Calcium; Magnesium; Vitamin D3

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Calcium; Magnesium; Vitamin D3 uses

Calcium; Magnesium; Vitamin D3 consists of Calcium (Calcium Carbonate), Calcium (Calcium Citrate), Calcium (Calcium Fumarate), Calcium (Calcium Glutarate), Calcium (Calcium Malate), Calcium (Calcium Succinate), Magnesium (Magnesium Citrate), Magnesium (Magnesium Fumarate), Magnesium (Magnesium Glutarate), Magnesium (Magnesium Malate), Magnesium (Magnesium Oxide), Magnesium (Magnesium Succinate), Vitamin D3.

Calcium (Calcium Carbonate):


1 INDICATIONS AND USAGE

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate capsule.

- Capsule: 667 mg Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Calcium; Magnesium; Vitamin D3 ) acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)), including Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate. Avoid the use of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) supplements, including Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) based nonprescription antacids, concurrently with Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate.

An overdose of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) levels twice weekly. Should hypercalcemia develop, reduce the Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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, Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate has been generally well tolerated.

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate

N=167

N (%)


3 month, open label study of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate

N=98

N (%)


Double blind, placebo-controlled, cross-over study of liquid Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate

N=69


Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) concentration could reduce the incidence and severity of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate: dizziness, edema, and weakness.

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7 DRUG INTERACTIONS

The drug interaction of Calcium; Magnesium; Vitamin D3 ) acetate is characterized by the potential of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate and most concomitant drugs. When administering an oral medication with Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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:

Calcium; Magnesium; Vitamin D3 ) acetate capsules contains Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate. Animal reproduction studies have not been conducted with Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate, and there are no adequate and well controlled studies of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Calcium; Magnesium; Vitamin D3 (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. Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate treatment, as recommended, is not expected to harm a fetus if maternal Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Calcium; Magnesium; Vitamin D3 ) Acetate Capsules contains Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate and is excreted in human milk. Human milk feeding by a mother receiving Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate is not expected to harm an infant, provided maternal serum Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate acts as a phosphate binder. Its chemical name is Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate USP (anhydrous; Ca(CH3COO)2; MW=158.17 grams) equal to 169 mg (8.45 mEq) Calcium; Magnesium; Vitamin D3 (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.

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 ) resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate.

14 CLINICAL STUDIES

Effectiveness of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Calcium; Magnesium; Vitamin D3 (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


Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate is shown in the Table 3.


* ANOVA of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate vs. placebo after 2 weeks of treatment.

Values expressed as mean ± SEM.


Parameter


Pre-Study


Post-Treatment


p-value*


Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) Acetate


Placebo


Phosphorus (mg/dL)


7.3 ± 0.18


5.9 ± 0.24


7.8 ± 0.22


<0.01


Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) acetate capsule.

- Capsule: 667 mg Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Calcium; Magnesium; Vitamin D3 ) acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)), including Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) acetate. Avoid the use of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) supplements, including Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) based nonprescription antacids, concurrently with Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) acetate.

An overdose of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) levels twice weekly. Should hypercalcemia develop, reduce the Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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, Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) acetate has been generally well tolerated.

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) acetate

N=167

N (%)


3 month, open label study of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) acetate

N=98

N (%)


Double blind, placebo-controlled, cross-over study of liquid Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) acetate

N=69


Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) concentration could reduce the incidence and severity of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of Calcium; Magnesium; Vitamin D3 ) acetate is characterized by the potential of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) acetate and most concomitant drugs. When administering an oral medication with Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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:

Calcium; Magnesium; Vitamin D3 ) acetate capsules contains Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) acetate. Animal reproduction studies have not been conducted with Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) acetate, and there are no adequate and well controlled studies of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Calcium; Magnesium; Vitamin D3 (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. Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) acetate treatment, as recommended, is not expected to harm a fetus if maternal Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Calcium; Magnesium; Vitamin D3 ) Acetate Capsules contains Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) acetate and is excreted in human milk. Human milk feeding by a mother receiving Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) acetate is not expected to harm an infant, provided maternal serum Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) acetate acts as a phosphate binder. Its chemical name is Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) acetate USP (anhydrous; Ca(CH3COO)2; MW=158.17 grams) equal to 169 mg (8.45 mEq) Calcium; Magnesium; Vitamin D3 (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.

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 ) resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) acetate.

14 CLINICAL STUDIES

Effectiveness of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Calcium; Magnesium; Vitamin D3 (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


Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) acetate is shown in the Table 3.


* ANOVA of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) acetate vs. placebo after 2 weeks of treatment.

Values expressed as mean ± SEM.


Parameter


Pre-Study


Post-Treatment


p-value*


Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) Acetate


Placebo


Phosphorus (mg/dL)


7.3 ± 0.18


5.9 ± 0.24


7.8 ± 0.22


<0.01


Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Citrate)) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Calcium (Calcium Fumarate):


1 INDICATIONS AND USAGE

Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate capsule.

- Capsule: 667 mg Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Calcium; Magnesium; Vitamin D3 ) acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)), including Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate. Avoid the use of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) supplements, including Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) based nonprescription antacids, concurrently with Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate.

An overdose of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) levels twice weekly. Should hypercalcemia develop, reduce the Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) 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, Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate has been generally well tolerated.

Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate

N=167

N (%)


3 month, open label study of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate

N=98

N (%)


Double blind, placebo-controlled, cross-over study of liquid Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate

N=69


Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) concentration could reduce the incidence and severity of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of Calcium; Magnesium; Vitamin D3 ) acetate is characterized by the potential of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate and most concomitant drugs. When administering an oral medication with Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

Calcium; Magnesium; Vitamin D3 ) acetate capsules contains Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate. Animal reproduction studies have not been conducted with Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate, and there are no adequate and well controlled studies of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) 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. Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate treatment, as recommended, is not expected to harm a fetus if maternal Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Calcium; Magnesium; Vitamin D3 ) Acetate Capsules contains Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate and is excreted in human milk. Human milk feeding by a mother receiving Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate is not expected to harm an infant, provided maternal serum Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate acts as a phosphate binder. Its chemical name is Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate USP (anhydrous; Ca(CH3COO)2; MW=158.17 grams) equal to 169 mg (8.45 mEq) Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)), 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.

Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Magnesium; Vitamin D3 ) resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate.

14 CLINICAL STUDIES

Effectiveness of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) 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


Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) (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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate is shown in the Table 3.


* ANOVA of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate vs. placebo after 2 weeks of treatment.

Values expressed as mean ± SEM.


Parameter


Pre-Study


Post-Treatment


p-value*


Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) Acetate


Placebo


Phosphorus (mg/dL)


7.3 ± 0.18


5.9 ± 0.24


7.8 ± 0.22


<0.01


Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) (mg/dL)


8.9 ± 0.11


9.5 ± 0.13


8.8 ± 0.12


<0.01


Overall, 2 weeks of treatment with Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Calcium (Calcium Glutarate):


1 INDICATIONS AND USAGE

Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate capsule.

- Capsule: 667 mg Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Calcium; Magnesium; Vitamin D3 ) acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)), including Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate. Avoid the use of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) supplements, including Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) based nonprescription antacids, concurrently with Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate.

An overdose of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) levels twice weekly. Should hypercalcemia develop, reduce the Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) 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, Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate has been generally well tolerated.

Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate

N=167

N (%)


3 month, open label study of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate

N=98

N (%)


Double blind, placebo-controlled, cross-over study of liquid Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate

N=69


Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) concentration could reduce the incidence and severity of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of Calcium; Magnesium; Vitamin D3 ) acetate is characterized by the potential of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate and most concomitant drugs. When administering an oral medication with Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

Calcium; Magnesium; Vitamin D3 ) acetate capsules contains Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate. Animal reproduction studies have not been conducted with Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate, and there are no adequate and well controlled studies of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) 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. Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate treatment, as recommended, is not expected to harm a fetus if maternal Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Calcium; Magnesium; Vitamin D3 ) Acetate Capsules contains Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate and is excreted in human milk. Human milk feeding by a mother receiving Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate is not expected to harm an infant, provided maternal serum Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate acts as a phosphate binder. Its chemical name is Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate USP (anhydrous; Ca(CH3COO)2; MW=158.17 grams) equal to 169 mg (8.45 mEq) Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)), 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.

Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 ) resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate.

14 CLINICAL STUDIES

Effectiveness of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) 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


Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) (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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate is shown in the Table 3.


* ANOVA of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate vs. placebo after 2 weeks of treatment.

Values expressed as mean ± SEM.


Parameter


Pre-Study


Post-Treatment


p-value*


Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) Acetate


Placebo


Phosphorus (mg/dL)


7.3 ± 0.18


5.9 ± 0.24


7.8 ± 0.22


<0.01


Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) (mg/dL)


8.9 ± 0.11


9.5 ± 0.13


8.8 ± 0.12


<0.01


Overall, 2 weeks of treatment with Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Calcium (Calcium Malate):


1 INDICATIONS AND USAGE

Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) acetate capsule.

- Capsule: 667 mg Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Calcium; Magnesium; Vitamin D3 ) acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)), including Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) acetate. Avoid the use of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) supplements, including Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) based nonprescription antacids, concurrently with Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) acetate.

An overdose of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) levels twice weekly. Should hypercalcemia develop, reduce the Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) 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, Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) acetate has been generally well tolerated.

Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) acetate

N=167

N (%)


3 month, open label study of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) acetate

N=98

N (%)


Double blind, placebo-controlled, cross-over study of liquid Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) acetate

N=69


Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) concentration could reduce the incidence and severity of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of Calcium; Magnesium; Vitamin D3 ) acetate is characterized by the potential of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) acetate and most concomitant drugs. When administering an oral medication with Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

Calcium; Magnesium; Vitamin D3 ) acetate capsules contains Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) acetate. Animal reproduction studies have not been conducted with Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) acetate, and there are no adequate and well controlled studies of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) 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. Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) acetate treatment, as recommended, is not expected to harm a fetus if maternal Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Calcium; Magnesium; Vitamin D3 ) Acetate Capsules contains Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) acetate and is excreted in human milk. Human milk feeding by a mother receiving Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) acetate is not expected to harm an infant, provided maternal serum Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) acetate acts as a phosphate binder. Its chemical name is Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) acetate USP (anhydrous; Ca(CH3COO)2; MW=158.17 grams) equal to 169 mg (8.45 mEq) Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)), 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.

Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Magnesium; Vitamin D3 ) resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) acetate.

14 CLINICAL STUDIES

Effectiveness of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) 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


Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) (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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) acetate is shown in the Table 3.


* ANOVA of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) acetate vs. placebo after 2 weeks of treatment.

Values expressed as mean ± SEM.


Parameter


Pre-Study


Post-Treatment


p-value*


Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) Acetate


Placebo


Phosphorus (mg/dL)


7.3 ± 0.18


5.9 ± 0.24


7.8 ± 0.22


<0.01


Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) (mg/dL)


8.9 ± 0.11


9.5 ± 0.13


8.8 ± 0.12


<0.01


Overall, 2 weeks of treatment with Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Malate)) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Calcium (Calcium Succinate):


1 INDICATIONS AND USAGE

Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) acetate capsule.

- Capsule: 667 mg Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Calcium; Magnesium; Vitamin D3 ) acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)), including Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) acetate. Avoid the use of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) supplements, including Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) based nonprescription antacids, concurrently with Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) acetate.

An overdose of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) levels twice weekly. Should hypercalcemia develop, reduce the Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) 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, Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) acetate has been generally well tolerated.

Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) acetate

N=167

N (%)


3 month, open label study of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) acetate

N=98

N (%)


Double blind, placebo-controlled, cross-over study of liquid Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) acetate

N=69


Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) concentration could reduce the incidence and severity of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of Calcium; Magnesium; Vitamin D3 ) acetate is characterized by the potential of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) acetate and most concomitant drugs. When administering an oral medication with Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

Calcium; Magnesium; Vitamin D3 ) acetate capsules contains Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) acetate. Animal reproduction studies have not been conducted with Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) acetate, and there are no adequate and well controlled studies of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) 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. Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) acetate treatment, as recommended, is not expected to harm a fetus if maternal Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Calcium; Magnesium; Vitamin D3 ) Acetate Capsules contains Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) acetate and is excreted in human milk. Human milk feeding by a mother receiving Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) acetate is not expected to harm an infant, provided maternal serum Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) acetate acts as a phosphate binder. Its chemical name is Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) acetate USP (anhydrous; Ca(CH3COO)2; MW=158.17 grams) equal to 169 mg (8.45 mEq) Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)), 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.

Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Magnesium; Vitamin D3 ) resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) acetate.

14 CLINICAL STUDIES

Effectiveness of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) 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


Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) (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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) acetate is shown in the Table 3.


* ANOVA of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) acetate vs. placebo after 2 weeks of treatment.

Values expressed as mean ± SEM.


Parameter


Pre-Study


Post-Treatment


p-value*


Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) Acetate


Placebo


Phosphorus (mg/dL)


7.3 ± 0.18


5.9 ± 0.24


7.8 ± 0.22


<0.01


Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) (mg/dL)


8.9 ± 0.11


9.5 ± 0.13


8.8 ± 0.12


<0.01


Overall, 2 weeks of treatment with Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Magnesium; Vitamin D3 (Calcium (Calcium Succinate)) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Magnesium (Magnesium Citrate):



Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Citrate)) Sulfate

Injection, USP

Ansyr Plastic Syringe

Rx only

Hospira Logo

DESCRIPTION

Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Citrate)) Sulfate Injection, USP is a sterile solution of Calcium; Magnesium; Vitamin D3 (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.

Calcium; Magnesium; Vitamin D3 (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

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Citrate)). While there are large stores of Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Citrate)) present intracellularly and in the bones of adults, these stores often are not mobilized sufficiently to maintain plasma levels. Parenteral Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Citrate)) therapy repairs the plasma deficit and causes deficiency symptoms and signs to cease.

Calcium; Magnesium; Vitamin D3 (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. Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Citrate)) levels range from 1.5 to 2.5 mEq/liter.

As plasma Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Citrate)). Serum Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Citrate)) concentrations in excess of 12 mEq/L may be fatal.

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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. Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Citrate)) is excreted solely by the kidneys at a rate proportional to the plasma concentration and glomerular filtration.

INDICATIONS AND USAGE

Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Citrate)) Sulfate Injection, USP is suitable for replacement therapy in Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Citrate)) deficiency, especially in acute hypomagnesemia accompanied by signs of tetany similar to those observed in hypocalcemia. In such cases, the serum Calcium; Magnesium; Vitamin D3 (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), Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Citrate)) sulfate may be added to the nutrient admixture to correct or prevent hypomagnesemia which can arise during the course of therapy.

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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. Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Citrate)) sulfate should be used during pregnancy only if clearly needed. If Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Citrate)), their dosage should be adjusted with caution because of additive CNS depressant effects of Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Citrate)).

Because Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Citrate)) should be given until they return. Serum Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Citrate)) intoxication in eclampsia.

50% Calcium; Magnesium; Vitamin D3 (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

Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Citrate)) sulfate injection should not be given unless hypomagnesemia has been confirmed and the serum concentration of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Citrate)), their dosage should be adjusted with caution because of additive CNS depressant effects of Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Citrate)). CNS depression and peripheral transmission defects produced by Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Citrate)) may be antagonized by calcium.

Neuromuscular Blocking Agents - Excessive neuromuscular block has occurred in patients receiving parenteral Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Citrate)) sulfate and a neuromuscular blocking agent; these drugs should be administered concomitantly with caution.

Cardiac Glycosides - Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Citrate)) toxicity.

Pregnancy

Teratogenic Effects

Pregnancy Category D (See WARNINGS and PRECAUTIONS )

See WARNINGS and PRECAUTIONS .

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Citrate)) sulfate for more than 5 to 7 days.1-10 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Citrate)) toxicity, including neuromuscular or respiratory depression (See OVERDOSAGE ).

Labor and Delivery

Continuous administration of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Citrate)) is distributed into milk during parenteral Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Citrate)) should be monitored in such patients.

ADVERSE REACTIONS

The adverse effects of parenterally administered Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Citrate)) usually are the result of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Citrate)) sulfate therapy for eclampsia has been reported.

OVERDOSAGE

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Citrate)) Deficiency

In the treatment of mild Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Citrate)) deficiency, the usual adult dose is 1 gram, equivalent to 8.12 mEq of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Citrate)) sulfate is 20 grams/48 hours and frequent serum Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Citrate)) concentrations must be obtained. Continuous use of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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, Calcium; Magnesium; Vitamin D3 (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

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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. Calcium; Magnesium; Vitamin D3 (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. Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Citrate)) sulfate infusion for tocolysis. J Pediatr. 1988; 113(6):1078-82.
  • McGuinness GA, Weinstein MM, Cruikshank DP, et al. Effects of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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% Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Citrate)) Sulfate 5 g/10 mL (500 mg/mL)

Rx only

NDC 0409-1754-10

10 mL Single-dose syringe

50% Calcium; Magnesium; Vitamin D3 (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):



Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Fumarate)) Sulfate

Injection, USP

Ansyr Plastic Syringe

Rx only

Hospira Logo

DESCRIPTION

Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Fumarate)) Sulfate Injection, USP is a sterile solution of Calcium; Magnesium; Vitamin D3 (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.

Calcium; Magnesium; Vitamin D3 (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

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Fumarate)). While there are large stores of Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Fumarate)) present intracellularly and in the bones of adults, these stores often are not mobilized sufficiently to maintain plasma levels. Parenteral Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Fumarate)) therapy repairs the plasma deficit and causes deficiency symptoms and signs to cease.

Calcium; Magnesium; Vitamin D3 (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. Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Fumarate)) levels range from 1.5 to 2.5 mEq/liter.

As plasma Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Fumarate)). Serum Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Fumarate)) concentrations in excess of 12 mEq/L may be fatal.

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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. Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Fumarate)) is excreted solely by the kidneys at a rate proportional to the plasma concentration and glomerular filtration.

INDICATIONS AND USAGE

Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Fumarate)) Sulfate Injection, USP is suitable for replacement therapy in Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Fumarate)) deficiency, especially in acute hypomagnesemia accompanied by signs of tetany similar to those observed in hypocalcemia. In such cases, the serum Calcium; Magnesium; Vitamin D3 (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), Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Fumarate)) sulfate may be added to the nutrient admixture to correct or prevent hypomagnesemia which can arise during the course of therapy.

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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. Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Fumarate)) sulfate should be used during pregnancy only if clearly needed. If Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Fumarate)), their dosage should be adjusted with caution because of additive CNS depressant effects of Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Fumarate)).

Because Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Fumarate)) should be given until they return. Serum Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Fumarate)) intoxication in eclampsia.

50% Calcium; Magnesium; Vitamin D3 (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

Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Fumarate)) sulfate injection should not be given unless hypomagnesemia has been confirmed and the serum concentration of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Fumarate)), their dosage should be adjusted with caution because of additive CNS depressant effects of Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Fumarate)). CNS depression and peripheral transmission defects produced by Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Fumarate)) may be antagonized by calcium.

Neuromuscular Blocking Agents - Excessive neuromuscular block has occurred in patients receiving parenteral Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Fumarate)) sulfate and a neuromuscular blocking agent; these drugs should be administered concomitantly with caution.

Cardiac Glycosides - Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Fumarate)) toxicity.

Pregnancy

Teratogenic Effects

Pregnancy Category D (See WARNINGS and PRECAUTIONS )

See WARNINGS and PRECAUTIONS .

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Fumarate)) sulfate for more than 5 to 7 days.1-10 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Fumarate)) toxicity, including neuromuscular or respiratory depression (See OVERDOSAGE ).

Labor and Delivery

Continuous administration of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Fumarate)) is distributed into milk during parenteral Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Fumarate)) should be monitored in such patients.

ADVERSE REACTIONS

The adverse effects of parenterally administered Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Fumarate)) usually are the result of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Fumarate)) sulfate therapy for eclampsia has been reported.

OVERDOSAGE

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Fumarate)) Deficiency

In the treatment of mild Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Fumarate)) deficiency, the usual adult dose is 1 gram, equivalent to 8.12 mEq of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Fumarate)) sulfate is 20 grams/48 hours and frequent serum Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Fumarate)) concentrations must be obtained. Continuous use of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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, Calcium; Magnesium; Vitamin D3 (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

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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. Calcium; Magnesium; Vitamin D3 (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. Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Fumarate)) sulfate infusion for tocolysis. J Pediatr. 1988; 113(6):1078-82.
  • McGuinness GA, Weinstein MM, Cruikshank DP, et al. Effects of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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% Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Fumarate)) Sulfate 5 g/10 mL (500 mg/mL)

Rx only

NDC 0409-1754-10

10 mL Single-dose syringe

50% Calcium; Magnesium; Vitamin D3 (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 Glutarate):



Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) Sulfate

Injection, USP

Ansyr Plastic Syringe

Rx only

Hospira Logo

DESCRIPTION

Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) Sulfate Injection, USP is a sterile solution of Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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.

Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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

Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)). While there are large stores of Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) present intracellularly and in the bones of adults, these stores often are not mobilized sufficiently to maintain plasma levels. Parenteral Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) therapy repairs the plasma deficit and causes deficiency symptoms and signs to cease.

Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) prevents or controls convulsions by blocking neuromuscular transmission and decreasing the amount of acetylcholine liberated at the end plate by the motor nerve impulse. Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) levels range from 1.5 to 2.5 mEq/liter.

As plasma Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)). Serum Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) concentrations in excess of 12 mEq/L may be fatal.

Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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. Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) is excreted solely by the kidneys at a rate proportional to the plasma concentration and glomerular filtration.

INDICATIONS AND USAGE

Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) Sulfate Injection, USP is suitable for replacement therapy in Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) deficiency, especially in acute hypomagnesemia accompanied by signs of tetany similar to those observed in hypocalcemia. In such cases, the serum Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) (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), Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) sulfate may be added to the nutrient admixture to correct or prevent hypomagnesemia which can arise during the course of therapy.

Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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. Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) sulfate should be used during pregnancy only if clearly needed. If Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)), their dosage should be adjusted with caution because of additive CNS depressant effects of Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)).

Because Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) should be given until they return. Serum Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) intoxication in eclampsia.

50% Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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

Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) sulfate injection should not be given unless hypomagnesemia has been confirmed and the serum concentration of Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)), their dosage should be adjusted with caution because of additive CNS depressant effects of Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)). CNS depression and peripheral transmission defects produced by Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) may be antagonized by calcium.

Neuromuscular Blocking Agents - Excessive neuromuscular block has occurred in patients receiving parenteral Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) sulfate and a neuromuscular blocking agent; these drugs should be administered concomitantly with caution.

Cardiac Glycosides - Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) toxicity.

Pregnancy

Teratogenic Effects

Pregnancy Category D (See WARNINGS and PRECAUTIONS )

See WARNINGS and PRECAUTIONS .

Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) sulfate for more than 5 to 7 days.1-10 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) toxicity, including neuromuscular or respiratory depression (See OVERDOSAGE ).

Labor and Delivery

Continuous administration of Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) sulfate is an unapproved treatment for preterm labor. The safety and efficacy of such use have not been established. The administration of Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) is distributed into milk during parenteral Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) should be monitored in such patients.

ADVERSE REACTIONS

The adverse effects of parenterally administered Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) usually are the result of Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) sulfate therapy for eclampsia has been reported.

OVERDOSAGE

Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) intoxication. In the event of overdosage, artificial ventilation must be provided until a calcium salt can be injected intravenously to antagonize the effects of Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)).

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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) Deficiency

In the treatment of mild Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) deficiency, the usual adult dose is 1 gram, equivalent to 8.12 mEq of Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) (2 mL of the 50% solution) injected intramuscularly every six hours for four doses (equivalent to a total of 32.5 mEq of Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) sulfate is 20 grams/48 hours and frequent serum Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) concentrations must be obtained. Continuous use of Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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, Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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

Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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

Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) sulfate tocolysis. Acta Obstet Gynecol Scan. 2006;85(9):1099-103.
  • Malaeb SN, Rassi A, Haddad MC. Bone mineralization in newborns whose mothers received Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) sulfate therapy on neonatal calcium metabolism and bone mineral content. Gynecol Obstet Invest. 1997;43(4):236-41.
  • Santi MD, Henry GW, Douglas GL. Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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. Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) sulfate infusion for tocolysis. J Pediatr. 1988; 113(6):1078-82.
  • McGuinness GA, Weinstein MM, Cruikshank DP, et al. Effects of Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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% Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) Sulfate 5 g/10 mL (500 mg/mL)

Rx only

NDC 0409-1754-10

10 mL Single-dose syringe

50% Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Glutarate)) 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):



Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Malate)) Sulfate

Injection, USP

Ansyr Plastic Syringe

Rx only

Hospira Logo

DESCRIPTION

Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Malate)) Sulfate Injection, USP is a sterile solution of Calcium; Magnesium; Vitamin D3 (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.

Calcium; Magnesium; Vitamin D3 (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

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Malate)). While there are large stores of Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Malate)) present intracellularly and in the bones of adults, these stores often are not mobilized sufficiently to maintain plasma levels. Parenteral Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Malate)) therapy repairs the plasma deficit and causes deficiency symptoms and signs to cease.

Calcium; Magnesium; Vitamin D3 (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. Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Malate)) levels range from 1.5 to 2.5 mEq/liter.

As plasma Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Malate)). Serum Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Malate)) concentrations in excess of 12 mEq/L may be fatal.

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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. Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Malate)) is excreted solely by the kidneys at a rate proportional to the plasma concentration and glomerular filtration.

INDICATIONS AND USAGE

Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Malate)) Sulfate Injection, USP is suitable for replacement therapy in Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Malate)) deficiency, especially in acute hypomagnesemia accompanied by signs of tetany similar to those observed in hypocalcemia. In such cases, the serum Calcium; Magnesium; Vitamin D3 (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), Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Malate)) sulfate may be added to the nutrient admixture to correct or prevent hypomagnesemia which can arise during the course of therapy.

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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. Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Malate)) sulfate should be used during pregnancy only if clearly needed. If Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Malate)), their dosage should be adjusted with caution because of additive CNS depressant effects of Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Malate)).

Because Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Malate)) should be given until they return. Serum Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Malate)) intoxication in eclampsia.

50% Calcium; Magnesium; Vitamin D3 (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

Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Malate)) sulfate injection should not be given unless hypomagnesemia has been confirmed and the serum concentration of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Malate)), their dosage should be adjusted with caution because of additive CNS depressant effects of Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Malate)). CNS depression and peripheral transmission defects produced by Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Malate)) may be antagonized by calcium.

Neuromuscular Blocking Agents - Excessive neuromuscular block has occurred in patients receiving parenteral Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Malate)) sulfate and a neuromuscular blocking agent; these drugs should be administered concomitantly with caution.

Cardiac Glycosides - Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Malate)) toxicity.

Pregnancy

Teratogenic Effects

Pregnancy Category D (See WARNINGS and PRECAUTIONS )

See WARNINGS and PRECAUTIONS .

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Malate)) sulfate for more than 5 to 7 days.1-10 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Malate)) toxicity, including neuromuscular or respiratory depression (See OVERDOSAGE ).

Labor and Delivery

Continuous administration of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Malate)) is distributed into milk during parenteral Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Malate)) should be monitored in such patients.

ADVERSE REACTIONS

The adverse effects of parenterally administered Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Malate)) usually are the result of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Malate)) sulfate therapy for eclampsia has been reported.

OVERDOSAGE

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Malate)) Deficiency

In the treatment of mild Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Malate)) deficiency, the usual adult dose is 1 gram, equivalent to 8.12 mEq of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Malate)) sulfate is 20 grams/48 hours and frequent serum Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Malate)) concentrations must be obtained. Continuous use of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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, Calcium; Magnesium; Vitamin D3 (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

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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. Calcium; Magnesium; Vitamin D3 (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. Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Malate)) sulfate infusion for tocolysis. J Pediatr. 1988; 113(6):1078-82.
  • McGuinness GA, Weinstein MM, Cruikshank DP, et al. Effects of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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% Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Malate)) Sulfate 5 g/10 mL (500 mg/mL)

Rx only

NDC 0409-1754-10

10 mL Single-dose syringe

50% Calcium; Magnesium; Vitamin D3 (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):



Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Oxide)) Sulfate

Injection, USP

Ansyr Plastic Syringe

Rx only

Hospira Logo

DESCRIPTION

Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Oxide)) Sulfate Injection, USP is a sterile solution of Calcium; Magnesium; Vitamin D3 (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.

Calcium; Magnesium; Vitamin D3 (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

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Oxide)). While there are large stores of Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Oxide)) present intracellularly and in the bones of adults, these stores often are not mobilized sufficiently to maintain plasma levels. Parenteral Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Oxide)) therapy repairs the plasma deficit and causes deficiency symptoms and signs to cease.

Calcium; Magnesium; Vitamin D3 (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. Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Oxide)) levels range from 1.5 to 2.5 mEq/liter.

As plasma Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Oxide)). Serum Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Oxide)) concentrations in excess of 12 mEq/L may be fatal.

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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. Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Oxide)) is excreted solely by the kidneys at a rate proportional to the plasma concentration and glomerular filtration.

INDICATIONS AND USAGE

Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Oxide)) Sulfate Injection, USP is suitable for replacement therapy in Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Oxide)) deficiency, especially in acute hypomagnesemia accompanied by signs of tetany similar to those observed in hypocalcemia. In such cases, the serum Calcium; Magnesium; Vitamin D3 (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), Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Oxide)) sulfate may be added to the nutrient admixture to correct or prevent hypomagnesemia which can arise during the course of therapy.

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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. Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Oxide)) sulfate should be used during pregnancy only if clearly needed. If Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Oxide)), their dosage should be adjusted with caution because of additive CNS depressant effects of Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Oxide)).

Because Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Oxide)) should be given until they return. Serum Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Oxide)) intoxication in eclampsia.

50% Calcium; Magnesium; Vitamin D3 (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

Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Oxide)) sulfate injection should not be given unless hypomagnesemia has been confirmed and the serum concentration of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Oxide)), their dosage should be adjusted with caution because of additive CNS depressant effects of Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Oxide)). CNS depression and peripheral transmission defects produced by Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Oxide)) may be antagonized by calcium.

Neuromuscular Blocking Agents - Excessive neuromuscular block has occurred in patients receiving parenteral Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Oxide)) sulfate and a neuromuscular blocking agent; these drugs should be administered concomitantly with caution.

Cardiac Glycosides - Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Oxide)) toxicity.

Pregnancy

Teratogenic Effects

Pregnancy Category D (See WARNINGS and PRECAUTIONS )

See WARNINGS and PRECAUTIONS .

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Oxide)) sulfate for more than 5 to 7 days.1-10 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Oxide)) toxicity, including neuromuscular or respiratory depression (See OVERDOSAGE ).

Labor and Delivery

Continuous administration of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Oxide)) is distributed into milk during parenteral Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Oxide)) should be monitored in such patients.

ADVERSE REACTIONS

The adverse effects of parenterally administered Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Oxide)) usually are the result of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Oxide)) sulfate therapy for eclampsia has been reported.

OVERDOSAGE

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Oxide)) Deficiency

In the treatment of mild Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Oxide)) deficiency, the usual adult dose is 1 gram, equivalent to 8.12 mEq of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Oxide)) sulfate is 20 grams/48 hours and frequent serum Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Oxide)) concentrations must be obtained. Continuous use of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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, Calcium; Magnesium; Vitamin D3 (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

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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. Calcium; Magnesium; Vitamin D3 (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. Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Oxide)) sulfate infusion for tocolysis. J Pediatr. 1988; 113(6):1078-82.
  • McGuinness GA, Weinstein MM, Cruikshank DP, et al. Effects of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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% Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Oxide)) Sulfate 5 g/10 mL (500 mg/mL)

Rx only

NDC 0409-1754-10

10 mL Single-dose syringe

50% Calcium; Magnesium; Vitamin D3 (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):



Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Succinate)) Sulfate

Injection, USP

Ansyr Plastic Syringe

Rx only

Hospira Logo

DESCRIPTION

Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Succinate)) Sulfate Injection, USP is a sterile solution of Calcium; Magnesium; Vitamin D3 (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.

Calcium; Magnesium; Vitamin D3 (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

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Succinate)). While there are large stores of Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Succinate)) present intracellularly and in the bones of adults, these stores often are not mobilized sufficiently to maintain plasma levels. Parenteral Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Succinate)) therapy repairs the plasma deficit and causes deficiency symptoms and signs to cease.

Calcium; Magnesium; Vitamin D3 (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. Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Succinate)) levels range from 1.5 to 2.5 mEq/liter.

As plasma Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Succinate)). Serum Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Succinate)) concentrations in excess of 12 mEq/L may be fatal.

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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. Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Succinate)) is excreted solely by the kidneys at a rate proportional to the plasma concentration and glomerular filtration.

INDICATIONS AND USAGE

Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Succinate)) Sulfate Injection, USP is suitable for replacement therapy in Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Succinate)) deficiency, especially in acute hypomagnesemia accompanied by signs of tetany similar to those observed in hypocalcemia. In such cases, the serum Calcium; Magnesium; Vitamin D3 (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), Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Succinate)) sulfate may be added to the nutrient admixture to correct or prevent hypomagnesemia which can arise during the course of therapy.

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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. Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Succinate)) sulfate should be used during pregnancy only if clearly needed. If Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Succinate)), their dosage should be adjusted with caution because of additive CNS depressant effects of Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Succinate)).

Because Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Succinate)) should be given until they return. Serum Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Succinate)) intoxication in eclampsia.

50% Calcium; Magnesium; Vitamin D3 (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

Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Succinate)) sulfate injection should not be given unless hypomagnesemia has been confirmed and the serum concentration of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Succinate)), their dosage should be adjusted with caution because of additive CNS depressant effects of Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Succinate)). CNS depression and peripheral transmission defects produced by Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Succinate)) may be antagonized by calcium.

Neuromuscular Blocking Agents - Excessive neuromuscular block has occurred in patients receiving parenteral Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Succinate)) sulfate and a neuromuscular blocking agent; these drugs should be administered concomitantly with caution.

Cardiac Glycosides - Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Succinate)) toxicity.

Pregnancy

Teratogenic Effects

Pregnancy Category D (See WARNINGS and PRECAUTIONS )

See WARNINGS and PRECAUTIONS .

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Succinate)) sulfate for more than 5 to 7 days.1-10 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Succinate)) toxicity, including neuromuscular or respiratory depression (See OVERDOSAGE ).

Labor and Delivery

Continuous administration of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Succinate)) is distributed into milk during parenteral Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Succinate)) should be monitored in such patients.

ADVERSE REACTIONS

The adverse effects of parenterally administered Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Succinate)) usually are the result of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Succinate)) sulfate therapy for eclampsia has been reported.

OVERDOSAGE

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Succinate)) Deficiency

In the treatment of mild Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Succinate)) deficiency, the usual adult dose is 1 gram, equivalent to 8.12 mEq of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Succinate)) sulfate is 20 grams/48 hours and frequent serum Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Succinate)) concentrations must be obtained. Continuous use of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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, Calcium; Magnesium; Vitamin D3 (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

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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

Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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. Calcium; Magnesium; Vitamin D3 (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. Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Succinate)) sulfate infusion for tocolysis. J Pediatr. 1988; 113(6):1078-82.
  • McGuinness GA, Weinstein MM, Cruikshank DP, et al. Effects of Calcium; Magnesium; Vitamin D3 (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 Calcium; Magnesium; Vitamin D3 (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% Calcium; Magnesium; Vitamin D3 (Magnesium (Magnesium Succinate)) Sulfate 5 g/10 mL (500 mg/mL)

Rx only

NDC 0409-1754-10

10 mL Single-dose syringe

50% Calcium; Magnesium; Vitamin D3 (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

Calcium; Magnesium; Vitamin D3 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.


Calcium; Magnesium; Vitamin D3 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.


Calcium; Magnesium; Vitamin D3 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.


Calcium; Magnesium; Vitamin D3 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.


Calcium; Magnesium; Vitamin D3 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."CHOLECALCIFEROL: 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. "Calcium". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Calcium; Magnesium; Vitamin D3?

Depending on the reaction of the Calcium; Magnesium; Vitamin D3 after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Calcium; Magnesium; Vitamin D3 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 Calcium; Magnesium; Vitamin D3 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 Calcium; Magnesium; Vitamin D3, 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 Calcium; Magnesium; Vitamin D3 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. Arunabha Ray, MD Pharmacology

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