearly needed. If this drug is used during pregnancy, the woman should be apprised of the potential harm to the fetus.

Nonteratogenic Effects

When administered by continuous intravenous infusion (especially for more than 24 hours preceding delivery) to control convulsions in a toxemic woman, the newborn may show signs of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) toxicity, including neuromuscular or respiratory depression (See OVERDOSAGE ).

Labor and Delivery

Continuous administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) sulfate is an unapproved treatment for preterm labor. The safety and efficacy of such use have not been established. The administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) sulfate outside of its approved indication in pregnant women should be by trained obstetrical personnel in a hospital setting with appropriate obstetrical care facilities.

Nursing Mothers

Since Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) is distributed into milk during parenteral Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) sulfate administration, the drug should be used with caution in nursing women.

Geriatrics

Geriatric patients often require reduced dosage because of impaired renal function. In patients with severe impairment, dosage should not exceed 20 grams in 48 hours. Serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) should be monitored in such patients.

ADVERSE REACTIONS

The adverse effects of parenterally administered Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) usually are the result of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) intoxication. These include flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, cardiac and central nervous system depression proceeding to respiratory paralysis. Hypocalcemia with signs of tetany secondary to Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) sulfate therapy for eclampsia has been reported.

OVERDOSAGE

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) intoxication is manifested by a sharp drop in blood pressure and respiratory paralysis. Disappearance of the patellar reflex is a useful clinical sign to detect the onset of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) intoxication. In the event of overdosage, artificial ventilation must be provided until a calcium salt can be injected intravenously to antagonize the effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)).

For Treatment of Overdose

Artificial respiration is often required. Intravenous calcium, 10 to 20 mL of a 5% solution (diluted if desirable with isotonic sodium chloride for injection) is used to counteract effects of hypermagnesemia. Subcutaneous physostigmine, 0.5 to 1 mg may be helpful.

Hypermagnesemia in the newborn may require resuscitation and assisted ventilation via endotracheal intubation or intermittent positive pressure ventilation as well as intravenous calcium.

DOSAGE AND ADMINISTRATION

Dosage of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) sulfate must be carefully adjusted according to individual requirements and response, and administration of the drug should be discontinued as soon as the desired effect is obtained.

Both intravenous and intramuscular administration are appropriate. Intramuscular administration of the undiluted 50% solution results in therapeutic plasma levels in 60 minutes, whereas intravenous doses will provide a therapeutic level almost immediately. The rate of intravenous injection should generally not exceed 150 mg/minute (1.5 mL of a 10% concentration or its equivalent), except in severe eclampsia with seizures. Continuous maternal administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

Solutions for intravenous infusion must be diluted to a concentration of 20% or less prior to administration. The diluents commonly used are 5% Dextrose Injection, USP and 0.9% Sodium Chloride Injection, USP. Deep intramuscular injection of the undiluted (50%) solution is appropriate for adults, but the solution should be diluted to a 20% or less concentration prior to such injection in children.

In Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) Deficiency

In the treatment of mild Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) deficiency, the usual adult dose is 1 gram, equivalent to 8.12 mEq of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) (2 mL of the 50% solution) injected intramuscularly every six hours for four doses (equivalent to a total of 32.5 mEq of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) per 24 hours). For severe hypomagnesemia, as much as 250 mg (approximately 2 mEq) per kg of body weight (0.5 mL of the 50% solution) may be given intramuscularly within a period of four hours if necessary. Alternatively, 5 grams, (approximately 40 mEq) can be added to one liter of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP for slow intravenous infusion over a three-hour period. In the treatment of deficiency states, caution must be observed to prevent exceeding the renal excretory capacity.

In Hyperalimentation

In total parenteral nutrition, maintenance requirements for Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) are not precisely known. The maintenance dose used in adults ranges from 8 to 24 mEq (1 gram to 3 grams) daily; for infants, the range is 2 to 10 mEq (0.25 gram to 1.25 grams) daily.

In Pre-eclampsia or Eclampsia

In severe pre-eclampsia or eclampsia, the total initial dose is 10 grams to 14 grams of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) sulfate. Intravenously, a dose of 4 grams to 5 grams in 250 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP may be infused. Simultaneously, intramuscular doses of up to 10 grams (5 grams or 10 mL of the undiluted 50% solution in each buttock) are given. Alternatively, the initial intravenous dose of 4 grams may be given by diluting the 50% solution to a 10 or 20% concentration; the diluted fluid (40 mL of a 10% solution or 20 mL of a 20% solution) may then be injected intravenously over a period of three to four minutes. Subsequently, 4 grams to 5 grams (8 to 10 mL of the 50% solution) are injected intramuscularly into alternate buttocks every four hours as needed, depending on the continuing presence of the patellar reflex and adequate respiratory function. Alternatively, after the initial intravenous dose, some clinicians administer 1 gram to 2 grams/hour by constant intravenous infusion. Therapy should continue until paroxysms cease. A serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) level of 6 mg/100 mL is considered optimal for control of seizures. A total daily (24 hr) dose of 30 grams to 40 grams should not be exceeded. In the presence of severe renal insufficiency, the maximum dosage of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) sulfate is 20 grams/48 hours and frequent serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) concentrations must be obtained. Continuous use of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

Other Uses

In counteracting the muscle-stimulating effects of barium poisoning, the usual dose of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) sulfate is 1 gram to 2 grams given intravenously.

For controlling seizures associated with epilepsy, glomerulonephritis or hypothyroidism, the usual adult dose is 1 gram administered intramuscularly or intravenously.

In paroxysmal atrial tachycardia, Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) should be used only if simpler measures have failed and there is no evidence of myocardial damage. The usual dose is 3 grams to 4 grams (30 to 40 mL of a 10% solution) administered intravenously over 30 seconds with extreme caution.

For reduction of cerebral edema, 2.5 grams (25 mL of a 10% solution) is given intravenously.

Incompatibilities

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) sulfate in solution may result in a precipitate formation when mixed with solutions containing:

Alcohol (in high Heavy Metals

concentrations) Hydrocortisone sodium

Alkali carbonates and succinate

bicarbonates Phosphates

Alkali hydroxides Polymixin B sulfate

Arsenates Procaine hydrochloride

Barium Salicylates

Calcium Strontium

Clindamycin phosphate Tartrates

The potential incompatibility will often be influenced by the changes in the concentration of reactants and the pH of the solutions.

It has been reported that Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) may reduce the antibiotic activity of streptomycin, tetracycline and tobramycin when given together.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

HOW SUPPLIED

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) Sulfate Injection, USP is supplied in single-dose containers as follows:


NDC No.


Container


Total

Amount


Concentration


mEq

Mg++/mL


0409-1754-10


Ansyr

Plastic Syringe


5 g/10 mL


50%


4 mEq/mL


Do not administer unless solution is clear and container is undamaged. Discard unused portion.

Store at 20 to 25°C (68 to 77°F).

REFERENCES

  • Yokoyama K, Takahashi N, Yada Y. Prolonged maternal Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) administration and bone metabolism in neonates. Early Hum Dev. 2010;86(3):187-91. Epub 2010 Mar 12.
  • Wedig KE, Kogan J, Schorry EK et al. Skeletal demineralization and fractures caused by fetal Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) toxicity. J. Perinatol. 2006; 26(6):371-4.
  • Nassar AH, Sakhel K, Maarouf H, et al. Adverse maternal and neonatal outcome of prolonged course of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) sulfate tocolysis. Acta Obstet Gynecol Scan. 2006;85(9):1099-103.
  • Malaeb SN, Rassi A, Haddad MC. Bone mineralization in newborns whose mothers received Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) sulphate for tocolysis of premature labor. Pediatr Radiol. 2004;34(5):384-6. Epub 2004 Feb 18.
  • Matsuda Y, Maeda Y, Ito M, et al. Effect of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) sulfate treatment on neonatal bone abnormalities. Gynecol Obstet Invest. 1997;44(2):82-8.
  • Schanler RJ, Smith LG, Burns PA. Effects of long-term maternal intravenous Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) sulfate therapy on neonatal calcium metabolism and bone mineral content. Gynecol Obstet Invest. 1997;43(4):236-41.
  • Santi MD, Henry GW, Douglas GL. Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) sulfate treatment of preterm labor as a cause of abnormal neonatal bone mineralization. J Pediatr Orthrop. 1994;14(2):249-53.
  • Holcomb WL, Shackelford GD, Petrie RH. Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) tocolysis and neonatal bone abnormalities; a controlled study. Obstet Gynecol. 1991; 78(4):611-4.
  • Cumming WA, Thomas VJ. Hypermagnesemia: a cause of abnormal metaphyses in the neonate. Am J Roentgenol. 1989; 152(5):1071-2.
  • Lamm CL, Norton KL, Murphy RJ. Congenital rickets associated with Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) sulfate infusion for tocolysis. J Pediatr. 1988; 113(6):1078-82.
  • McGuinness GA, Weinstein MM, Cruikshank DP, et al. Effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) sulfate treatment on perinatal calcium metabolism. II. Neonatal responses. Obstet Gynecol. 1980; 56(5): 595-600.
  • Riaz M, Porat R, Brodsky NL, et al. The effects of maternal Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) sulfate treatment on newborns: a prospective controlled study. J. Perinatol. 1998;18(6 pt 1):449-54.

Hospira, Inc., Lake Forest, IL 60045 USA

LAB-1024-1.0

April 2017

Hospira Logo

50% Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) Sulfate 5 g/10 mL (500 mg/mL)

Rx only

NDC 0409-1754-10

10 mL Single-dose syringe

50% Super Multi-Minerals Regular Strength (Magnesium (Magnesium Ascorbate)) Sulfate Injection, USP

5 g/10 mL (500 mg/mL) (4 mEq Mg++/mL)

MUST BE DILUTED FOR INTRAVENOUS USE.

For Intravenous or Intramuscular Use. Sterile. 4.06 mOsmol/mL (calc.).

Contains no more than 75 mcg/L of aluminum.

Hospira, Inc., Lake Forest, IL 60045 USA

Hospira

RL-6891

Magnesium (Magnesium Citrate):



Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) Sulfate

Injection, USP

Ansyr Plastic Syringe

Rx only

Hospira Logo

DESCRIPTION

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) Sulfate Injection, USP is a sterile solution of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) sulfate heptahydrate in Water for Injection, USP administered by the intravenous or intramuscular routes as an electrolyte replenisher or anticonvulsant. Must be diluted before intravenous use. May contain sulfuric acid and/or sodium hydroxide for pH adjustment. The pH is 5.5 to 7.0. The 50% concentration has an osmolarity of 4.06 mOsmol/mL (calc.).

The solution contains no bacteriostat, antimicrobial agent or added buffer (except for pH adjustment) and is intended only for use as a single-dose injection. When smaller doses are required the unused portion should be discarded with the entire unit.

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) Sulfate, USP heptahydrate is chemically designated MgSO4 - 7H2O with molecular weight of 246.48 and occurs as colorless crystals or white powder freely soluble in water.

The plastic syringe is molded from a specially formulated polypropylene. Water permeates from inside the container at an extremely slow rate which will have an insignificant effect on solution concentration over the expected shelf life. Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the syringe material.

CLINICAL PHARMACOLOGY

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) (Mg++) is an important cofactor for enzymatic reactions and plays an important role in neurochemical transmission and muscular excitability.

As a nutritional adjunct in hyperalimentation, the precise mechanism of action for Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) is uncertain. Early symptoms of hypomagnesemia (less than 1.5 mEq/liter) may develop as early as three to four days or within weeks.

Predominant deficiency effects are neurological, e.g., muscle irritability, clonic twitching and tremors. Hypocalcemia and hypokalemia often follow low serum levels of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)). While there are large stores of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) present intracellularly and in the bones of adults, these stores often are not mobilized sufficiently to maintain plasma levels. Parenteral Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) therapy repairs the plasma deficit and causes deficiency symptoms and signs to cease.

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) prevents or controls convulsions by blocking neuromuscular transmission and decreasing the amount of acetylcholine liberated at the end plate by the motor nerve impulse. Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) is said to have a depressant effect on the central nervous system (CNS), but it does not adversely affect the woman, fetus or neonate when used as directed in eclampsia or pre-eclampsia. Normal plasma Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) levels range from 1.5 to 2.5 mEq/liter.

As plasma Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) rises above 4 mEq/liter, the deep tendon reflexes are first decreased and then disappear as the plasma level approaches 10 mEq/liter. At this level respiratory paralysis may occur. Heart block also may occur at this or lower plasma levels of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)). Serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) concentrations in excess of 12 mEq/L may be fatal.

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) acts peripherally to produce vasodilation. With low doses only flushing and sweating occur, but larger doses cause lowering of blood pressure. The central and peripheral effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) poisoning are antagonized to some extent by intravenous administration of calcium.

Pharmacokinetics

With intravenous administration the onset of anticonvulsant action is immediate and lasts about 30 minutes. Following intramuscular administration the onset of action occurs in about one hour and persists for three to four hours. Effective anticonvulsant serum levels range from 2.5 to 7.5 mEq/liter. Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) is excreted solely by the kidneys at a rate proportional to the plasma concentration and glomerular filtration.

INDICATIONS AND USAGE

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) Sulfate Injection, USP is suitable for replacement therapy in Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) deficiency, especially in acute hypomagnesemia accompanied by signs of tetany similar to those observed in hypocalcemia. In such cases, the serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) (Mg++) level is usually below the lower limit of normal (1.5 to 2.5 mEq/liter) and the serum calcium (Ca++) level is normal (4.3 to 5.3 mEq/liter) or elevated.

In total parenteral nutrition (TPN), Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) sulfate may be added to the nutrient admixture to correct or prevent hypomagnesemia which can arise during the course of therapy.

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) Sulfate Injection, USP is also indicated for the prevention and control of seizures (convulsions) in pre-eclampsia and eclampsia, respectively.

CONTRAINDICATIONS

Parenteral administration of the drug is contraindicated in patients with heart block or myocardial damage.

WARNINGS

FETAL HARM: Continuous administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) sulfate beyond 5 to 7 days to pregnant women can lead to hypocalcemia and bone abnormalities in the developing fetus. These bone abnormalities include skeletal demineralization and osteopenia. In addition, cases of neonatal fracture have been reported. The shortest duration of treatment that can lead to fetal harm is not known. Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) sulfate should be used during pregnancy only if clearly needed. If Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) sulfate is given for treatment of preterm labor, the woman should be informed that the efficacy and safety of such use have not been established and that use of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) sulfate beyond 5 to 7 days may cause fetal abnormalities.

ALUMINUM TOXICITY: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

Parenteral use in the presence of renal insufficiency may lead to Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) intoxication. Intravenous use in the eclampsia should be reserved for immediate control of life-threatening convulsions.

PRECAUTIONS

General

Administer with caution if flushing and sweating occurs. When barbiturates, narcotics or other hypnotics (or systemic anesthetics) are to be given in conjunction with Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)), their dosage should be adjusted with caution because of additive CNS depressant effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)).

Because Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) is removed from the body solely by the kidneys, the drug should be used with caution in patients with renal impairment. Urine output should be maintained at a level of 100 mL or more during the four hours preceding each dose. Monitoring serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) levels and the patient's clinical status is essential to avoid the consequences of overdosage in toxemia. Clinical indications of a safe dosage regimen include the presence of the patellar reflex (knee jerk) and absence of respiratory depression (approximately 16 breaths or more/minute). When repeated doses of the drug are given parenterally, knee jerk reflexes should be tested before each dose and if they are absent, no additional Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) should be given until they return. Serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) levels usually sufficient to control convulsions range from 3 to 6 mg/100 mL (2.5 to 5 mEq/liter). The strength of the deep tendon reflexes begins to diminish when Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) levels exceed 4 mEq/liter. Reflexes may be absent at 10 mEq magnesium/liter, where respiratory paralysis is a potential hazard. An injectable calcium salt should be immediately available to counteract the potential hazards of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) intoxication in eclampsia.

50% Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) Sulfate Injection, USP must be diluted to a concentration of 20% or less prior to intravenous infusion. Rate of administration should be slow and cautious, to avoid producing hypermagnesemia. The 50% solution also should be diluted to 20% or less for intramuscular injection in infants and children.

Laboratory Tests

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) sulfate injection should not be given unless hypomagnesemia has been confirmed and the serum concentration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) is monitored. The normal serum level is 1.5 to 2.5 mEq/L.

Drug Interactions

CNS Depressants - When barbiturates, narcotics or other hypnotics (or systemic anesthetics), or other CNS depressants are to be given in conjunction with Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)), their dosage should be adjusted with caution because of additive CNS depressant effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)). CNS depression and peripheral transmission defects produced by Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) may be antagonized by calcium.

Neuromuscular Blocking Agents - Excessive neuromuscular block has occurred in patients receiving parenteral Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) sulfate and a neuromuscular blocking agent; these drugs should be administered concomitantly with caution.

Cardiac Glycosides - Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) sulfate should be administered with extreme caution in digitalized patients, because serious changes in cardiac conduction which can result in heart block may occur if administration of calcium is required to treat Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) toxicity.

Pregnancy

Teratogenic Effects

Pregnancy Category D (See WARNINGS and PRECAUTIONS )

See WARNINGS and PRECAUTIONS .

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) sulfate can cause fetal abnormalities when administered beyond 5 to 7 days to pregnant women. There are retrospective epidemiological studies and case reports documenting fetal abnormalities such as hypocalcemia, skeletal demineralization, osteopenia and other skeletal abnormalities with continuous maternal administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) sulfate for more than 5 to 7 days.1-10 Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) sulfate injection should be used during pregnancy only if clearly needed. If this drug is used during pregnancy, the woman should be apprised of the potential harm to the fetus.

Nonteratogenic Effects

When administered by continuous intravenous infusion (especially for more than 24 hours preceding delivery) to control convulsions in a toxemic woman, the newborn may show signs of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) toxicity, including neuromuscular or respiratory depression (See OVERDOSAGE ).

Labor and Delivery

Continuous administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) sulfate is an unapproved treatment for preterm labor. The safety and efficacy of such use have not been established. The administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) sulfate outside of its approved indication in pregnant women should be by trained obstetrical personnel in a hospital setting with appropriate obstetrical care facilities.

Nursing Mothers

Since Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) is distributed into milk during parenteral Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) sulfate administration, the drug should be used with caution in nursing women.

Geriatrics

Geriatric patients often require reduced dosage because of impaired renal function. In patients with severe impairment, dosage should not exceed 20 grams in 48 hours. Serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) should be monitored in such patients.

ADVERSE REACTIONS

The adverse effects of parenterally administered Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) usually are the result of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) intoxication. These include flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, cardiac and central nervous system depression proceeding to respiratory paralysis. Hypocalcemia with signs of tetany secondary to Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) sulfate therapy for eclampsia has been reported.

OVERDOSAGE

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) intoxication is manifested by a sharp drop in blood pressure and respiratory paralysis. Disappearance of the patellar reflex is a useful clinical sign to detect the onset of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) intoxication. In the event of overdosage, artificial ventilation must be provided until a calcium salt can be injected intravenously to antagonize the effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)).

For Treatment of Overdose

Artificial respiration is often required. Intravenous calcium, 10 to 20 mL of a 5% solution (diluted if desirable with isotonic sodium chloride for injection) is used to counteract effects of hypermagnesemia. Subcutaneous physostigmine, 0.5 to 1 mg may be helpful.

Hypermagnesemia in the newborn may require resuscitation and assisted ventilation via endotracheal intubation or intermittent positive pressure ventilation as well as intravenous calcium.

DOSAGE AND ADMINISTRATION

Dosage of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) sulfate must be carefully adjusted according to individual requirements and response, and administration of the drug should be discontinued as soon as the desired effect is obtained.

Both intravenous and intramuscular administration are appropriate. Intramuscular administration of the undiluted 50% solution results in therapeutic plasma levels in 60 minutes, whereas intravenous doses will provide a therapeutic level almost immediately. The rate of intravenous injection should generally not exceed 150 mg/minute (1.5 mL of a 10% concentration or its equivalent), except in severe eclampsia with seizures. Continuous maternal administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

Solutions for intravenous infusion must be diluted to a concentration of 20% or less prior to administration. The diluents commonly used are 5% Dextrose Injection, USP and 0.9% Sodium Chloride Injection, USP. Deep intramuscular injection of the undiluted (50%) solution is appropriate for adults, but the solution should be diluted to a 20% or less concentration prior to such injection in children.

In Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) Deficiency

In the treatment of mild Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) deficiency, the usual adult dose is 1 gram, equivalent to 8.12 mEq of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) (2 mL of the 50% solution) injected intramuscularly every six hours for four doses (equivalent to a total of 32.5 mEq of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) per 24 hours). For severe hypomagnesemia, as much as 250 mg (approximately 2 mEq) per kg of body weight (0.5 mL of the 50% solution) may be given intramuscularly within a period of four hours if necessary. Alternatively, 5 grams, (approximately 40 mEq) can be added to one liter of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP for slow intravenous infusion over a three-hour period. In the treatment of deficiency states, caution must be observed to prevent exceeding the renal excretory capacity.

In Hyperalimentation

In total parenteral nutrition, maintenance requirements for Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) are not precisely known. The maintenance dose used in adults ranges from 8 to 24 mEq (1 gram to 3 grams) daily; for infants, the range is 2 to 10 mEq (0.25 gram to 1.25 grams) daily.

In Pre-eclampsia or Eclampsia

In severe pre-eclampsia or eclampsia, the total initial dose is 10 grams to 14 grams of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) sulfate. Intravenously, a dose of 4 grams to 5 grams in 250 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP may be infused. Simultaneously, intramuscular doses of up to 10 grams (5 grams or 10 mL of the undiluted 50% solution in each buttock) are given. Alternatively, the initial intravenous dose of 4 grams may be given by diluting the 50% solution to a 10 or 20% concentration; the diluted fluid (40 mL of a 10% solution or 20 mL of a 20% solution) may then be injected intravenously over a period of three to four minutes. Subsequently, 4 grams to 5 grams (8 to 10 mL of the 50% solution) are injected intramuscularly into alternate buttocks every four hours as needed, depending on the continuing presence of the patellar reflex and adequate respiratory function. Alternatively, after the initial intravenous dose, some clinicians administer 1 gram to 2 grams/hour by constant intravenous infusion. Therapy should continue until paroxysms cease. A serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) level of 6 mg/100 mL is considered optimal for control of seizures. A total daily (24 hr) dose of 30 grams to 40 grams should not be exceeded. In the presence of severe renal insufficiency, the maximum dosage of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) sulfate is 20 grams/48 hours and frequent serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) concentrations must be obtained. Continuous use of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

Other Uses

In counteracting the muscle-stimulating effects of barium poisoning, the usual dose of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) sulfate is 1 gram to 2 grams given intravenously.

For controlling seizures associated with epilepsy, glomerulonephritis or hypothyroidism, the usual adult dose is 1 gram administered intramuscularly or intravenously.

In paroxysmal atrial tachycardia, Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) should be used only if simpler measures have failed and there is no evidence of myocardial damage. The usual dose is 3 grams to 4 grams (30 to 40 mL of a 10% solution) administered intravenously over 30 seconds with extreme caution.

For reduction of cerebral edema, 2.5 grams (25 mL of a 10% solution) is given intravenously.

Incompatibilities

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) sulfate in solution may result in a precipitate formation when mixed with solutions containing:

Alcohol (in high Heavy Metals

concentrations) Hydrocortisone sodium

Alkali carbonates and succinate

bicarbonates Phosphates

Alkali hydroxides Polymixin B sulfate

Arsenates Procaine hydrochloride

Barium Salicylates

Calcium Strontium

Clindamycin phosphate Tartrates

The potential incompatibility will often be influenced by the changes in the concentration of reactants and the pH of the solutions.

It has been reported that Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) may reduce the antibiotic activity of streptomycin, tetracycline and tobramycin when given together.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

HOW SUPPLIED

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) Sulfate Injection, USP is supplied in single-dose containers as follows:


NDC No.


Container


Total

Amount


Concentration


mEq

Mg++/mL


0409-1754-10


Ansyr

Plastic Syringe


5 g/10 mL


50%


4 mEq/mL


Do not administer unless solution is clear and container is undamaged. Discard unused portion.

Store at 20 to 25°C (68 to 77°F).

REFERENCES

  • Yokoyama K, Takahashi N, Yada Y. Prolonged maternal Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) administration and bone metabolism in neonates. Early Hum Dev. 2010;86(3):187-91. Epub 2010 Mar 12.
  • Wedig KE, Kogan J, Schorry EK et al. Skeletal demineralization and fractures caused by fetal Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) toxicity. J. Perinatol. 2006; 26(6):371-4.
  • Nassar AH, Sakhel K, Maarouf H, et al. Adverse maternal and neonatal outcome of prolonged course of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) sulfate tocolysis. Acta Obstet Gynecol Scan. 2006;85(9):1099-103.
  • Malaeb SN, Rassi A, Haddad MC. Bone mineralization in newborns whose mothers received Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) sulphate for tocolysis of premature labor. Pediatr Radiol. 2004;34(5):384-6. Epub 2004 Feb 18.
  • Matsuda Y, Maeda Y, Ito M, et al. Effect of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) sulfate treatment on neonatal bone abnormalities. Gynecol Obstet Invest. 1997;44(2):82-8.
  • Schanler RJ, Smith LG, Burns PA. Effects of long-term maternal intravenous Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) sulfate therapy on neonatal calcium metabolism and bone mineral content. Gynecol Obstet Invest. 1997;43(4):236-41.
  • Santi MD, Henry GW, Douglas GL. Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) sulfate treatment of preterm labor as a cause of abnormal neonatal bone mineralization. J Pediatr Orthrop. 1994;14(2):249-53.
  • Holcomb WL, Shackelford GD, Petrie RH. Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) tocolysis and neonatal bone abnormalities; a controlled study. Obstet Gynecol. 1991; 78(4):611-4.
  • Cumming WA, Thomas VJ. Hypermagnesemia: a cause of abnormal metaphyses in the neonate. Am J Roentgenol. 1989; 152(5):1071-2.
  • Lamm CL, Norton KL, Murphy RJ. Congenital rickets associated with Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) sulfate infusion for tocolysis. J Pediatr. 1988; 113(6):1078-82.
  • McGuinness GA, Weinstein MM, Cruikshank DP, et al. Effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) sulfate treatment on perinatal calcium metabolism. II. Neonatal responses. Obstet Gynecol. 1980; 56(5): 595-600.
  • Riaz M, Porat R, Brodsky NL, et al. The effects of maternal Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) sulfate treatment on newborns: a prospective controlled study. J. Perinatol. 1998;18(6 pt 1):449-54.

Hospira, Inc., Lake Forest, IL 60045 USA

LAB-1024-1.0

April 2017

Hospira Logo

50% Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) Sulfate 5 g/10 mL (500 mg/mL)

Rx only

NDC 0409-1754-10

10 mL Single-dose syringe

50% Super Multi-Minerals Regular Strength (Magnesium (Magnesium Citrate)) Sulfate Injection, USP

5 g/10 mL (500 mg/mL) (4 mEq Mg++/mL)

MUST BE DILUTED FOR INTRAVENOUS USE.

For Intravenous or Intramuscular Use. Sterile. 4.06 mOsmol/mL (calc.).

Contains no more than 75 mcg/L of aluminum.

Hospira, Inc., Lake Forest, IL 60045 USA

Hospira

RL-6891

Magnesium (Magnesium Fumarate):



Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) Sulfate

Injection, USP

Ansyr Plastic Syringe

Rx only

Hospira Logo

DESCRIPTION

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) Sulfate Injection, USP is a sterile solution of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) sulfate heptahydrate in Water for Injection, USP administered by the intravenous or intramuscular routes as an electrolyte replenisher or anticonvulsant. Must be diluted before intravenous use. May contain sulfuric acid and/or sodium hydroxide for pH adjustment. The pH is 5.5 to 7.0. The 50% concentration has an osmolarity of 4.06 mOsmol/mL (calc.).

The solution contains no bacteriostat, antimicrobial agent or added buffer (except for pH adjustment) and is intended only for use as a single-dose injection. When smaller doses are required the unused portion should be discarded with the entire unit.

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) Sulfate, USP heptahydrate is chemically designated MgSO4 - 7H2O with molecular weight of 246.48 and occurs as colorless crystals or white powder freely soluble in water.

The plastic syringe is molded from a specially formulated polypropylene. Water permeates from inside the container at an extremely slow rate which will have an insignificant effect on solution concentration over the expected shelf life. Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the syringe material.

CLINICAL PHARMACOLOGY

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) (Mg++) is an important cofactor for enzymatic reactions and plays an important role in neurochemical transmission and muscular excitability.

As a nutritional adjunct in hyperalimentation, the precise mechanism of action for Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) is uncertain. Early symptoms of hypomagnesemia (less than 1.5 mEq/liter) may develop as early as three to four days or within weeks.

Predominant deficiency effects are neurological, e.g., muscle irritability, clonic twitching and tremors. Hypocalcemia and hypokalemia often follow low serum levels of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)). While there are large stores of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) present intracellularly and in the bones of adults, these stores often are not mobilized sufficiently to maintain plasma levels. Parenteral Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) therapy repairs the plasma deficit and causes deficiency symptoms and signs to cease.

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) prevents or controls convulsions by blocking neuromuscular transmission and decreasing the amount of acetylcholine liberated at the end plate by the motor nerve impulse. Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) is said to have a depressant effect on the central nervous system (CNS), but it does not adversely affect the woman, fetus or neonate when used as directed in eclampsia or pre-eclampsia. Normal plasma Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) levels range from 1.5 to 2.5 mEq/liter.

As plasma Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) rises above 4 mEq/liter, the deep tendon reflexes are first decreased and then disappear as the plasma level approaches 10 mEq/liter. At this level respiratory paralysis may occur. Heart block also may occur at this or lower plasma levels of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)). Serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) concentrations in excess of 12 mEq/L may be fatal.

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) acts peripherally to produce vasodilation. With low doses only flushing and sweating occur, but larger doses cause lowering of blood pressure. The central and peripheral effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) poisoning are antagonized to some extent by intravenous administration of calcium.

Pharmacokinetics

With intravenous administration the onset of anticonvulsant action is immediate and lasts about 30 minutes. Following intramuscular administration the onset of action occurs in about one hour and persists for three to four hours. Effective anticonvulsant serum levels range from 2.5 to 7.5 mEq/liter. Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) is excreted solely by the kidneys at a rate proportional to the plasma concentration and glomerular filtration.

INDICATIONS AND USAGE

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) Sulfate Injection, USP is suitable for replacement therapy in Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) deficiency, especially in acute hypomagnesemia accompanied by signs of tetany similar to those observed in hypocalcemia. In such cases, the serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) (Mg++) level is usually below the lower limit of normal (1.5 to 2.5 mEq/liter) and the serum calcium (Ca++) level is normal (4.3 to 5.3 mEq/liter) or elevated.

In total parenteral nutrition (TPN), Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) sulfate may be added to the nutrient admixture to correct or prevent hypomagnesemia which can arise during the course of therapy.

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) Sulfate Injection, USP is also indicated for the prevention and control of seizures (convulsions) in pre-eclampsia and eclampsia, respectively.

CONTRAINDICATIONS

Parenteral administration of the drug is contraindicated in patients with heart block or myocardial damage.

WARNINGS

FETAL HARM: Continuous administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) sulfate beyond 5 to 7 days to pregnant women can lead to hypocalcemia and bone abnormalities in the developing fetus. These bone abnormalities include skeletal demineralization and osteopenia. In addition, cases of neonatal fracture have been reported. The shortest duration of treatment that can lead to fetal harm is not known. Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) sulfate should be used during pregnancy only if clearly needed. If Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) sulfate is given for treatment of preterm labor, the woman should be informed that the efficacy and safety of such use have not been established and that use of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) sulfate beyond 5 to 7 days may cause fetal abnormalities.

ALUMINUM TOXICITY: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

Parenteral use in the presence of renal insufficiency may lead to Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) intoxication. Intravenous use in the eclampsia should be reserved for immediate control of life-threatening convulsions.

PRECAUTIONS

General

Administer with caution if flushing and sweating occurs. When barbiturates, narcotics or other hypnotics (or systemic anesthetics) are to be given in conjunction with Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)), their dosage should be adjusted with caution because of additive CNS depressant effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)).

Because Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) is removed from the body solely by the kidneys, the drug should be used with caution in patients with renal impairment. Urine output should be maintained at a level of 100 mL or more during the four hours preceding each dose. Monitoring serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) levels and the patient's clinical status is essential to avoid the consequences of overdosage in toxemia. Clinical indications of a safe dosage regimen include the presence of the patellar reflex (knee jerk) and absence of respiratory depression (approximately 16 breaths or more/minute). When repeated doses of the drug are given parenterally, knee jerk reflexes should be tested before each dose and if they are absent, no additional Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) should be given until they return. Serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) levels usually sufficient to control convulsions range from 3 to 6 mg/100 mL (2.5 to 5 mEq/liter). The strength of the deep tendon reflexes begins to diminish when Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) levels exceed 4 mEq/liter. Reflexes may be absent at 10 mEq magnesium/liter, where respiratory paralysis is a potential hazard. An injectable calcium salt should be immediately available to counteract the potential hazards of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) intoxication in eclampsia.

50% Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) Sulfate Injection, USP must be diluted to a concentration of 20% or less prior to intravenous infusion. Rate of administration should be slow and cautious, to avoid producing hypermagnesemia. The 50% solution also should be diluted to 20% or less for intramuscular injection in infants and children.

Laboratory Tests

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) sulfate injection should not be given unless hypomagnesemia has been confirmed and the serum concentration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) is monitored. The normal serum level is 1.5 to 2.5 mEq/L.

Drug Interactions

CNS Depressants - When barbiturates, narcotics or other hypnotics (or systemic anesthetics), or other CNS depressants are to be given in conjunction with Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)), their dosage should be adjusted with caution because of additive CNS depressant effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)). CNS depression and peripheral transmission defects produced by Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) may be antagonized by calcium.

Neuromuscular Blocking Agents - Excessive neuromuscular block has occurred in patients receiving parenteral Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) sulfate and a neuromuscular blocking agent; these drugs should be administered concomitantly with caution.

Cardiac Glycosides - Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) sulfate should be administered with extreme caution in digitalized patients, because serious changes in cardiac conduction which can result in heart block may occur if administration of calcium is required to treat Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) toxicity.

Pregnancy

Teratogenic Effects

Pregnancy Category D (See WARNINGS and PRECAUTIONS )

See WARNINGS and PRECAUTIONS .

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) sulfate can cause fetal abnormalities when administered beyond 5 to 7 days to pregnant women. There are retrospective epidemiological studies and case reports documenting fetal abnormalities such as hypocalcemia, skeletal demineralization, osteopenia and other skeletal abnormalities with continuous maternal administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) sulfate for more than 5 to 7 days.1-10 Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) sulfate injection should be used during pregnancy only if clearly needed. If this drug is used during pregnancy, the woman should be apprised of the potential harm to the fetus.

Nonteratogenic Effects

When administered by continuous intravenous infusion (especially for more than 24 hours preceding delivery) to control convulsions in a toxemic woman, the newborn may show signs of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) toxicity, including neuromuscular or respiratory depression (See OVERDOSAGE ).

Labor and Delivery

Continuous administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) sulfate is an unapproved treatment for preterm labor. The safety and efficacy of such use have not been established. The administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) sulfate outside of its approved indication in pregnant women should be by trained obstetrical personnel in a hospital setting with appropriate obstetrical care facilities.

Nursing Mothers

Since Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) is distributed into milk during parenteral Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) sulfate administration, the drug should be used with caution in nursing women.

Geriatrics

Geriatric patients often require reduced dosage because of impaired renal function. In patients with severe impairment, dosage should not exceed 20 grams in 48 hours. Serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) should be monitored in such patients.

ADVERSE REACTIONS

The adverse effects of parenterally administered Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) usually are the result of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) intoxication. These include flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, cardiac and central nervous system depression proceeding to respiratory paralysis. Hypocalcemia with signs of tetany secondary to Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) sulfate therapy for eclampsia has been reported.

OVERDOSAGE

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) intoxication is manifested by a sharp drop in blood pressure and respiratory paralysis. Disappearance of the patellar reflex is a useful clinical sign to detect the onset of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) intoxication. In the event of overdosage, artificial ventilation must be provided until a calcium salt can be injected intravenously to antagonize the effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)).

For Treatment of Overdose

Artificial respiration is often required. Intravenous calcium, 10 to 20 mL of a 5% solution (diluted if desirable with isotonic sodium chloride for injection) is used to counteract effects of hypermagnesemia. Subcutaneous physostigmine, 0.5 to 1 mg may be helpful.

Hypermagnesemia in the newborn may require resuscitation and assisted ventilation via endotracheal intubation or intermittent positive pressure ventilation as well as intravenous calcium.

DOSAGE AND ADMINISTRATION

Dosage of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) sulfate must be carefully adjusted according to individual requirements and response, and administration of the drug should be discontinued as soon as the desired effect is obtained.

Both intravenous and intramuscular administration are appropriate. Intramuscular administration of the undiluted 50% solution results in therapeutic plasma levels in 60 minutes, whereas intravenous doses will provide a therapeutic level almost immediately. The rate of intravenous injection should generally not exceed 150 mg/minute (1.5 mL of a 10% concentration or its equivalent), except in severe eclampsia with seizures. Continuous maternal administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

Solutions for intravenous infusion must be diluted to a concentration of 20% or less prior to administration. The diluents commonly used are 5% Dextrose Injection, USP and 0.9% Sodium Chloride Injection, USP. Deep intramuscular injection of the undiluted (50%) solution is appropriate for adults, but the solution should be diluted to a 20% or less concentration prior to such injection in children.

In Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) Deficiency

In the treatment of mild Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) deficiency, the usual adult dose is 1 gram, equivalent to 8.12 mEq of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) (2 mL of the 50% solution) injected intramuscularly every six hours for four doses (equivalent to a total of 32.5 mEq of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) per 24 hours). For severe hypomagnesemia, as much as 250 mg (approximately 2 mEq) per kg of body weight (0.5 mL of the 50% solution) may be given intramuscularly within a period of four hours if necessary. Alternatively, 5 grams, (approximately 40 mEq) can be added to one liter of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP for slow intravenous infusion over a three-hour period. In the treatment of deficiency states, caution must be observed to prevent exceeding the renal excretory capacity.

In Hyperalimentation

In total parenteral nutrition, maintenance requirements for Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) are not precisely known. The maintenance dose used in adults ranges from 8 to 24 mEq (1 gram to 3 grams) daily; for infants, the range is 2 to 10 mEq (0.25 gram to 1.25 grams) daily.

In Pre-eclampsia or Eclampsia

In severe pre-eclampsia or eclampsia, the total initial dose is 10 grams to 14 grams of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) sulfate. Intravenously, a dose of 4 grams to 5 grams in 250 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP may be infused. Simultaneously, intramuscular doses of up to 10 grams (5 grams or 10 mL of the undiluted 50% solution in each buttock) are given. Alternatively, the initial intravenous dose of 4 grams may be given by diluting the 50% solution to a 10 or 20% concentration; the diluted fluid (40 mL of a 10% solution or 20 mL of a 20% solution) may then be injected intravenously over a period of three to four minutes. Subsequently, 4 grams to 5 grams (8 to 10 mL of the 50% solution) are injected intramuscularly into alternate buttocks every four hours as needed, depending on the continuing presence of the patellar reflex and adequate respiratory function. Alternatively, after the initial intravenous dose, some clinicians administer 1 gram to 2 grams/hour by constant intravenous infusion. Therapy should continue until paroxysms cease. A serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) level of 6 mg/100 mL is considered optimal for control of seizures. A total daily (24 hr) dose of 30 grams to 40 grams should not be exceeded. In the presence of severe renal insufficiency, the maximum dosage of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) sulfate is 20 grams/48 hours and frequent serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) concentrations must be obtained. Continuous use of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

Other Uses

In counteracting the muscle-stimulating effects of barium poisoning, the usual dose of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) sulfate is 1 gram to 2 grams given intravenously.

For controlling seizures associated with epilepsy, glomerulonephritis or hypothyroidism, the usual adult dose is 1 gram administered intramuscularly or intravenously.

In paroxysmal atrial tachycardia, Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) should be used only if simpler measures have failed and there is no evidence of myocardial damage. The usual dose is 3 grams to 4 grams (30 to 40 mL of a 10% solution) administered intravenously over 30 seconds with extreme caution.

For reduction of cerebral edema, 2.5 grams (25 mL of a 10% solution) is given intravenously.

Incompatibilities

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) sulfate in solution may result in a precipitate formation when mixed with solutions containing:

Alcohol (in high Heavy Metals

concentrations) Hydrocortisone sodium

Alkali carbonates and succinate

bicarbonates Phosphates

Alkali hydroxides Polymixin B sulfate

Arsenates Procaine hydrochloride

Barium Salicylates

Calcium Strontium

Clindamycin phosphate Tartrates

The potential incompatibility will often be influenced by the changes in the concentration of reactants and the pH of the solutions.

It has been reported that Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) may reduce the antibiotic activity of streptomycin, tetracycline and tobramycin when given together.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

HOW SUPPLIED

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) Sulfate Injection, USP is supplied in single-dose containers as follows:


NDC No.


Container


Total

Amount


Concentration


mEq

Mg++/mL


0409-1754-10


Ansyr

Plastic Syringe


5 g/10 mL


50%


4 mEq/mL


Do not administer unless solution is clear and container is undamaged. Discard unused portion.

Store at 20 to 25°C (68 to 77°F).

REFERENCES

  • Yokoyama K, Takahashi N, Yada Y. Prolonged maternal Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) administration and bone metabolism in neonates. Early Hum Dev. 2010;86(3):187-91. Epub 2010 Mar 12.
  • Wedig KE, Kogan J, Schorry EK et al. Skeletal demineralization and fractures caused by fetal Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) toxicity. J. Perinatol. 2006; 26(6):371-4.
  • Nassar AH, Sakhel K, Maarouf H, et al. Adverse maternal and neonatal outcome of prolonged course of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) sulfate tocolysis. Acta Obstet Gynecol Scan. 2006;85(9):1099-103.
  • Malaeb SN, Rassi A, Haddad MC. Bone mineralization in newborns whose mothers received Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) sulphate for tocolysis of premature labor. Pediatr Radiol. 2004;34(5):384-6. Epub 2004 Feb 18.
  • Matsuda Y, Maeda Y, Ito M, et al. Effect of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) sulfate treatment on neonatal bone abnormalities. Gynecol Obstet Invest. 1997;44(2):82-8.
  • Schanler RJ, Smith LG, Burns PA. Effects of long-term maternal intravenous Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) sulfate therapy on neonatal calcium metabolism and bone mineral content. Gynecol Obstet Invest. 1997;43(4):236-41.
  • Santi MD, Henry GW, Douglas GL. Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) sulfate treatment of preterm labor as a cause of abnormal neonatal bone mineralization. J Pediatr Orthrop. 1994;14(2):249-53.
  • Holcomb WL, Shackelford GD, Petrie RH. Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) tocolysis and neonatal bone abnormalities; a controlled study. Obstet Gynecol. 1991; 78(4):611-4.
  • Cumming WA, Thomas VJ. Hypermagnesemia: a cause of abnormal metaphyses in the neonate. Am J Roentgenol. 1989; 152(5):1071-2.
  • Lamm CL, Norton KL, Murphy RJ. Congenital rickets associated with Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) sulfate infusion for tocolysis. J Pediatr. 1988; 113(6):1078-82.
  • McGuinness GA, Weinstein MM, Cruikshank DP, et al. Effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) sulfate treatment on perinatal calcium metabolism. II. Neonatal responses. Obstet Gynecol. 1980; 56(5): 595-600.
  • Riaz M, Porat R, Brodsky NL, et al. The effects of maternal Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) sulfate treatment on newborns: a prospective controlled study. J. Perinatol. 1998;18(6 pt 1):449-54.

Hospira, Inc., Lake Forest, IL 60045 USA

LAB-1024-1.0

April 2017

Hospira Logo

50% Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) Sulfate 5 g/10 mL (500 mg/mL)

Rx only

NDC 0409-1754-10

10 mL Single-dose syringe

50% Super Multi-Minerals Regular Strength (Magnesium (Magnesium Fumarate)) Sulfate Injection, USP

5 g/10 mL (500 mg/mL) (4 mEq Mg++/mL)

MUST BE DILUTED FOR INTRAVENOUS USE.

For Intravenous or Intramuscular Use. Sterile. 4.06 mOsmol/mL (calc.).

Contains no more than 75 mcg/L of aluminum.

Hospira, Inc., Lake Forest, IL 60045 USA

Hospira

RL-6891

Magnesium (Magnesium Gluconate):



Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) Sulfate

Injection, USP

Ansyr Plastic Syringe

Rx only

Hospira Logo

DESCRIPTION

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) Sulfate Injection, USP is a sterile solution of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) sulfate heptahydrate in Water for Injection, USP administered by the intravenous or intramuscular routes as an electrolyte replenisher or anticonvulsant. Must be diluted before intravenous use. May contain sulfuric acid and/or sodium hydroxide for pH adjustment. The pH is 5.5 to 7.0. The 50% concentration has an osmolarity of 4.06 mOsmol/mL (calc.).

The solution contains no bacteriostat, antimicrobial agent or added buffer (except for pH adjustment) and is intended only for use as a single-dose injection. When smaller doses are required the unused portion should be discarded with the entire unit.

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) Sulfate, USP heptahydrate is chemically designated MgSO4 - 7H2O with molecular weight of 246.48 and occurs as colorless crystals or white powder freely soluble in water.

The plastic syringe is molded from a specially formulated polypropylene. Water permeates from inside the container at an extremely slow rate which will have an insignificant effect on solution concentration over the expected shelf life. Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the syringe material.

CLINICAL PHARMACOLOGY

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) (Mg++) is an important cofactor for enzymatic reactions and plays an important role in neurochemical transmission and muscular excitability.

As a nutritional adjunct in hyperalimentation, the precise mechanism of action for Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) is uncertain. Early symptoms of hypomagnesemia (less than 1.5 mEq/liter) may develop as early as three to four days or within weeks.

Predominant deficiency effects are neurological, e.g., muscle irritability, clonic twitching and tremors. Hypocalcemia and hypokalemia often follow low serum levels of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)). While there are large stores of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) present intracellularly and in the bones of adults, these stores often are not mobilized sufficiently to maintain plasma levels. Parenteral Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) therapy repairs the plasma deficit and causes deficiency symptoms and signs to cease.

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) prevents or controls convulsions by blocking neuromuscular transmission and decreasing the amount of acetylcholine liberated at the end plate by the motor nerve impulse. Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) is said to have a depressant effect on the central nervous system (CNS), but it does not adversely affect the woman, fetus or neonate when used as directed in eclampsia or pre-eclampsia. Normal plasma Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) levels range from 1.5 to 2.5 mEq/liter.

As plasma Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) rises above 4 mEq/liter, the deep tendon reflexes are first decreased and then disappear as the plasma level approaches 10 mEq/liter. At this level respiratory paralysis may occur. Heart block also may occur at this or lower plasma levels of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)). Serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) concentrations in excess of 12 mEq/L may be fatal.

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) acts peripherally to produce vasodilation. With low doses only flushing and sweating occur, but larger doses cause lowering of blood pressure. The central and peripheral effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) poisoning are antagonized to some extent by intravenous administration of calcium.

Pharmacokinetics

With intravenous administration the onset of anticonvulsant action is immediate and lasts about 30 minutes. Following intramuscular administration the onset of action occurs in about one hour and persists for three to four hours. Effective anticonvulsant serum levels range from 2.5 to 7.5 mEq/liter. Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) is excreted solely by the kidneys at a rate proportional to the plasma concentration and glomerular filtration.

INDICATIONS AND USAGE

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) Sulfate Injection, USP is suitable for replacement therapy in Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) deficiency, especially in acute hypomagnesemia accompanied by signs of tetany similar to those observed in hypocalcemia. In such cases, the serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) (Mg++) level is usually below the lower limit of normal (1.5 to 2.5 mEq/liter) and the serum calcium (Ca++) level is normal (4.3 to 5.3 mEq/liter) or elevated.

In total parenteral nutrition (TPN), Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) sulfate may be added to the nutrient admixture to correct or prevent hypomagnesemia which can arise during the course of therapy.

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) Sulfate Injection, USP is also indicated for the prevention and control of seizures (convulsions) in pre-eclampsia and eclampsia, respectively.

CONTRAINDICATIONS

Parenteral administration of the drug is contraindicated in patients with heart block or myocardial damage.

WARNINGS

FETAL HARM: Continuous administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) sulfate beyond 5 to 7 days to pregnant women can lead to hypocalcemia and bone abnormalities in the developing fetus. These bone abnormalities include skeletal demineralization and osteopenia. In addition, cases of neonatal fracture have been reported. The shortest duration of treatment that can lead to fetal harm is not known. Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) sulfate should be used during pregnancy only if clearly needed. If Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) sulfate is given for treatment of preterm labor, the woman should be informed that the efficacy and safety of such use have not been established and that use of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) sulfate beyond 5 to 7 days may cause fetal abnormalities.

ALUMINUM TOXICITY: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

Parenteral use in the presence of renal insufficiency may lead to Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) intoxication. Intravenous use in the eclampsia should be reserved for immediate control of life-threatening convulsions.

PRECAUTIONS

General

Administer with caution if flushing and sweating occurs. When barbiturates, narcotics or other hypnotics (or systemic anesthetics) are to be given in conjunction with Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)), their dosage should be adjusted with caution because of additive CNS depressant effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)).

Because Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) is removed from the body solely by the kidneys, the drug should be used with caution in patients with renal impairment. Urine output should be maintained at a level of 100 mL or more during the four hours preceding each dose. Monitoring serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) levels and the patient's clinical status is essential to avoid the consequences of overdosage in toxemia. Clinical indications of a safe dosage regimen include the presence of the patellar reflex (knee jerk) and absence of respiratory depression (approximately 16 breaths or more/minute). When repeated doses of the drug are given parenterally, knee jerk reflexes should be tested before each dose and if they are absent, no additional Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) should be given until they return. Serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) levels usually sufficient to control convulsions range from 3 to 6 mg/100 mL (2.5 to 5 mEq/liter). The strength of the deep tendon reflexes begins to diminish when Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) levels exceed 4 mEq/liter. Reflexes may be absent at 10 mEq magnesium/liter, where respiratory paralysis is a potential hazard. An injectable calcium salt should be immediately available to counteract the potential hazards of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) intoxication in eclampsia.

50% Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) Sulfate Injection, USP must be diluted to a concentration of 20% or less prior to intravenous infusion. Rate of administration should be slow and cautious, to avoid producing hypermagnesemia. The 50% solution also should be diluted to 20% or less for intramuscular injection in infants and children.

Laboratory Tests

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) sulfate injection should not be given unless hypomagnesemia has been confirmed and the serum concentration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) is monitored. The normal serum level is 1.5 to 2.5 mEq/L.

Drug Interactions

CNS Depressants - When barbiturates, narcotics or other hypnotics (or systemic anesthetics), or other CNS depressants are to be given in conjunction with Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)), their dosage should be adjusted with caution because of additive CNS depressant effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)). CNS depression and peripheral transmission defects produced by Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) may be antagonized by calcium.

Neuromuscular Blocking Agents - Excessive neuromuscular block has occurred in patients receiving parenteral Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) sulfate and a neuromuscular blocking agent; these drugs should be administered concomitantly with caution.

Cardiac Glycosides - Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) sulfate should be administered with extreme caution in digitalized patients, because serious changes in cardiac conduction which can result in heart block may occur if administration of calcium is required to treat Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) toxicity.

Pregnancy

Teratogenic Effects

Pregnancy Category D (See WARNINGS and PRECAUTIONS )

See WARNINGS and PRECAUTIONS .

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) sulfate can cause fetal abnormalities when administered beyond 5 to 7 days to pregnant women. There are retrospective epidemiological studies and case reports documenting fetal abnormalities such as hypocalcemia, skeletal demineralization, osteopenia and other skeletal abnormalities with continuous maternal administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) sulfate for more than 5 to 7 days.1-10 Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) sulfate injection should be used during pregnancy only if clearly needed. If this drug is used during pregnancy, the woman should be apprised of the potential harm to the fetus.

Nonteratogenic Effects

When administered by continuous intravenous infusion (especially for more than 24 hours preceding delivery) to control convulsions in a toxemic woman, the newborn may show signs of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) toxicity, including neuromuscular or respiratory depression (See OVERDOSAGE ).

Labor and Delivery

Continuous administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) sulfate is an unapproved treatment for preterm labor. The safety and efficacy of such use have not been established. The administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) sulfate outside of its approved indication in pregnant women should be by trained obstetrical personnel in a hospital setting with appropriate obstetrical care facilities.

Nursing Mothers

Since Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) is distributed into milk during parenteral Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) sulfate administration, the drug should be used with caution in nursing women.

Geriatrics

Geriatric patients often require reduced dosage because of impaired renal function. In patients with severe impairment, dosage should not exceed 20 grams in 48 hours. Serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) should be monitored in such patients.

ADVERSE REACTIONS

The adverse effects of parenterally administered Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) usually are the result of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) intoxication. These include flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, cardiac and central nervous system depression proceeding to respiratory paralysis. Hypocalcemia with signs of tetany secondary to Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) sulfate therapy for eclampsia has been reported.

OVERDOSAGE

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) intoxication is manifested by a sharp drop in blood pressure and respiratory paralysis. Disappearance of the patellar reflex is a useful clinical sign to detect the onset of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) intoxication. In the event of overdosage, artificial ventilation must be provided until a calcium salt can be injected intravenously to antagonize the effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)).

For Treatment of Overdose

Artificial respiration is often required. Intravenous calcium, 10 to 20 mL of a 5% solution (diluted if desirable with isotonic sodium chloride for injection) is used to counteract effects of hypermagnesemia. Subcutaneous physostigmine, 0.5 to 1 mg may be helpful.

Hypermagnesemia in the newborn may require resuscitation and assisted ventilation via endotracheal intubation or intermittent positive pressure ventilation as well as intravenous calcium.

DOSAGE AND ADMINISTRATION

Dosage of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) sulfate must be carefully adjusted according to individual requirements and response, and administration of the drug should be discontinued as soon as the desired effect is obtained.

Both intravenous and intramuscular administration are appropriate. Intramuscular administration of the undiluted 50% solution results in therapeutic plasma levels in 60 minutes, whereas intravenous doses will provide a therapeutic level almost immediately. The rate of intravenous injection should generally not exceed 150 mg/minute (1.5 mL of a 10% concentration or its equivalent), except in severe eclampsia with seizures. Continuous maternal administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

Solutions for intravenous infusion must be diluted to a concentration of 20% or less prior to administration. The diluents commonly used are 5% Dextrose Injection, USP and 0.9% Sodium Chloride Injection, USP. Deep intramuscular injection of the undiluted (50%) solution is appropriate for adults, but the solution should be diluted to a 20% or less concentration prior to such injection in children.

In Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) Deficiency

In the treatment of mild Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) deficiency, the usual adult dose is 1 gram, equivalent to 8.12 mEq of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) (2 mL of the 50% solution) injected intramuscularly every six hours for four doses (equivalent to a total of 32.5 mEq of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) per 24 hours). For severe hypomagnesemia, as much as 250 mg (approximately 2 mEq) per kg of body weight (0.5 mL of the 50% solution) may be given intramuscularly within a period of four hours if necessary. Alternatively, 5 grams, (approximately 40 mEq) can be added to one liter of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP for slow intravenous infusion over a three-hour period. In the treatment of deficiency states, caution must be observed to prevent exceeding the renal excretory capacity.

In Hyperalimentation

In total parenteral nutrition, maintenance requirements for Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) are not precisely known. The maintenance dose used in adults ranges from 8 to 24 mEq (1 gram to 3 grams) daily; for infants, the range is 2 to 10 mEq (0.25 gram to 1.25 grams) daily.

In Pre-eclampsia or Eclampsia

In severe pre-eclampsia or eclampsia, the total initial dose is 10 grams to 14 grams of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) sulfate. Intravenously, a dose of 4 grams to 5 grams in 250 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP may be infused. Simultaneously, intramuscular doses of up to 10 grams (5 grams or 10 mL of the undiluted 50% solution in each buttock) are given. Alternatively, the initial intravenous dose of 4 grams may be given by diluting the 50% solution to a 10 or 20% concentration; the diluted fluid (40 mL of a 10% solution or 20 mL of a 20% solution) may then be injected intravenously over a period of three to four minutes. Subsequently, 4 grams to 5 grams (8 to 10 mL of the 50% solution) are injected intramuscularly into alternate buttocks every four hours as needed, depending on the continuing presence of the patellar reflex and adequate respiratory function. Alternatively, after the initial intravenous dose, some clinicians administer 1 gram to 2 grams/hour by constant intravenous infusion. Therapy should continue until paroxysms cease. A serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) level of 6 mg/100 mL is considered optimal for control of seizures. A total daily (24 hr) dose of 30 grams to 40 grams should not be exceeded. In the presence of severe renal insufficiency, the maximum dosage of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) sulfate is 20 grams/48 hours and frequent serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) concentrations must be obtained. Continuous use of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

Other Uses

In counteracting the muscle-stimulating effects of barium poisoning, the usual dose of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) sulfate is 1 gram to 2 grams given intravenously.

For controlling seizures associated with epilepsy, glomerulonephritis or hypothyroidism, the usual adult dose is 1 gram administered intramuscularly or intravenously.

In paroxysmal atrial tachycardia, Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) should be used only if simpler measures have failed and there is no evidence of myocardial damage. The usual dose is 3 grams to 4 grams (30 to 40 mL of a 10% solution) administered intravenously over 30 seconds with extreme caution.

For reduction of cerebral edema, 2.5 grams (25 mL of a 10% solution) is given intravenously.

Incompatibilities

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) sulfate in solution may result in a precipitate formation when mixed with solutions containing:

Alcohol (in high Heavy Metals

concentrations) Hydrocortisone sodium

Alkali carbonates and succinate

bicarbonates Phosphates

Alkali hydroxides Polymixin B sulfate

Arsenates Procaine hydrochloride

Barium Salicylates

Calcium Strontium

Clindamycin phosphate Tartrates

The potential incompatibility will often be influenced by the changes in the concentration of reactants and the pH of the solutions.

It has been reported that Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) may reduce the antibiotic activity of streptomycin, tetracycline and tobramycin when given together.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

HOW SUPPLIED

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) Sulfate Injection, USP is supplied in single-dose containers as follows:


NDC No.


Container


Total

Amount


Concentration


mEq

Mg++/mL


0409-1754-10


Ansyr

Plastic Syringe


5 g/10 mL


50%


4 mEq/mL


Do not administer unless solution is clear and container is undamaged. Discard unused portion.

Store at 20 to 25°C (68 to 77°F).

REFERENCES

  • Yokoyama K, Takahashi N, Yada Y. Prolonged maternal Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) administration and bone metabolism in neonates. Early Hum Dev. 2010;86(3):187-91. Epub 2010 Mar 12.
  • Wedig KE, Kogan J, Schorry EK et al. Skeletal demineralization and fractures caused by fetal Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) toxicity. J. Perinatol. 2006; 26(6):371-4.
  • Nassar AH, Sakhel K, Maarouf H, et al. Adverse maternal and neonatal outcome of prolonged course of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) sulfate tocolysis. Acta Obstet Gynecol Scan. 2006;85(9):1099-103.
  • Malaeb SN, Rassi A, Haddad MC. Bone mineralization in newborns whose mothers received Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) sulphate for tocolysis of premature labor. Pediatr Radiol. 2004;34(5):384-6. Epub 2004 Feb 18.
  • Matsuda Y, Maeda Y, Ito M, et al. Effect of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) sulfate treatment on neonatal bone abnormalities. Gynecol Obstet Invest. 1997;44(2):82-8.
  • Schanler RJ, Smith LG, Burns PA. Effects of long-term maternal intravenous Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) sulfate therapy on neonatal calcium metabolism and bone mineral content. Gynecol Obstet Invest. 1997;43(4):236-41.
  • Santi MD, Henry GW, Douglas GL. Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) sulfate treatment of preterm labor as a cause of abnormal neonatal bone mineralization. J Pediatr Orthrop. 1994;14(2):249-53.
  • Holcomb WL, Shackelford GD, Petrie RH. Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) tocolysis and neonatal bone abnormalities; a controlled study. Obstet Gynecol. 1991; 78(4):611-4.
  • Cumming WA, Thomas VJ. Hypermagnesemia: a cause of abnormal metaphyses in the neonate. Am J Roentgenol. 1989; 152(5):1071-2.
  • Lamm CL, Norton KL, Murphy RJ. Congenital rickets associated with Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) sulfate infusion for tocolysis. J Pediatr. 1988; 113(6):1078-82.
  • McGuinness GA, Weinstein MM, Cruikshank DP, et al. Effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) sulfate treatment on perinatal calcium metabolism. II. Neonatal responses. Obstet Gynecol. 1980; 56(5): 595-600.
  • Riaz M, Porat R, Brodsky NL, et al. The effects of maternal Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) sulfate treatment on newborns: a prospective controlled study. J. Perinatol. 1998;18(6 pt 1):449-54.

Hospira, Inc., Lake Forest, IL 60045 USA

LAB-1024-1.0

April 2017

Hospira Logo

50% Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) Sulfate 5 g/10 mL (500 mg/mL)

Rx only

NDC 0409-1754-10

10 mL Single-dose syringe

50% Super Multi-Minerals Regular Strength (Magnesium (Magnesium Gluconate)) Sulfate Injection, USP

5 g/10 mL (500 mg/mL) (4 mEq Mg++/mL)

MUST BE DILUTED FOR INTRAVENOUS USE.

For Intravenous or Intramuscular Use. Sterile. 4.06 mOsmol/mL (calc.).

Contains no more than 75 mcg/L of aluminum.

Hospira, Inc., Lake Forest, IL 60045 USA

Hospira

RL-6891

Magnesium (Magnesium HVP Chelate):



Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) Sulfate

Injection, USP

Ansyr Plastic Syringe

Rx only

Hospira Logo

DESCRIPTION

Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) Sulfate Injection, USP is a sterile solution of Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) sulfate heptahydrate in Water for Injection, USP administered by the intravenous or intramuscular routes as an electrolyte replenisher or anticonvulsant. Must be diluted before intravenous use. May contain sulfuric acid and/or sodium hydroxide for pH adjustment. The pH is 5.5 to 7.0. The 50% concentration has an osmolarity of 4.06 mOsmol/mL (calc.).

The solution contains no bacteriostat, antimicrobial agent or added buffer (except for pH adjustment) and is intended only for use as a single-dose injection. When smaller doses are required the unused portion should be discarded with the entire unit.

Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) Sulfate, USP heptahydrate is chemically designated MgSO4 - 7H2O with molecular weight of 246.48 and occurs as colorless crystals or white powder freely soluble in water.

The plastic syringe is molded from a specially formulated polypropylene. Water permeates from inside the container at an extremely slow rate which will have an insignificant effect on solution concentration over the expected shelf life. Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the syringe material.

CLINICAL PHARMACOLOGY

Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) (Mg++) is an important cofactor for enzymatic reactions and plays an important role in neurochemical transmission and muscular excitability.

As a nutritional adjunct in hyperalimentation, the precise mechanism of action for Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) is uncertain. Early symptoms of hypomagnesemia (less than 1.5 mEq/liter) may develop as early as three to four days or within weeks.

Predominant deficiency effects are neurological, e.g., muscle irritability, clonic twitching and tremors. Hypocalcemia and hypokalemia often follow low serum levels of Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)). While there are large stores of Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) present intracellularly and in the bones of adults, these stores often are not mobilized sufficiently to maintain plasma levels. Parenteral Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) therapy repairs the plasma deficit and causes deficiency symptoms and signs to cease.

Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) prevents or controls convulsions by blocking neuromuscular transmission and decreasing the amount of acetylcholine liberated at the end plate by the motor nerve impulse. Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) is said to have a depressant effect on the central nervous system (CNS), but it does not adversely affect the woman, fetus or neonate when used as directed in eclampsia or pre-eclampsia. Normal plasma Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) levels range from 1.5 to 2.5 mEq/liter.

As plasma Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) rises above 4 mEq/liter, the deep tendon reflexes are first decreased and then disappear as the plasma level approaches 10 mEq/liter. At this level respiratory paralysis may occur. Heart block also may occur at this or lower plasma levels of Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)). Serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) concentrations in excess of 12 mEq/L may be fatal.

Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) acts peripherally to produce vasodilation. With low doses only flushing and sweating occur, but larger doses cause lowering of blood pressure. The central and peripheral effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) poisoning are antagonized to some extent by intravenous administration of calcium.

Pharmacokinetics

With intravenous administration the onset of anticonvulsant action is immediate and lasts about 30 minutes. Following intramuscular administration the onset of action occurs in about one hour and persists for three to four hours. Effective anticonvulsant serum levels range from 2.5 to 7.5 mEq/liter. Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) is excreted solely by the kidneys at a rate proportional to the plasma concentration and glomerular filtration.

INDICATIONS AND USAGE

Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) Sulfate Injection, USP is suitable for replacement therapy in Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) deficiency, especially in acute hypomagnesemia accompanied by signs of tetany similar to those observed in hypocalcemia. In such cases, the serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) (Mg++) level is usually below the lower limit of normal (1.5 to 2.5 mEq/liter) and the serum calcium (Ca++) level is normal (4.3 to 5.3 mEq/liter) or elevated.

In total parenteral nutrition (TPN), Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) sulfate may be added to the nutrient admixture to correct or prevent hypomagnesemia which can arise during the course of therapy.

Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) Sulfate Injection, USP is also indicated for the prevention and control of seizures (convulsions) in pre-eclampsia and eclampsia, respectively.

CONTRAINDICATIONS

Parenteral administration of the drug is contraindicated in patients with heart block or myocardial damage.

WARNINGS

FETAL HARM: Continuous administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) sulfate beyond 5 to 7 days to pregnant women can lead to hypocalcemia and bone abnormalities in the developing fetus. These bone abnormalities include skeletal demineralization and osteopenia. In addition, cases of neonatal fracture have been reported. The shortest duration of treatment that can lead to fetal harm is not known. Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) sulfate should be used during pregnancy only if clearly needed. If Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) sulfate is given for treatment of preterm labor, the woman should be informed that the efficacy and safety of such use have not been established and that use of Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) sulfate beyond 5 to 7 days may cause fetal abnormalities.

ALUMINUM TOXICITY: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

Parenteral use in the presence of renal insufficiency may lead to Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) intoxication. Intravenous use in the eclampsia should be reserved for immediate control of life-threatening convulsions.

PRECAUTIONS

General

Administer with caution if flushing and sweating occurs. When barbiturates, narcotics or other hypnotics (or systemic anesthetics) are to be given in conjunction with Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)), their dosage should be adjusted with caution because of additive CNS depressant effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)).

Because Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) is removed from the body solely by the kidneys, the drug should be used with caution in patients with renal impairment. Urine output should be maintained at a level of 100 mL or more during the four hours preceding each dose. Monitoring serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) levels and the patient's clinical status is essential to avoid the consequences of overdosage in toxemia. Clinical indications of a safe dosage regimen include the presence of the patellar reflex (knee jerk) and absence of respiratory depression (approximately 16 breaths or more/minute). When repeated doses of the drug are given parenterally, knee jerk reflexes should be tested before each dose and if they are absent, no additional Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) should be given until they return. Serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) levels usually sufficient to control convulsions range from 3 to 6 mg/100 mL (2.5 to 5 mEq/liter). The strength of the deep tendon reflexes begins to diminish when Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) levels exceed 4 mEq/liter. Reflexes may be absent at 10 mEq magnesium/liter, where respiratory paralysis is a potential hazard. An injectable calcium salt should be immediately available to counteract the potential hazards of Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) intoxication in eclampsia.

50% Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) Sulfate Injection, USP must be diluted to a concentration of 20% or less prior to intravenous infusion. Rate of administration should be slow and cautious, to avoid producing hypermagnesemia. The 50% solution also should be diluted to 20% or less for intramuscular injection in infants and children.

Laboratory Tests

Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) sulfate injection should not be given unless hypomagnesemia has been confirmed and the serum concentration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) is monitored. The normal serum level is 1.5 to 2.5 mEq/L.

Drug Interactions

CNS Depressants - When barbiturates, narcotics or other hypnotics (or systemic anesthetics), or other CNS depressants are to be given in conjunction with Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)), their dosage should be adjusted with caution because of additive CNS depressant effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)). CNS depression and peripheral transmission defects produced by Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) may be antagonized by calcium.

Neuromuscular Blocking Agents - Excessive neuromuscular block has occurred in patients receiving parenteral Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) sulfate and a neuromuscular blocking agent; these drugs should be administered concomitantly with caution.

Cardiac Glycosides - Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) sulfate should be administered with extreme caution in digitalized patients, because serious changes in cardiac conduction which can result in heart block may occur if administration of calcium is required to treat Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) toxicity.

Pregnancy

Teratogenic Effects

Pregnancy Category D (See WARNINGS and PRECAUTIONS )

See WARNINGS and PRECAUTIONS .

Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) sulfate can cause fetal abnormalities when administered beyond 5 to 7 days to pregnant women. There are retrospective epidemiological studies and case reports documenting fetal abnormalities such as hypocalcemia, skeletal demineralization, osteopenia and other skeletal abnormalities with continuous maternal administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) sulfate for more than 5 to 7 days.1-10 Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) sulfate injection should be used during pregnancy only if clearly needed. If this drug is used during pregnancy, the woman should be apprised of the potential harm to the fetus.

Nonteratogenic Effects

When administered by continuous intravenous infusion (especially for more than 24 hours preceding delivery) to control convulsions in a toxemic woman, the newborn may show signs of Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) toxicity, including neuromuscular or respiratory depression (See OVERDOSAGE ).

Labor and Delivery

Continuous administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) sulfate is an unapproved treatment for preterm labor. The safety and efficacy of such use have not been established. The administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) sulfate outside of its approved indication in pregnant women should be by trained obstetrical personnel in a hospital setting with appropriate obstetrical care facilities.

Nursing Mothers

Since Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) is distributed into milk during parenteral Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) sulfate administration, the drug should be used with caution in nursing women.

Geriatrics

Geriatric patients often require reduced dosage because of impaired renal function. In patients with severe impairment, dosage should not exceed 20 grams in 48 hours. Serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) should be monitored in such patients.

ADVERSE REACTIONS

The adverse effects of parenterally administered Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) usually are the result of Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) intoxication. These include flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, cardiac and central nervous system depression proceeding to respiratory paralysis. Hypocalcemia with signs of tetany secondary to Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) sulfate therapy for eclampsia has been reported.

OVERDOSAGE

Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) intoxication is manifested by a sharp drop in blood pressure and respiratory paralysis. Disappearance of the patellar reflex is a useful clinical sign to detect the onset of Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) intoxication. In the event of overdosage, artificial ventilation must be provided until a calcium salt can be injected intravenously to antagonize the effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)).

For Treatment of Overdose

Artificial respiration is often required. Intravenous calcium, 10 to 20 mL of a 5% solution (diluted if desirable with isotonic sodium chloride for injection) is used to counteract effects of hypermagnesemia. Subcutaneous physostigmine, 0.5 to 1 mg may be helpful.

Hypermagnesemia in the newborn may require resuscitation and assisted ventilation via endotracheal intubation or intermittent positive pressure ventilation as well as intravenous calcium.

DOSAGE AND ADMINISTRATION

Dosage of Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) sulfate must be carefully adjusted according to individual requirements and response, and administration of the drug should be discontinued as soon as the desired effect is obtained.

Both intravenous and intramuscular administration are appropriate. Intramuscular administration of the undiluted 50% solution results in therapeutic plasma levels in 60 minutes, whereas intravenous doses will provide a therapeutic level almost immediately. The rate of intravenous injection should generally not exceed 150 mg/minute (1.5 mL of a 10% concentration or its equivalent), except in severe eclampsia with seizures. Continuous maternal administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

Solutions for intravenous infusion must be diluted to a concentration of 20% or less prior to administration. The diluents commonly used are 5% Dextrose Injection, USP and 0.9% Sodium Chloride Injection, USP. Deep intramuscular injection of the undiluted (50%) solution is appropriate for adults, but the solution should be diluted to a 20% or less concentration prior to such injection in children.

In Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) Deficiency

In the treatment of mild Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) deficiency, the usual adult dose is 1 gram, equivalent to 8.12 mEq of Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) (2 mL of the 50% solution) injected intramuscularly every six hours for four doses (equivalent to a total of 32.5 mEq of Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) per 24 hours). For severe hypomagnesemia, as much as 250 mg (approximately 2 mEq) per kg of body weight (0.5 mL of the 50% solution) may be given intramuscularly within a period of four hours if necessary. Alternatively, 5 grams, (approximately 40 mEq) can be added to one liter of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP for slow intravenous infusion over a three-hour period. In the treatment of deficiency states, caution must be observed to prevent exceeding the renal excretory capacity.

In Hyperalimentation

In total parenteral nutrition, maintenance requirements for Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) are not precisely known. The maintenance dose used in adults ranges from 8 to 24 mEq (1 gram to 3 grams) daily; for infants, the range is 2 to 10 mEq (0.25 gram to 1.25 grams) daily.

In Pre-eclampsia or Eclampsia

In severe pre-eclampsia or eclampsia, the total initial dose is 10 grams to 14 grams of Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) sulfate. Intravenously, a dose of 4 grams to 5 grams in 250 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP may be infused. Simultaneously, intramuscular doses of up to 10 grams (5 grams or 10 mL of the undiluted 50% solution in each buttock) are given. Alternatively, the initial intravenous dose of 4 grams may be given by diluting the 50% solution to a 10 or 20% concentration; the diluted fluid (40 mL of a 10% solution or 20 mL of a 20% solution) may then be injected intravenously over a period of three to four minutes. Subsequently, 4 grams to 5 grams (8 to 10 mL of the 50% solution) are injected intramuscularly into alternate buttocks every four hours as needed, depending on the continuing presence of the patellar reflex and adequate respiratory function. Alternatively, after the initial intravenous dose, some clinicians administer 1 gram to 2 grams/hour by constant intravenous infusion. Therapy should continue until paroxysms cease. A serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) level of 6 mg/100 mL is considered optimal for control of seizures. A total daily (24 hr) dose of 30 grams to 40 grams should not be exceeded. In the presence of severe renal insufficiency, the maximum dosage of Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) sulfate is 20 grams/48 hours and frequent serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) concentrations must be obtained. Continuous use of Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

Other Uses

In counteracting the muscle-stimulating effects of barium poisoning, the usual dose of Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) sulfate is 1 gram to 2 grams given intravenously.

For controlling seizures associated with epilepsy, glomerulonephritis or hypothyroidism, the usual adult dose is 1 gram administered intramuscularly or intravenously.

In paroxysmal atrial tachycardia, Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) should be used only if simpler measures have failed and there is no evidence of myocardial damage. The usual dose is 3 grams to 4 grams (30 to 40 mL of a 10% solution) administered intravenously over 30 seconds with extreme caution.

For reduction of cerebral edema, 2.5 grams (25 mL of a 10% solution) is given intravenously.

Incompatibilities

Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) sulfate in solution may result in a precipitate formation when mixed with solutions containing:

Alcohol (in high Heavy Metals

concentrations) Hydrocortisone sodium

Alkali carbonates and succinate

bicarbonates Phosphates

Alkali hydroxides Polymixin B sulfate

Arsenates Procaine hydrochloride

Barium Salicylates

Calcium Strontium

Clindamycin phosphate Tartrates

The potential incompatibility will often be influenced by the changes in the concentration of reactants and the pH of the solutions.

It has been reported that Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) may reduce the antibiotic activity of streptomycin, tetracycline and tobramycin when given together.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

HOW SUPPLIED

Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) Sulfate Injection, USP is supplied in single-dose containers as follows:


NDC No.


Container


Total

Amount


Concentration


mEq

Mg++/mL


0409-1754-10


Ansyr

Plastic Syringe


5 g/10 mL


50%


4 mEq/mL


Do not administer unless solution is clear and container is undamaged. Discard unused portion.

Store at 20 to 25°C (68 to 77°F).

REFERENCES

  • Yokoyama K, Takahashi N, Yada Y. Prolonged maternal Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) administration and bone metabolism in neonates. Early Hum Dev. 2010;86(3):187-91. Epub 2010 Mar 12.
  • Wedig KE, Kogan J, Schorry EK et al. Skeletal demineralization and fractures caused by fetal Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) toxicity. J. Perinatol. 2006; 26(6):371-4.
  • Nassar AH, Sakhel K, Maarouf H, et al. Adverse maternal and neonatal outcome of prolonged course of Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) sulfate tocolysis. Acta Obstet Gynecol Scan. 2006;85(9):1099-103.
  • Malaeb SN, Rassi A, Haddad MC. Bone mineralization in newborns whose mothers received Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) sulphate for tocolysis of premature labor. Pediatr Radiol. 2004;34(5):384-6. Epub 2004 Feb 18.
  • Matsuda Y, Maeda Y, Ito M, et al. Effect of Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) sulfate treatment on neonatal bone abnormalities. Gynecol Obstet Invest. 1997;44(2):82-8.
  • Schanler RJ, Smith LG, Burns PA. Effects of long-term maternal intravenous Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) sulfate therapy on neonatal calcium metabolism and bone mineral content. Gynecol Obstet Invest. 1997;43(4):236-41.
  • Santi MD, Henry GW, Douglas GL. Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) sulfate treatment of preterm labor as a cause of abnormal neonatal bone mineralization. J Pediatr Orthrop. 1994;14(2):249-53.
  • Holcomb WL, Shackelford GD, Petrie RH. Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) tocolysis and neonatal bone abnormalities; a controlled study. Obstet Gynecol. 1991; 78(4):611-4.
  • Cumming WA, Thomas VJ. Hypermagnesemia: a cause of abnormal metaphyses in the neonate. Am J Roentgenol. 1989; 152(5):1071-2.
  • Lamm CL, Norton KL, Murphy RJ. Congenital rickets associated with Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) sulfate infusion for tocolysis. J Pediatr. 1988; 113(6):1078-82.
  • McGuinness GA, Weinstein MM, Cruikshank DP, et al. Effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) sulfate treatment on perinatal calcium metabolism. II. Neonatal responses. Obstet Gynecol. 1980; 56(5): 595-600.
  • Riaz M, Porat R, Brodsky NL, et al. The effects of maternal Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) sulfate treatment on newborns: a prospective controlled study. J. Perinatol. 1998;18(6 pt 1):449-54.

Hospira, Inc., Lake Forest, IL 60045 USA

LAB-1024-1.0

April 2017

Hospira Logo

50% Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) Sulfate 5 g/10 mL (500 mg/mL)

Rx only

NDC 0409-1754-10

10 mL Single-dose syringe

50% Super Multi-Minerals Regular Strength (Magnesium (Magnesium HVP Chelate)) Sulfate Injection, USP

5 g/10 mL (500 mg/mL) (4 mEq Mg++/mL)

MUST BE DILUTED FOR INTRAVENOUS USE.

For Intravenous or Intramuscular Use. Sterile. 4.06 mOsmol/mL (calc.).

Contains no more than 75 mcg/L of aluminum.

Hospira, Inc., Lake Forest, IL 60045 USA

Hospira

RL-6891

Magnesium (Magnesium Malate):



Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) Sulfate

Injection, USP

Ansyr Plastic Syringe

Rx only

Hospira Logo

DESCRIPTION

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) Sulfate Injection, USP is a sterile solution of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) sulfate heptahydrate in Water for Injection, USP administered by the intravenous or intramuscular routes as an electrolyte replenisher or anticonvulsant. Must be diluted before intravenous use. May contain sulfuric acid and/or sodium hydroxide for pH adjustment. The pH is 5.5 to 7.0. The 50% concentration has an osmolarity of 4.06 mOsmol/mL (calc.).

The solution contains no bacteriostat, antimicrobial agent or added buffer (except for pH adjustment) and is intended only for use as a single-dose injection. When smaller doses are required the unused portion should be discarded with the entire unit.

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) Sulfate, USP heptahydrate is chemically designated MgSO4 - 7H2O with molecular weight of 246.48 and occurs as colorless crystals or white powder freely soluble in water.

The plastic syringe is molded from a specially formulated polypropylene. Water permeates from inside the container at an extremely slow rate which will have an insignificant effect on solution concentration over the expected shelf life. Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the syringe material.

CLINICAL PHARMACOLOGY

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) (Mg++) is an important cofactor for enzymatic reactions and plays an important role in neurochemical transmission and muscular excitability.

As a nutritional adjunct in hyperalimentation, the precise mechanism of action for Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) is uncertain. Early symptoms of hypomagnesemia (less than 1.5 mEq/liter) may develop as early as three to four days or within weeks.

Predominant deficiency effects are neurological, e.g., muscle irritability, clonic twitching and tremors. Hypocalcemia and hypokalemia often follow low serum levels of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)). While there are large stores of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) present intracellularly and in the bones of adults, these stores often are not mobilized sufficiently to maintain plasma levels. Parenteral Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) therapy repairs the plasma deficit and causes deficiency symptoms and signs to cease.

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) prevents or controls convulsions by blocking neuromuscular transmission and decreasing the amount of acetylcholine liberated at the end plate by the motor nerve impulse. Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) is said to have a depressant effect on the central nervous system (CNS), but it does not adversely affect the woman, fetus or neonate when used as directed in eclampsia or pre-eclampsia. Normal plasma Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) levels range from 1.5 to 2.5 mEq/liter.

As plasma Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) rises above 4 mEq/liter, the deep tendon reflexes are first decreased and then disappear as the plasma level approaches 10 mEq/liter. At this level respiratory paralysis may occur. Heart block also may occur at this or lower plasma levels of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)). Serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) concentrations in excess of 12 mEq/L may be fatal.

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) acts peripherally to produce vasodilation. With low doses only flushing and sweating occur, but larger doses cause lowering of blood pressure. The central and peripheral effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) poisoning are antagonized to some extent by intravenous administration of calcium.

Pharmacokinetics

With intravenous administration the onset of anticonvulsant action is immediate and lasts about 30 minutes. Following intramuscular administration the onset of action occurs in about one hour and persists for three to four hours. Effective anticonvulsant serum levels range from 2.5 to 7.5 mEq/liter. Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) is excreted solely by the kidneys at a rate proportional to the plasma concentration and glomerular filtration.

INDICATIONS AND USAGE

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) Sulfate Injection, USP is suitable for replacement therapy in Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) deficiency, especially in acute hypomagnesemia accompanied by signs of tetany similar to those observed in hypocalcemia. In such cases, the serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) (Mg++) level is usually below the lower limit of normal (1.5 to 2.5 mEq/liter) and the serum calcium (Ca++) level is normal (4.3 to 5.3 mEq/liter) or elevated.

In total parenteral nutrition (TPN), Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) sulfate may be added to the nutrient admixture to correct or prevent hypomagnesemia which can arise during the course of therapy.

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) Sulfate Injection, USP is also indicated for the prevention and control of seizures (convulsions) in pre-eclampsia and eclampsia, respectively.

CONTRAINDICATIONS

Parenteral administration of the drug is contraindicated in patients with heart block or myocardial damage.

WARNINGS

FETAL HARM: Continuous administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) sulfate beyond 5 to 7 days to pregnant women can lead to hypocalcemia and bone abnormalities in the developing fetus. These bone abnormalities include skeletal demineralization and osteopenia. In addition, cases of neonatal fracture have been reported. The shortest duration of treatment that can lead to fetal harm is not known. Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) sulfate should be used during pregnancy only if clearly needed. If Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) sulfate is given for treatment of preterm labor, the woman should be informed that the efficacy and safety of such use have not been established and that use of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) sulfate beyond 5 to 7 days may cause fetal abnormalities.

ALUMINUM TOXICITY: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

Parenteral use in the presence of renal insufficiency may lead to Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) intoxication. Intravenous use in the eclampsia should be reserved for immediate control of life-threatening convulsions.

PRECAUTIONS

General

Administer with caution if flushing and sweating occurs. When barbiturates, narcotics or other hypnotics (or systemic anesthetics) are to be given in conjunction with Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)), their dosage should be adjusted with caution because of additive CNS depressant effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)).

Because Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) is removed from the body solely by the kidneys, the drug should be used with caution in patients with renal impairment. Urine output should be maintained at a level of 100 mL or more during the four hours preceding each dose. Monitoring serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) levels and the patient's clinical status is essential to avoid the consequences of overdosage in toxemia. Clinical indications of a safe dosage regimen include the presence of the patellar reflex (knee jerk) and absence of respiratory depression (approximately 16 breaths or more/minute). When repeated doses of the drug are given parenterally, knee jerk reflexes should be tested before each dose and if they are absent, no additional Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) should be given until they return. Serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) levels usually sufficient to control convulsions range from 3 to 6 mg/100 mL (2.5 to 5 mEq/liter). The strength of the deep tendon reflexes begins to diminish when Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) levels exceed 4 mEq/liter. Reflexes may be absent at 10 mEq magnesium/liter, where respiratory paralysis is a potential hazard. An injectable calcium salt should be immediately available to counteract the potential hazards of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) intoxication in eclampsia.

50% Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) Sulfate Injection, USP must be diluted to a concentration of 20% or less prior to intravenous infusion. Rate of administration should be slow and cautious, to avoid producing hypermagnesemia. The 50% solution also should be diluted to 20% or less for intramuscular injection in infants and children.

Laboratory Tests

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) sulfate injection should not be given unless hypomagnesemia has been confirmed and the serum concentration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) is monitored. The normal serum level is 1.5 to 2.5 mEq/L.

Drug Interactions

CNS Depressants - When barbiturates, narcotics or other hypnotics (or systemic anesthetics), or other CNS depressants are to be given in conjunction with Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)), their dosage should be adjusted with caution because of additive CNS depressant effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)). CNS depression and peripheral transmission defects produced by Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) may be antagonized by calcium.

Neuromuscular Blocking Agents - Excessive neuromuscular block has occurred in patients receiving parenteral Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) sulfate and a neuromuscular blocking agent; these drugs should be administered concomitantly with caution.

Cardiac Glycosides - Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) sulfate should be administered with extreme caution in digitalized patients, because serious changes in cardiac conduction which can result in heart block may occur if administration of calcium is required to treat Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) toxicity.

Pregnancy

Teratogenic Effects

Pregnancy Category D (See WARNINGS and PRECAUTIONS )

See WARNINGS and PRECAUTIONS .

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) sulfate can cause fetal abnormalities when administered beyond 5 to 7 days to pregnant women. There are retrospective epidemiological studies and case reports documenting fetal abnormalities such as hypocalcemia, skeletal demineralization, osteopenia and other skeletal abnormalities with continuous maternal administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) sulfate for more than 5 to 7 days.1-10 Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) sulfate injection should be used during pregnancy only if clearly needed. If this drug is used during pregnancy, the woman should be apprised of the potential harm to the fetus.

Nonteratogenic Effects

When administered by continuous intravenous infusion (especially for more than 24 hours preceding delivery) to control convulsions in a toxemic woman, the newborn may show signs of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) toxicity, including neuromuscular or respiratory depression (See OVERDOSAGE ).

Labor and Delivery

Continuous administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) sulfate is an unapproved treatment for preterm labor. The safety and efficacy of such use have not been established. The administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) sulfate outside of its approved indication in pregnant women should be by trained obstetrical personnel in a hospital setting with appropriate obstetrical care facilities.

Nursing Mothers

Since Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) is distributed into milk during parenteral Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) sulfate administration, the drug should be used with caution in nursing women.

Geriatrics

Geriatric patients often require reduced dosage because of impaired renal function. In patients with severe impairment, dosage should not exceed 20 grams in 48 hours. Serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) should be monitored in such patients.

ADVERSE REACTIONS

The adverse effects of parenterally administered Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) usually are the result of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) intoxication. These include flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, cardiac and central nervous system depression proceeding to respiratory paralysis. Hypocalcemia with signs of tetany secondary to Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) sulfate therapy for eclampsia has been reported.

OVERDOSAGE

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) intoxication is manifested by a sharp drop in blood pressure and respiratory paralysis. Disappearance of the patellar reflex is a useful clinical sign to detect the onset of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) intoxication. In the event of overdosage, artificial ventilation must be provided until a calcium salt can be injected intravenously to antagonize the effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)).

For Treatment of Overdose

Artificial respiration is often required. Intravenous calcium, 10 to 20 mL of a 5% solution (diluted if desirable with isotonic sodium chloride for injection) is used to counteract effects of hypermagnesemia. Subcutaneous physostigmine, 0.5 to 1 mg may be helpful.

Hypermagnesemia in the newborn may require resuscitation and assisted ventilation via endotracheal intubation or intermittent positive pressure ventilation as well as intravenous calcium.

DOSAGE AND ADMINISTRATION

Dosage of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) sulfate must be carefully adjusted according to individual requirements and response, and administration of the drug should be discontinued as soon as the desired effect is obtained.

Both intravenous and intramuscular administration are appropriate. Intramuscular administration of the undiluted 50% solution results in therapeutic plasma levels in 60 minutes, whereas intravenous doses will provide a therapeutic level almost immediately. The rate of intravenous injection should generally not exceed 150 mg/minute (1.5 mL of a 10% concentration or its equivalent), except in severe eclampsia with seizures. Continuous maternal administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

Solutions for intravenous infusion must be diluted to a concentration of 20% or less prior to administration. The diluents commonly used are 5% Dextrose Injection, USP and 0.9% Sodium Chloride Injection, USP. Deep intramuscular injection of the undiluted (50%) solution is appropriate for adults, but the solution should be diluted to a 20% or less concentration prior to such injection in children.

In Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) Deficiency

In the treatment of mild Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) deficiency, the usual adult dose is 1 gram, equivalent to 8.12 mEq of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) (2 mL of the 50% solution) injected intramuscularly every six hours for four doses (equivalent to a total of 32.5 mEq of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) per 24 hours). For severe hypomagnesemia, as much as 250 mg (approximately 2 mEq) per kg of body weight (0.5 mL of the 50% solution) may be given intramuscularly within a period of four hours if necessary. Alternatively, 5 grams, (approximately 40 mEq) can be added to one liter of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP for slow intravenous infusion over a three-hour period. In the treatment of deficiency states, caution must be observed to prevent exceeding the renal excretory capacity.

In Hyperalimentation

In total parenteral nutrition, maintenance requirements for Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) are not precisely known. The maintenance dose used in adults ranges from 8 to 24 mEq (1 gram to 3 grams) daily; for infants, the range is 2 to 10 mEq (0.25 gram to 1.25 grams) daily.

In Pre-eclampsia or Eclampsia

In severe pre-eclampsia or eclampsia, the total initial dose is 10 grams to 14 grams of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) sulfate. Intravenously, a dose of 4 grams to 5 grams in 250 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP may be infused. Simultaneously, intramuscular doses of up to 10 grams (5 grams or 10 mL of the undiluted 50% solution in each buttock) are given. Alternatively, the initial intravenous dose of 4 grams may be given by diluting the 50% solution to a 10 or 20% concentration; the diluted fluid (40 mL of a 10% solution or 20 mL of a 20% solution) may then be injected intravenously over a period of three to four minutes. Subsequently, 4 grams to 5 grams (8 to 10 mL of the 50% solution) are injected intramuscularly into alternate buttocks every four hours as needed, depending on the continuing presence of the patellar reflex and adequate respiratory function. Alternatively, after the initial intravenous dose, some clinicians administer 1 gram to 2 grams/hour by constant intravenous infusion. Therapy should continue until paroxysms cease. A serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) level of 6 mg/100 mL is considered optimal for control of seizures. A total daily (24 hr) dose of 30 grams to 40 grams should not be exceeded. In the presence of severe renal insufficiency, the maximum dosage of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) sulfate is 20 grams/48 hours and frequent serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) concentrations must be obtained. Continuous use of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

Other Uses

In counteracting the muscle-stimulating effects of barium poisoning, the usual dose of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) sulfate is 1 gram to 2 grams given intravenously.

For controlling seizures associated with epilepsy, glomerulonephritis or hypothyroidism, the usual adult dose is 1 gram administered intramuscularly or intravenously.

In paroxysmal atrial tachycardia, Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) should be used only if simpler measures have failed and there is no evidence of myocardial damage. The usual dose is 3 grams to 4 grams (30 to 40 mL of a 10% solution) administered intravenously over 30 seconds with extreme caution.

For reduction of cerebral edema, 2.5 grams (25 mL of a 10% solution) is given intravenously.

Incompatibilities

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) sulfate in solution may result in a precipitate formation when mixed with solutions containing:

Alcohol (in high Heavy Metals

concentrations) Hydrocortisone sodium

Alkali carbonates and succinate

bicarbonates Phosphates

Alkali hydroxides Polymixin B sulfate

Arsenates Procaine hydrochloride

Barium Salicylates

Calcium Strontium

Clindamycin phosphate Tartrates

The potential incompatibility will often be influenced by the changes in the concentration of reactants and the pH of the solutions.

It has been reported that Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) may reduce the antibiotic activity of streptomycin, tetracycline and tobramycin when given together.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

HOW SUPPLIED

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) Sulfate Injection, USP is supplied in single-dose containers as follows:


NDC No.


Container


Total

Amount


Concentration


mEq

Mg++/mL


0409-1754-10


Ansyr

Plastic Syringe


5 g/10 mL


50%


4 mEq/mL


Do not administer unless solution is clear and container is undamaged. Discard unused portion.

Store at 20 to 25°C (68 to 77°F).

REFERENCES

  • Yokoyama K, Takahashi N, Yada Y. Prolonged maternal Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) administration and bone metabolism in neonates. Early Hum Dev. 2010;86(3):187-91. Epub 2010 Mar 12.
  • Wedig KE, Kogan J, Schorry EK et al. Skeletal demineralization and fractures caused by fetal Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) toxicity. J. Perinatol. 2006; 26(6):371-4.
  • Nassar AH, Sakhel K, Maarouf H, et al. Adverse maternal and neonatal outcome of prolonged course of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) sulfate tocolysis. Acta Obstet Gynecol Scan. 2006;85(9):1099-103.
  • Malaeb SN, Rassi A, Haddad MC. Bone mineralization in newborns whose mothers received Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) sulphate for tocolysis of premature labor. Pediatr Radiol. 2004;34(5):384-6. Epub 2004 Feb 18.
  • Matsuda Y, Maeda Y, Ito M, et al. Effect of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) sulfate treatment on neonatal bone abnormalities. Gynecol Obstet Invest. 1997;44(2):82-8.
  • Schanler RJ, Smith LG, Burns PA. Effects of long-term maternal intravenous Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) sulfate therapy on neonatal calcium metabolism and bone mineral content. Gynecol Obstet Invest. 1997;43(4):236-41.
  • Santi MD, Henry GW, Douglas GL. Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) sulfate treatment of preterm labor as a cause of abnormal neonatal bone mineralization. J Pediatr Orthrop. 1994;14(2):249-53.
  • Holcomb WL, Shackelford GD, Petrie RH. Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) tocolysis and neonatal bone abnormalities; a controlled study. Obstet Gynecol. 1991; 78(4):611-4.
  • Cumming WA, Thomas VJ. Hypermagnesemia: a cause of abnormal metaphyses in the neonate. Am J Roentgenol. 1989; 152(5):1071-2.
  • Lamm CL, Norton KL, Murphy RJ. Congenital rickets associated with Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) sulfate infusion for tocolysis. J Pediatr. 1988; 113(6):1078-82.
  • McGuinness GA, Weinstein MM, Cruikshank DP, et al. Effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) sulfate treatment on perinatal calcium metabolism. II. Neonatal responses. Obstet Gynecol. 1980; 56(5): 595-600.
  • Riaz M, Porat R, Brodsky NL, et al. The effects of maternal Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) sulfate treatment on newborns: a prospective controlled study. J. Perinatol. 1998;18(6 pt 1):449-54.

Hospira, Inc., Lake Forest, IL 60045 USA

LAB-1024-1.0

April 2017

Hospira Logo

50% Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) Sulfate 5 g/10 mL (500 mg/mL)

Rx only

NDC 0409-1754-10

10 mL Single-dose syringe

50% Super Multi-Minerals Regular Strength (Magnesium (Magnesium Malate)) Sulfate Injection, USP

5 g/10 mL (500 mg/mL) (4 mEq Mg++/mL)

MUST BE DILUTED FOR INTRAVENOUS USE.

For Intravenous or Intramuscular Use. Sterile. 4.06 mOsmol/mL (calc.).

Contains no more than 75 mcg/L of aluminum.

Hospira, Inc., Lake Forest, IL 60045 USA

Hospira

RL-6891

Magnesium (Magnesium Oxide):



Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) Sulfate

Injection, USP

Ansyr Plastic Syringe

Rx only

Hospira Logo

DESCRIPTION

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) Sulfate Injection, USP is a sterile solution of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) sulfate heptahydrate in Water for Injection, USP administered by the intravenous or intramuscular routes as an electrolyte replenisher or anticonvulsant. Must be diluted before intravenous use. May contain sulfuric acid and/or sodium hydroxide for pH adjustment. The pH is 5.5 to 7.0. The 50% concentration has an osmolarity of 4.06 mOsmol/mL (calc.).

The solution contains no bacteriostat, antimicrobial agent or added buffer (except for pH adjustment) and is intended only for use as a single-dose injection. When smaller doses are required the unused portion should be discarded with the entire unit.

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) Sulfate, USP heptahydrate is chemically designated MgSO4 - 7H2O with molecular weight of 246.48 and occurs as colorless crystals or white powder freely soluble in water.

The plastic syringe is molded from a specially formulated polypropylene. Water permeates from inside the container at an extremely slow rate which will have an insignificant effect on solution concentration over the expected shelf life. Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the syringe material.

CLINICAL PHARMACOLOGY

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) (Mg++) is an important cofactor for enzymatic reactions and plays an important role in neurochemical transmission and muscular excitability.

As a nutritional adjunct in hyperalimentation, the precise mechanism of action for Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) is uncertain. Early symptoms of hypomagnesemia (less than 1.5 mEq/liter) may develop as early as three to four days or within weeks.

Predominant deficiency effects are neurological, e.g., muscle irritability, clonic twitching and tremors. Hypocalcemia and hypokalemia often follow low serum levels of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)). While there are large stores of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) present intracellularly and in the bones of adults, these stores often are not mobilized sufficiently to maintain plasma levels. Parenteral Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) therapy repairs the plasma deficit and causes deficiency symptoms and signs to cease.

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) prevents or controls convulsions by blocking neuromuscular transmission and decreasing the amount of acetylcholine liberated at the end plate by the motor nerve impulse. Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) is said to have a depressant effect on the central nervous system (CNS), but it does not adversely affect the woman, fetus or neonate when used as directed in eclampsia or pre-eclampsia. Normal plasma Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) levels range from 1.5 to 2.5 mEq/liter.

As plasma Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) rises above 4 mEq/liter, the deep tendon reflexes are first decreased and then disappear as the plasma level approaches 10 mEq/liter. At this level respiratory paralysis may occur. Heart block also may occur at this or lower plasma levels of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)). Serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) concentrations in excess of 12 mEq/L may be fatal.

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) acts peripherally to produce vasodilation. With low doses only flushing and sweating occur, but larger doses cause lowering of blood pressure. The central and peripheral effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) poisoning are antagonized to some extent by intravenous administration of calcium.

Pharmacokinetics

With intravenous administration the onset of anticonvulsant action is immediate and lasts about 30 minutes. Following intramuscular administration the onset of action occurs in about one hour and persists for three to four hours. Effective anticonvulsant serum levels range from 2.5 to 7.5 mEq/liter. Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) is excreted solely by the kidneys at a rate proportional to the plasma concentration and glomerular filtration.

INDICATIONS AND USAGE

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) Sulfate Injection, USP is suitable for replacement therapy in Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) deficiency, especially in acute hypomagnesemia accompanied by signs of tetany similar to those observed in hypocalcemia. In such cases, the serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) (Mg++) level is usually below the lower limit of normal (1.5 to 2.5 mEq/liter) and the serum calcium (Ca++) level is normal (4.3 to 5.3 mEq/liter) or elevated.

In total parenteral nutrition (TPN), Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) sulfate may be added to the nutrient admixture to correct or prevent hypomagnesemia which can arise during the course of therapy.

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) Sulfate Injection, USP is also indicated for the prevention and control of seizures (convulsions) in pre-eclampsia and eclampsia, respectively.

CONTRAINDICATIONS

Parenteral administration of the drug is contraindicated in patients with heart block or myocardial damage.

WARNINGS

FETAL HARM: Continuous administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) sulfate beyond 5 to 7 days to pregnant women can lead to hypocalcemia and bone abnormalities in the developing fetus. These bone abnormalities include skeletal demineralization and osteopenia. In addition, cases of neonatal fracture have been reported. The shortest duration of treatment that can lead to fetal harm is not known. Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) sulfate should be used during pregnancy only if clearly needed. If Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) sulfate is given for treatment of preterm labor, the woman should be informed that the efficacy and safety of such use have not been established and that use of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) sulfate beyond 5 to 7 days may cause fetal abnormalities.

ALUMINUM TOXICITY: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

Parenteral use in the presence of renal insufficiency may lead to Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) intoxication. Intravenous use in the eclampsia should be reserved for immediate control of life-threatening convulsions.

PRECAUTIONS

General

Administer with caution if flushing and sweating occurs. When barbiturates, narcotics or other hypnotics (or systemic anesthetics) are to be given in conjunction with Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)), their dosage should be adjusted with caution because of additive CNS depressant effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)).

Because Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) is removed from the body solely by the kidneys, the drug should be used with caution in patients with renal impairment. Urine output should be maintained at a level of 100 mL or more during the four hours preceding each dose. Monitoring serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) levels and the patient's clinical status is essential to avoid the consequences of overdosage in toxemia. Clinical indications of a safe dosage regimen include the presence of the patellar reflex (knee jerk) and absence of respiratory depression (approximately 16 breaths or more/minute). When repeated doses of the drug are given parenterally, knee jerk reflexes should be tested before each dose and if they are absent, no additional Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) should be given until they return. Serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) levels usually sufficient to control convulsions range from 3 to 6 mg/100 mL (2.5 to 5 mEq/liter). The strength of the deep tendon reflexes begins to diminish when Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) levels exceed 4 mEq/liter. Reflexes may be absent at 10 mEq magnesium/liter, where respiratory paralysis is a potential hazard. An injectable calcium salt should be immediately available to counteract the potential hazards of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) intoxication in eclampsia.

50% Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) Sulfate Injection, USP must be diluted to a concentration of 20% or less prior to intravenous infusion. Rate of administration should be slow and cautious, to avoid producing hypermagnesemia. The 50% solution also should be diluted to 20% or less for intramuscular injection in infants and children.

Laboratory Tests

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) sulfate injection should not be given unless hypomagnesemia has been confirmed and the serum concentration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) is monitored. The normal serum level is 1.5 to 2.5 mEq/L.

Drug Interactions

CNS Depressants - When barbiturates, narcotics or other hypnotics (or systemic anesthetics), or other CNS depressants are to be given in conjunction with Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)), their dosage should be adjusted with caution because of additive CNS depressant effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)). CNS depression and peripheral transmission defects produced by Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) may be antagonized by calcium.

Neuromuscular Blocking Agents - Excessive neuromuscular block has occurred in patients receiving parenteral Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) sulfate and a neuromuscular blocking agent; these drugs should be administered concomitantly with caution.

Cardiac Glycosides - Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) sulfate should be administered with extreme caution in digitalized patients, because serious changes in cardiac conduction which can result in heart block may occur if administration of calcium is required to treat Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) toxicity.

Pregnancy

Teratogenic Effects

Pregnancy Category D (See WARNINGS and PRECAUTIONS )

See WARNINGS and PRECAUTIONS .

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) sulfate can cause fetal abnormalities when administered beyond 5 to 7 days to pregnant women. There are retrospective epidemiological studies and case reports documenting fetal abnormalities such as hypocalcemia, skeletal demineralization, osteopenia and other skeletal abnormalities with continuous maternal administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) sulfate for more than 5 to 7 days.1-10 Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) sulfate injection should be used during pregnancy only if clearly needed. If this drug is used during pregnancy, the woman should be apprised of the potential harm to the fetus.

Nonteratogenic Effects

When administered by continuous intravenous infusion (especially for more than 24 hours preceding delivery) to control convulsions in a toxemic woman, the newborn may show signs of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) toxicity, including neuromuscular or respiratory depression (See OVERDOSAGE ).

Labor and Delivery

Continuous administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) sulfate is an unapproved treatment for preterm labor. The safety and efficacy of such use have not been established. The administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) sulfate outside of its approved indication in pregnant women should be by trained obstetrical personnel in a hospital setting with appropriate obstetrical care facilities.

Nursing Mothers

Since Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) is distributed into milk during parenteral Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) sulfate administration, the drug should be used with caution in nursing women.

Geriatrics

Geriatric patients often require reduced dosage because of impaired renal function. In patients with severe impairment, dosage should not exceed 20 grams in 48 hours. Serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) should be monitored in such patients.

ADVERSE REACTIONS

The adverse effects of parenterally administered Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) usually are the result of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) intoxication. These include flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, cardiac and central nervous system depression proceeding to respiratory paralysis. Hypocalcemia with signs of tetany secondary to Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) sulfate therapy for eclampsia has been reported.

OVERDOSAGE

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) intoxication is manifested by a sharp drop in blood pressure and respiratory paralysis. Disappearance of the patellar reflex is a useful clinical sign to detect the onset of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) intoxication. In the event of overdosage, artificial ventilation must be provided until a calcium salt can be injected intravenously to antagonize the effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)).

For Treatment of Overdose

Artificial respiration is often required. Intravenous calcium, 10 to 20 mL of a 5% solution (diluted if desirable with isotonic sodium chloride for injection) is used to counteract effects of hypermagnesemia. Subcutaneous physostigmine, 0.5 to 1 mg may be helpful.

Hypermagnesemia in the newborn may require resuscitation and assisted ventilation via endotracheal intubation or intermittent positive pressure ventilation as well as intravenous calcium.

DOSAGE AND ADMINISTRATION

Dosage of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) sulfate must be carefully adjusted according to individual requirements and response, and administration of the drug should be discontinued as soon as the desired effect is obtained.

Both intravenous and intramuscular administration are appropriate. Intramuscular administration of the undiluted 50% solution results in therapeutic plasma levels in 60 minutes, whereas intravenous doses will provide a therapeutic level almost immediately. The rate of intravenous injection should generally not exceed 150 mg/minute (1.5 mL of a 10% concentration or its equivalent), except in severe eclampsia with seizures. Continuous maternal administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

Solutions for intravenous infusion must be diluted to a concentration of 20% or less prior to administration. The diluents commonly used are 5% Dextrose Injection, USP and 0.9% Sodium Chloride Injection, USP. Deep intramuscular injection of the undiluted (50%) solution is appropriate for adults, but the solution should be diluted to a 20% or less concentration prior to such injection in children.

In Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) Deficiency

In the treatment of mild Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) deficiency, the usual adult dose is 1 gram, equivalent to 8.12 mEq of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) (2 mL of the 50% solution) injected intramuscularly every six hours for four doses (equivalent to a total of 32.5 mEq of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) per 24 hours). For severe hypomagnesemia, as much as 250 mg (approximately 2 mEq) per kg of body weight (0.5 mL of the 50% solution) may be given intramuscularly within a period of four hours if necessary. Alternatively, 5 grams, (approximately 40 mEq) can be added to one liter of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP for slow intravenous infusion over a three-hour period. In the treatment of deficiency states, caution must be observed to prevent exceeding the renal excretory capacity.

In Hyperalimentation

In total parenteral nutrition, maintenance requirements for Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) are not precisely known. The maintenance dose used in adults ranges from 8 to 24 mEq (1 gram to 3 grams) daily; for infants, the range is 2 to 10 mEq (0.25 gram to 1.25 grams) daily.

In Pre-eclampsia or Eclampsia

In severe pre-eclampsia or eclampsia, the total initial dose is 10 grams to 14 grams of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) sulfate. Intravenously, a dose of 4 grams to 5 grams in 250 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP may be infused. Simultaneously, intramuscular doses of up to 10 grams (5 grams or 10 mL of the undiluted 50% solution in each buttock) are given. Alternatively, the initial intravenous dose of 4 grams may be given by diluting the 50% solution to a 10 or 20% concentration; the diluted fluid (40 mL of a 10% solution or 20 mL of a 20% solution) may then be injected intravenously over a period of three to four minutes. Subsequently, 4 grams to 5 grams (8 to 10 mL of the 50% solution) are injected intramuscularly into alternate buttocks every four hours as needed, depending on the continuing presence of the patellar reflex and adequate respiratory function. Alternatively, after the initial intravenous dose, some clinicians administer 1 gram to 2 grams/hour by constant intravenous infusion. Therapy should continue until paroxysms cease. A serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) level of 6 mg/100 mL is considered optimal for control of seizures. A total daily (24 hr) dose of 30 grams to 40 grams should not be exceeded. In the presence of severe renal insufficiency, the maximum dosage of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) sulfate is 20 grams/48 hours and frequent serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) concentrations must be obtained. Continuous use of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

Other Uses

In counteracting the muscle-stimulating effects of barium poisoning, the usual dose of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) sulfate is 1 gram to 2 grams given intravenously.

For controlling seizures associated with epilepsy, glomerulonephritis or hypothyroidism, the usual adult dose is 1 gram administered intramuscularly or intravenously.

In paroxysmal atrial tachycardia, Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) should be used only if simpler measures have failed and there is no evidence of myocardial damage. The usual dose is 3 grams to 4 grams (30 to 40 mL of a 10% solution) administered intravenously over 30 seconds with extreme caution.

For reduction of cerebral edema, 2.5 grams (25 mL of a 10% solution) is given intravenously.

Incompatibilities

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) sulfate in solution may result in a precipitate formation when mixed with solutions containing:

Alcohol (in high Heavy Metals

concentrations) Hydrocortisone sodium

Alkali carbonates and succinate

bicarbonates Phosphates

Alkali hydroxides Polymixin B sulfate

Arsenates Procaine hydrochloride

Barium Salicylates

Calcium Strontium

Clindamycin phosphate Tartrates

The potential incompatibility will often be influenced by the changes in the concentration of reactants and the pH of the solutions.

It has been reported that Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) may reduce the antibiotic activity of streptomycin, tetracycline and tobramycin when given together.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

HOW SUPPLIED

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) Sulfate Injection, USP is supplied in single-dose containers as follows:


NDC No.


Container


Total

Amount


Concentration


mEq

Mg++/mL


0409-1754-10


Ansyr

Plastic Syringe


5 g/10 mL


50%


4 mEq/mL


Do not administer unless solution is clear and container is undamaged. Discard unused portion.

Store at 20 to 25°C (68 to 77°F).

REFERENCES

  • Yokoyama K, Takahashi N, Yada Y. Prolonged maternal Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) administration and bone metabolism in neonates. Early Hum Dev. 2010;86(3):187-91. Epub 2010 Mar 12.
  • Wedig KE, Kogan J, Schorry EK et al. Skeletal demineralization and fractures caused by fetal Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) toxicity. J. Perinatol. 2006; 26(6):371-4.
  • Nassar AH, Sakhel K, Maarouf H, et al. Adverse maternal and neonatal outcome of prolonged course of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) sulfate tocolysis. Acta Obstet Gynecol Scan. 2006;85(9):1099-103.
  • Malaeb SN, Rassi A, Haddad MC. Bone mineralization in newborns whose mothers received Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) sulphate for tocolysis of premature labor. Pediatr Radiol. 2004;34(5):384-6. Epub 2004 Feb 18.
  • Matsuda Y, Maeda Y, Ito M, et al. Effect of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) sulfate treatment on neonatal bone abnormalities. Gynecol Obstet Invest. 1997;44(2):82-8.
  • Schanler RJ, Smith LG, Burns PA. Effects of long-term maternal intravenous Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) sulfate therapy on neonatal calcium metabolism and bone mineral content. Gynecol Obstet Invest. 1997;43(4):236-41.
  • Santi MD, Henry GW, Douglas GL. Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) sulfate treatment of preterm labor as a cause of abnormal neonatal bone mineralization. J Pediatr Orthrop. 1994;14(2):249-53.
  • Holcomb WL, Shackelford GD, Petrie RH. Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) tocolysis and neonatal bone abnormalities; a controlled study. Obstet Gynecol. 1991; 78(4):611-4.
  • Cumming WA, Thomas VJ. Hypermagnesemia: a cause of abnormal metaphyses in the neonate. Am J Roentgenol. 1989; 152(5):1071-2.
  • Lamm CL, Norton KL, Murphy RJ. Congenital rickets associated with Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) sulfate infusion for tocolysis. J Pediatr. 1988; 113(6):1078-82.
  • McGuinness GA, Weinstein MM, Cruikshank DP, et al. Effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) sulfate treatment on perinatal calcium metabolism. II. Neonatal responses. Obstet Gynecol. 1980; 56(5): 595-600.
  • Riaz M, Porat R, Brodsky NL, et al. The effects of maternal Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) sulfate treatment on newborns: a prospective controlled study. J. Perinatol. 1998;18(6 pt 1):449-54.

Hospira, Inc., Lake Forest, IL 60045 USA

LAB-1024-1.0

April 2017

Hospira Logo

50% Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) Sulfate 5 g/10 mL (500 mg/mL)

Rx only

NDC 0409-1754-10

10 mL Single-dose syringe

50% Super Multi-Minerals Regular Strength (Magnesium (Magnesium Oxide)) Sulfate Injection, USP

5 g/10 mL (500 mg/mL) (4 mEq Mg++/mL)

MUST BE DILUTED FOR INTRAVENOUS USE.

For Intravenous or Intramuscular Use. Sterile. 4.06 mOsmol/mL (calc.).

Contains no more than 75 mcg/L of aluminum.

Hospira, Inc., Lake Forest, IL 60045 USA

Hospira

RL-6891

Magnesium (Magnesium Succinate):



Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) Sulfate

Injection, USP

Ansyr Plastic Syringe

Rx only

Hospira Logo

DESCRIPTION

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) Sulfate Injection, USP is a sterile solution of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) sulfate heptahydrate in Water for Injection, USP administered by the intravenous or intramuscular routes as an electrolyte replenisher or anticonvulsant. Must be diluted before intravenous use. May contain sulfuric acid and/or sodium hydroxide for pH adjustment. The pH is 5.5 to 7.0. The 50% concentration has an osmolarity of 4.06 mOsmol/mL (calc.).

The solution contains no bacteriostat, antimicrobial agent or added buffer (except for pH adjustment) and is intended only for use as a single-dose injection. When smaller doses are required the unused portion should be discarded with the entire unit.

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) Sulfate, USP heptahydrate is chemically designated MgSO4 - 7H2O with molecular weight of 246.48 and occurs as colorless crystals or white powder freely soluble in water.

The plastic syringe is molded from a specially formulated polypropylene. Water permeates from inside the container at an extremely slow rate which will have an insignificant effect on solution concentration over the expected shelf life. Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the syringe material.

CLINICAL PHARMACOLOGY

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) (Mg++) is an important cofactor for enzymatic reactions and plays an important role in neurochemical transmission and muscular excitability.

As a nutritional adjunct in hyperalimentation, the precise mechanism of action for Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) is uncertain. Early symptoms of hypomagnesemia (less than 1.5 mEq/liter) may develop as early as three to four days or within weeks.

Predominant deficiency effects are neurological, e.g., muscle irritability, clonic twitching and tremors. Hypocalcemia and hypokalemia often follow low serum levels of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)). While there are large stores of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) present intracellularly and in the bones of adults, these stores often are not mobilized sufficiently to maintain plasma levels. Parenteral Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) therapy repairs the plasma deficit and causes deficiency symptoms and signs to cease.

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) prevents or controls convulsions by blocking neuromuscular transmission and decreasing the amount of acetylcholine liberated at the end plate by the motor nerve impulse. Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) is said to have a depressant effect on the central nervous system (CNS), but it does not adversely affect the woman, fetus or neonate when used as directed in eclampsia or pre-eclampsia. Normal plasma Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) levels range from 1.5 to 2.5 mEq/liter.

As plasma Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) rises above 4 mEq/liter, the deep tendon reflexes are first decreased and then disappear as the plasma level approaches 10 mEq/liter. At this level respiratory paralysis may occur. Heart block also may occur at this or lower plasma levels of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)). Serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) concentrations in excess of 12 mEq/L may be fatal.

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) acts peripherally to produce vasodilation. With low doses only flushing and sweating occur, but larger doses cause lowering of blood pressure. The central and peripheral effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) poisoning are antagonized to some extent by intravenous administration of calcium.

Pharmacokinetics

With intravenous administration the onset of anticonvulsant action is immediate and lasts about 30 minutes. Following intramuscular administration the onset of action occurs in about one hour and persists for three to four hours. Effective anticonvulsant serum levels range from 2.5 to 7.5 mEq/liter. Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) is excreted solely by the kidneys at a rate proportional to the plasma concentration and glomerular filtration.

INDICATIONS AND USAGE

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) Sulfate Injection, USP is suitable for replacement therapy in Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) deficiency, especially in acute hypomagnesemia accompanied by signs of tetany similar to those observed in hypocalcemia. In such cases, the serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) (Mg++) level is usually below the lower limit of normal (1.5 to 2.5 mEq/liter) and the serum calcium (Ca++) level is normal (4.3 to 5.3 mEq/liter) or elevated.

In total parenteral nutrition (TPN), Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) sulfate may be added to the nutrient admixture to correct or prevent hypomagnesemia which can arise during the course of therapy.

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) Sulfate Injection, USP is also indicated for the prevention and control of seizures (convulsions) in pre-eclampsia and eclampsia, respectively.

CONTRAINDICATIONS

Parenteral administration of the drug is contraindicated in patients with heart block or myocardial damage.

WARNINGS

FETAL HARM: Continuous administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) sulfate beyond 5 to 7 days to pregnant women can lead to hypocalcemia and bone abnormalities in the developing fetus. These bone abnormalities include skeletal demineralization and osteopenia. In addition, cases of neonatal fracture have been reported. The shortest duration of treatment that can lead to fetal harm is not known. Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) sulfate should be used during pregnancy only if clearly needed. If Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) sulfate is given for treatment of preterm labor, the woman should be informed that the efficacy and safety of such use have not been established and that use of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) sulfate beyond 5 to 7 days may cause fetal abnormalities.

ALUMINUM TOXICITY: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

Parenteral use in the presence of renal insufficiency may lead to Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) intoxication. Intravenous use in the eclampsia should be reserved for immediate control of life-threatening convulsions.

PRECAUTIONS

General

Administer with caution if flushing and sweating occurs. When barbiturates, narcotics or other hypnotics (or systemic anesthetics) are to be given in conjunction with Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)), their dosage should be adjusted with caution because of additive CNS depressant effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)).

Because Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) is removed from the body solely by the kidneys, the drug should be used with caution in patients with renal impairment. Urine output should be maintained at a level of 100 mL or more during the four hours preceding each dose. Monitoring serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) levels and the patient's clinical status is essential to avoid the consequences of overdosage in toxemia. Clinical indications of a safe dosage regimen include the presence of the patellar reflex (knee jerk) and absence of respiratory depression (approximately 16 breaths or more/minute). When repeated doses of the drug are given parenterally, knee jerk reflexes should be tested before each dose and if they are absent, no additional Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) should be given until they return. Serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) levels usually sufficient to control convulsions range from 3 to 6 mg/100 mL (2.5 to 5 mEq/liter). The strength of the deep tendon reflexes begins to diminish when Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) levels exceed 4 mEq/liter. Reflexes may be absent at 10 mEq magnesium/liter, where respiratory paralysis is a potential hazard. An injectable calcium salt should be immediately available to counteract the potential hazards of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) intoxication in eclampsia.

50% Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) Sulfate Injection, USP must be diluted to a concentration of 20% or less prior to intravenous infusion. Rate of administration should be slow and cautious, to avoid producing hypermagnesemia. The 50% solution also should be diluted to 20% or less for intramuscular injection in infants and children.

Laboratory Tests

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) sulfate injection should not be given unless hypomagnesemia has been confirmed and the serum concentration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) is monitored. The normal serum level is 1.5 to 2.5 mEq/L.

Drug Interactions

CNS Depressants - When barbiturates, narcotics or other hypnotics (or systemic anesthetics), or other CNS depressants are to be given in conjunction with Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)), their dosage should be adjusted with caution because of additive CNS depressant effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)). CNS depression and peripheral transmission defects produced by Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) may be antagonized by calcium.

Neuromuscular Blocking Agents - Excessive neuromuscular block has occurred in patients receiving parenteral Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) sulfate and a neuromuscular blocking agent; these drugs should be administered concomitantly with caution.

Cardiac Glycosides - Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) sulfate should be administered with extreme caution in digitalized patients, because serious changes in cardiac conduction which can result in heart block may occur if administration of calcium is required to treat Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) toxicity.

Pregnancy

Teratogenic Effects

Pregnancy Category D (See WARNINGS and PRECAUTIONS )

See WARNINGS and PRECAUTIONS .

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) sulfate can cause fetal abnormalities when administered beyond 5 to 7 days to pregnant women. There are retrospective epidemiological studies and case reports documenting fetal abnormalities such as hypocalcemia, skeletal demineralization, osteopenia and other skeletal abnormalities with continuous maternal administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) sulfate for more than 5 to 7 days.1-10 Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) sulfate injection should be used during pregnancy only if clearly needed. If this drug is used during pregnancy, the woman should be apprised of the potential harm to the fetus.

Nonteratogenic Effects

When administered by continuous intravenous infusion (especially for more than 24 hours preceding delivery) to control convulsions in a toxemic woman, the newborn may show signs of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) toxicity, including neuromuscular or respiratory depression (See OVERDOSAGE ).

Labor and Delivery

Continuous administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) sulfate is an unapproved treatment for preterm labor. The safety and efficacy of such use have not been established. The administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) sulfate outside of its approved indication in pregnant women should be by trained obstetrical personnel in a hospital setting with appropriate obstetrical care facilities.

Nursing Mothers

Since Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) is distributed into milk during parenteral Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) sulfate administration, the drug should be used with caution in nursing women.

Geriatrics

Geriatric patients often require reduced dosage because of impaired renal function. In patients with severe impairment, dosage should not exceed 20 grams in 48 hours. Serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) should be monitored in such patients.

ADVERSE REACTIONS

The adverse effects of parenterally administered Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) usually are the result of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) intoxication. These include flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, cardiac and central nervous system depression proceeding to respiratory paralysis. Hypocalcemia with signs of tetany secondary to Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) sulfate therapy for eclampsia has been reported.

OVERDOSAGE

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) intoxication is manifested by a sharp drop in blood pressure and respiratory paralysis. Disappearance of the patellar reflex is a useful clinical sign to detect the onset of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) intoxication. In the event of overdosage, artificial ventilation must be provided until a calcium salt can be injected intravenously to antagonize the effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)).

For Treatment of Overdose

Artificial respiration is often required. Intravenous calcium, 10 to 20 mL of a 5% solution (diluted if desirable with isotonic sodium chloride for injection) is used to counteract effects of hypermagnesemia. Subcutaneous physostigmine, 0.5 to 1 mg may be helpful.

Hypermagnesemia in the newborn may require resuscitation and assisted ventilation via endotracheal intubation or intermittent positive pressure ventilation as well as intravenous calcium.

DOSAGE AND ADMINISTRATION

Dosage of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) sulfate must be carefully adjusted according to individual requirements and response, and administration of the drug should be discontinued as soon as the desired effect is obtained.

Both intravenous and intramuscular administration are appropriate. Intramuscular administration of the undiluted 50% solution results in therapeutic plasma levels in 60 minutes, whereas intravenous doses will provide a therapeutic level almost immediately. The rate of intravenous injection should generally not exceed 150 mg/minute (1.5 mL of a 10% concentration or its equivalent), except in severe eclampsia with seizures. Continuous maternal administration of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

Solutions for intravenous infusion must be diluted to a concentration of 20% or less prior to administration. The diluents commonly used are 5% Dextrose Injection, USP and 0.9% Sodium Chloride Injection, USP. Deep intramuscular injection of the undiluted (50%) solution is appropriate for adults, but the solution should be diluted to a 20% or less concentration prior to such injection in children.

In Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) Deficiency

In the treatment of mild Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) deficiency, the usual adult dose is 1 gram, equivalent to 8.12 mEq of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) (2 mL of the 50% solution) injected intramuscularly every six hours for four doses (equivalent to a total of 32.5 mEq of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) per 24 hours). For severe hypomagnesemia, as much as 250 mg (approximately 2 mEq) per kg of body weight (0.5 mL of the 50% solution) may be given intramuscularly within a period of four hours if necessary. Alternatively, 5 grams, (approximately 40 mEq) can be added to one liter of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP for slow intravenous infusion over a three-hour period. In the treatment of deficiency states, caution must be observed to prevent exceeding the renal excretory capacity.

In Hyperalimentation

In total parenteral nutrition, maintenance requirements for Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) are not precisely known. The maintenance dose used in adults ranges from 8 to 24 mEq (1 gram to 3 grams) daily; for infants, the range is 2 to 10 mEq (0.25 gram to 1.25 grams) daily.

In Pre-eclampsia or Eclampsia

In severe pre-eclampsia or eclampsia, the total initial dose is 10 grams to 14 grams of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) sulfate. Intravenously, a dose of 4 grams to 5 grams in 250 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP may be infused. Simultaneously, intramuscular doses of up to 10 grams (5 grams or 10 mL of the undiluted 50% solution in each buttock) are given. Alternatively, the initial intravenous dose of 4 grams may be given by diluting the 50% solution to a 10 or 20% concentration; the diluted fluid (40 mL of a 10% solution or 20 mL of a 20% solution) may then be injected intravenously over a period of three to four minutes. Subsequently, 4 grams to 5 grams (8 to 10 mL of the 50% solution) are injected intramuscularly into alternate buttocks every four hours as needed, depending on the continuing presence of the patellar reflex and adequate respiratory function. Alternatively, after the initial intravenous dose, some clinicians administer 1 gram to 2 grams/hour by constant intravenous infusion. Therapy should continue until paroxysms cease. A serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) level of 6 mg/100 mL is considered optimal for control of seizures. A total daily (24 hr) dose of 30 grams to 40 grams should not be exceeded. In the presence of severe renal insufficiency, the maximum dosage of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) sulfate is 20 grams/48 hours and frequent serum Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) concentrations must be obtained. Continuous use of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

Other Uses

In counteracting the muscle-stimulating effects of barium poisoning, the usual dose of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) sulfate is 1 gram to 2 grams given intravenously.

For controlling seizures associated with epilepsy, glomerulonephritis or hypothyroidism, the usual adult dose is 1 gram administered intramuscularly or intravenously.

In paroxysmal atrial tachycardia, Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) should be used only if simpler measures have failed and there is no evidence of myocardial damage. The usual dose is 3 grams to 4 grams (30 to 40 mL of a 10% solution) administered intravenously over 30 seconds with extreme caution.

For reduction of cerebral edema, 2.5 grams (25 mL of a 10% solution) is given intravenously.

Incompatibilities

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) sulfate in solution may result in a precipitate formation when mixed with solutions containing:

Alcohol (in high Heavy Metals

concentrations) Hydrocortisone sodium

Alkali carbonates and succinate

bicarbonates Phosphates

Alkali hydroxides Polymixin B sulfate

Arsenates Procaine hydrochloride

Barium Salicylates

Calcium Strontium

Clindamycin phosphate Tartrates

The potential incompatibility will often be influenced by the changes in the concentration of reactants and the pH of the solutions.

It has been reported that Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) may reduce the antibiotic activity of streptomycin, tetracycline and tobramycin when given together.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

HOW SUPPLIED

Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) Sulfate Injection, USP is supplied in single-dose containers as follows:


NDC No.


Container


Total

Amount


Concentration


mEq

Mg++/mL


0409-1754-10


Ansyr

Plastic Syringe


5 g/10 mL


50%


4 mEq/mL


Do not administer unless solution is clear and container is undamaged. Discard unused portion.

Store at 20 to 25°C (68 to 77°F).

REFERENCES

  • Yokoyama K, Takahashi N, Yada Y. Prolonged maternal Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) administration and bone metabolism in neonates. Early Hum Dev. 2010;86(3):187-91. Epub 2010 Mar 12.
  • Wedig KE, Kogan J, Schorry EK et al. Skeletal demineralization and fractures caused by fetal Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) toxicity. J. Perinatol. 2006; 26(6):371-4.
  • Nassar AH, Sakhel K, Maarouf H, et al. Adverse maternal and neonatal outcome of prolonged course of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) sulfate tocolysis. Acta Obstet Gynecol Scan. 2006;85(9):1099-103.
  • Malaeb SN, Rassi A, Haddad MC. Bone mineralization in newborns whose mothers received Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) sulphate for tocolysis of premature labor. Pediatr Radiol. 2004;34(5):384-6. Epub 2004 Feb 18.
  • Matsuda Y, Maeda Y, Ito M, et al. Effect of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) sulfate treatment on neonatal bone abnormalities. Gynecol Obstet Invest. 1997;44(2):82-8.
  • Schanler RJ, Smith LG, Burns PA. Effects of long-term maternal intravenous Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) sulfate therapy on neonatal calcium metabolism and bone mineral content. Gynecol Obstet Invest. 1997;43(4):236-41.
  • Santi MD, Henry GW, Douglas GL. Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) sulfate treatment of preterm labor as a cause of abnormal neonatal bone mineralization. J Pediatr Orthrop. 1994;14(2):249-53.
  • Holcomb WL, Shackelford GD, Petrie RH. Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) tocolysis and neonatal bone abnormalities; a controlled study. Obstet Gynecol. 1991; 78(4):611-4.
  • Cumming WA, Thomas VJ. Hypermagnesemia: a cause of abnormal metaphyses in the neonate. Am J Roentgenol. 1989; 152(5):1071-2.
  • Lamm CL, Norton KL, Murphy RJ. Congenital rickets associated with Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) sulfate infusion for tocolysis. J Pediatr. 1988; 113(6):1078-82.
  • McGuinness GA, Weinstein MM, Cruikshank DP, et al. Effects of Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) sulfate treatment on perinatal calcium metabolism. II. Neonatal responses. Obstet Gynecol. 1980; 56(5): 595-600.
  • Riaz M, Porat R, Brodsky NL, et al. The effects of maternal Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) sulfate treatment on newborns: a prospective controlled study. J. Perinatol. 1998;18(6 pt 1):449-54.

Hospira, Inc., Lake Forest, IL 60045 USA

LAB-1024-1.0

April 2017

Hospira Logo

50% Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) Sulfate 5 g/10 mL (500 mg/mL)

Rx only

NDC 0409-1754-10

10 mL Single-dose syringe

50% Super Multi-Minerals Regular Strength (Magnesium (Magnesium Succinate)) Sulfate Injection, USP

5 g/10 mL (500 mg/mL) (4 mEq Mg++/mL)

MUST BE DILUTED FOR INTRAVENOUS USE.

For Intravenous or Intramuscular Use. Sterile. 4.06 mOsmol/mL (calc.).

Contains no more than 75 mcg/L of aluminum.

Hospira, Inc., Lake Forest, IL 60045 USA

Hospira

RL-6891

Super Multi-Minerals Regular Strength pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Super Multi-Minerals Regular Strength available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Super Multi-Minerals Regular Strength destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Super Multi-Minerals Regular Strength Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Super Multi-Minerals Regular Strength pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."COPPER: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."CALCIUM: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "Iodine". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Super Multi-Minerals Regular Strength?

Depending on the reaction of the Super Multi-Minerals Regular Strength after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Super Multi-Minerals Regular Strength not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Super Multi-Minerals Regular Strength addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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sdrugs.com conducted a study on Super Multi-Minerals Regular Strength, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Super Multi-Minerals Regular Strength consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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