Pre-Natal Supplement

Calcium (Calcium Carbonate):

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Pre-Natal Supplement (Calcium (Calcium Carbonate)) reviews

1 INDICATIONS AND USAGE

Pre-Natal Supplement (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 Pre-Natal Supplement (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 Pre-Natal Supplement (Calcium (Calcium Carbonate)) acetate capsule.

- Capsule: 667 mg Pre-Natal Supplement (Calcium (Calcium Carbonate)) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

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

An overdose of Pre-Natal Supplement (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 Pre-Natal Supplement (Calcium (Calcium Carbonate)) levels twice weekly. Should hypercalcemia develop, reduce the Pre-Natal Supplement (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 Pre-Natal Supplement (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 Pre-Natal Supplement (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 Pre-Natal Supplement (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 Pre-Natal Supplement (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.

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 Pre-Natal Supplement (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, Pre-Natal Supplement (Calcium (Calcium Carbonate)) acetate has been generally well tolerated.

Pre-Natal Supplement (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 Pre-Natal Supplement (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.

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 Pre-Natal Supplement (Calcium (Calcium Carbonate)) concentration could reduce the incidence and severity of Pre-Natal Supplement (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 Pre-Natal Supplement (Calcium (Calcium Carbonate)) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

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

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

8.2 Labor and Delivery

The effects of Pre-Natal Supplement (Calcium (Calcium Carbonate)) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Pre-Natal Supplement ) Acetate Capsules contains Pre-Natal Supplement (Calcium (Calcium Carbonate)) acetate and is excreted in human milk. Human milk feeding by a mother receiving Pre-Natal Supplement (Calcium (Calcium Carbonate)) acetate is not expected to harm an infant, provided maternal serum Pre-Natal Supplement (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 Pre-Natal Supplement (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.

10 OVERDOSAGE

Administration of Pre-Natal Supplement (Calcium (Calcium Carbonate)) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

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

Pre-Natal Supplement (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 Pre-Natal Supplement ) resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Pre-Natal Supplement (Calcium (Calcium Carbonate)) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Pre-Natal Supplement (Calcium (Calcium Carbonate)) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Pre-Natal Supplement (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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with Pre-Natal Supplement (Calcium (Calcium Carbonate)) acetate.

14 CLINICAL STUDIES

Effectiveness of Pre-Natal Supplement (Calcium (Calcium Carbonate)) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Pre-Natal Supplement (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 Pre-Natal Supplement (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 Pre-Natal Supplement (Calcium (Calcium Carbonate)) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Pre-Natal Supplement (Calcium (Calcium Carbonate)) levels are also presented.

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 Pre-Natal Supplement (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 Pre-Natal Supplement (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 Pre-Natal Supplement (Calcium (Calcium Carbonate)) acetate is shown in the Table 3.

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

16 HOW SUPPLIED/STORAGE AND HANDLING

Pre-Natal Supplement (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 Pre-Natal Supplement (Calcium (Calcium Carbonate)) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Pre-Natal Supplement (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 Pre-Natal Supplement (Calcium (Calcium Carbonate)) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Calcium (Calcium HVP Chelate):

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Pre-Natal Supplement (Calcium (Calcium HVP Chelate)) reviews

1 INDICATIONS AND USAGE

Pre-Natal Supplement (Calcium (Calcium HVP Chelate)) acetate is a phosphate binder indicated to reduce serum phosphorus in patients with end stage renal disease (ESRD).

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

2 DOSAGE AND ADMINISTRATION

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

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

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

3 DOSAGE FORMS AND STRENGTHS

Capsule: 667 mg Pre-Natal Supplement (Calcium (Calcium HVP Chelate)) acetate capsule.

- Capsule: 667 mg Pre-Natal Supplement (Calcium (Calcium HVP Chelate)) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Pre-Natal Supplement ) acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Pre-Natal Supplement (Calcium (Calcium HVP Chelate)) acetate. (5.1)

- Hypercalcemia may aggravate digitalis toxicity. (5.2)

5.1 Hypercalcemia

Patients with end stage renal disease may develop hypercalcemia when treated with Pre-Natal Supplement (Calcium (Calcium HVP Chelate)), including Pre-Natal Supplement (Calcium (Calcium HVP Chelate)) acetate. Avoid the use of Pre-Natal Supplement (Calcium (Calcium HVP Chelate)) supplements, including Pre-Natal Supplement (Calcium (Calcium HVP Chelate)) based nonprescription antacids, concurrently with Pre-Natal Supplement (Calcium (Calcium HVP Chelate)) acetate.

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

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

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

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

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

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

5.2 Concomitant Use with Medications

Hypercalcemia may aggravate digitalis toxicity.

6 ADVERSE REACTIONS

Hypercalcemia is discussed elsewhere [see Warnings and Precautions ].

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

- In clinical studies, patients have occasionally experienced nausea during Pre-Natal Supplement (Calcium (Calcium HVP Chelate)) acetate therapy. (6)

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

6.1 Clinical Trial Experience

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

In clinical studies, Pre-Natal Supplement (Calcium (Calcium HVP Chelate)) acetate has been generally well tolerated.

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

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 Pre-Natal Supplement (Calcium (Calcium HVP Chelate)) concentration could reduce the incidence and severity of Pre-Natal Supplement (Calcium (Calcium HVP Chelate)) acetate-induced hypercalcemia. Isolated cases pruritus have been reported, which may represent allergic reactions.

6.2 Postmarketing Experience

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

The following additional adverse reactions have been identified during post-approval of Pre-Natal Supplement (Calcium (Calcium HVP Chelate)) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

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

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

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

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

7.1 Ciprofloxacin

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

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

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

8.2 Labor and Delivery

The effects of Pre-Natal Supplement (Calcium (Calcium HVP Chelate)) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

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

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

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

10 OVERDOSAGE

Administration of Pre-Natal Supplement (Calcium (Calcium HVP Chelate)) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Pre-Natal Supplement (Calcium (Calcium HVP Chelate)) acetate acts as a phosphate binder. Its chemical name is Pre-Natal Supplement (Calcium (Calcium HVP Chelate)) acetate. Its molecular formula is C₄H₆CaO₄, and its molecular weight is 158.17. Its structural formula is:

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

Pre-Natal Supplement (Calcium (Calcium HVP Chelate)) Acetate Capsules are administered orally for the control of hyperphosphatemia in end-stage renal failure.

Chemical Structure

12 CLINICAL PHARMACOLOGY

Patients with ESRD retain phosphorus and can develop hyperphosphatemia. High serum phosphorus can precipitate serum Pre-Natal Supplement ) resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with Pre-Natal Supplement (Calcium (Calcium HVP Chelate)) acetate.

14 CLINICAL STUDIES

Effectiveness of Pre-Natal Supplement (Calcium (Calcium HVP Chelate)) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Pre-Natal Supplement (Calcium (Calcium HVP Chelate)) acetate solid oral dosage form.

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

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

The data presented in Table 2 demonstrate the efficacy of Pre-Natal Supplement (Calcium (Calcium HVP Chelate)) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Pre-Natal Supplement (Calcium (Calcium HVP Chelate)) levels are also presented.

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 Pre-Natal Supplement (Calcium (Calcium HVP Chelate)) increased 9% during the study mostly in the first month of the study.

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

The phosphate binding effect of Pre-Natal Supplement (Calcium (Calcium HVP Chelate)) acetate is shown in the Table 3.

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

16 HOW SUPPLIED/STORAGE AND HANDLING

Pre-Natal Supplement (Calcium (Calcium HVP Chelate)) Acetate Capsules

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

NDC 0615-2303-39: Blistercards of 30 Capsules

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

STORAGE

Store at 20° to 25°C (68° to 77°F).

17 PATIENT COUNSELING INFORMATION

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

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

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Copper (Copper HVP Chelate):

• Indications:
• General directions:
• Active ingredient:
• Inactive ingredients:
• Caution:
• Storage:
• Net contents:
• Pre-Natal Supplement (Copper (Copper HVP Chelate)) reviews

Water-Resistant Protection Without Bandaging

Recommended as an Aid in Treating Horses and Ponies With Thrush Due to Organisms Susceptible to Pre-Natal Supplement (Copper (Copper HVP Chelate)) Naphthenate.

For Animal Use Only.

INDICATIONS:

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

GENERAL DIRECTIONS:

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

NOTE: Pre-Natal Supplement (Copper (Copper HVP Chelate))^® is easily removed from hands, clothing and surfaces with light grade fuel oil or any type of lighter fluid.

CONTAINS FOIL SEAL – REMOVE BEFORE USE.

SHAKE WELL BEFORE USE.

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

ACTIVE INGREDIENT:

Pre-Natal Supplement (Copper (Copper HVP Chelate)) Naphthenate...37.5% w/w

INACTIVE INGREDIENTS:

Inert Ingredients...62.5% w/w

Total... 100.0%

CAUTION:

Do not use in horses intended for human consumption.

CAUTION: COMBUSTIBLE MIXTURE.

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

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

KEEP OUT OF REACH OF CHILDREN AND PETS.

STORAGE:

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

Manufactured for:

Aspen Veterinary Resources,^® Ltd.

Liberty, MO 64068, USA

FC163FP 11/13

Manufactured by:

First Priority, Inc.

Elgin, IL 60123-1146, USA

NET CONTENTS:

16 OZ (473 mL)

ANADA 200-304, Approved by FDA

Image of 473 mL bottle/case label

Folic Acid:

• Indications and usage
• Contraindications
• Precautions
• Adverse reactions
• Dosage and administration
• How supplied
• Storage
• Pre-Natal Supplement (Folic Acid) reviews

INDICATIONS AND USAGE

Pre-Natal Supplement (Folic Acid)^® is a prescription iron supplement indicated for use in improving the nutritional status of iron deficiency.

CONTRAINDICATIONS

This product is contraindicated in patients with a known hypersensitivity to any of the ingredients. Hemochromatosis and hemosiderosis are contraindications to iron therapy.

PRECAUTIONS

Pre-Natal Supplement (Folic Acid) acid when administered as a single agent in doses above 0.1 mg daily may obscure pernicious anemia in that hematological remission can occur while neurological manifestations remain progressive. While prescribing this nutritional supplement for pregnant women, nursing mothers, or for women prior to conception, their medical condition and other drugs, herbs, and/or supplements consumption should be considered.

ADVERSE REACTIONS

Allergic sensitization has been reported following both oral and parenteral administration of Pre-Natal Supplement (Folic Acid) acid.

DOSAGE AND ADMINISTRATION

One tablet daily with or without food or as prescribed by a licensed healthcare provider with prescribing authority.

HOW SUPPLIED

Pre-Natal Supplement (Folic Acid)^® tablets are supplied in child-resistant bottles of 90 tablets (NDC 0037-6885-90)

KEEP OUT OF REACH OF CHILDREN.

STORAGE

Store at controlled room temperature 20°-25°C (68°-77°F). Excursions permitted to 15°-30°C (59°-86°F).

Dispense in a tight, light-resistant container to protect from light and moisture.

To report SUSPECTED ADVERSE REACTIONS contact Meda Pharmaceuticals Inc. at 1-888-349-5556 or FDA at 1-800-FDA-1088 or www.fda.gov/safety/medwatch

Distributed by:

Meda Pharmaceuticals Inc.

Somerset New Jersey 08873-4120

© 2014 Meda Pharmaceuticals Inc.

U.S. Patent Nos. 7,585,527 and 8,080,520

Proferrin® is a registered trademark of Colorado BioLabs, Inc., Cozad, NE.

Pre-Natal Supplement (Folic Acid) and the BIFERA logo are registered trademarks and the Pre-Natal Supplement (Folic Acid) logo is a trademark of Alaven Pharmaceutical LLC, used under license by Meda Pharmaceuticals Inc.

MEDA PHARMACEUTICALS mark and logo are trademarks of Meda AB.

IN-6885-02 Rev 6/2014

Iodine (Kelp):

• Iodine tincture 7%
• Iodine tincture 7%
• Pre-Natal Supplement (Iodine (Kelp)) reviews

Pre-Natal Supplement ) Tincture 7%

Directions:

Topical Antiseptic

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

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

Apply Pre-Natal Supplement (Iodine (Kelp)) Tincture 7% only once daily. Dilute product 3 to 1 if repeating application.

Do not apply under bandage.

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

Storage:

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

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

DANGER - Poison

Caution:

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

activated charcoal. A 5% solutions of sodium thiosulfate

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

rate of 10 ml per kilogram of body weight.

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

Avoid contamination of food.

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

Pre-Natal Supplement ) Tincture 7%

image description

Iron (Ferrous Fumarate):

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Pre-Natal Supplement (Iron (Ferrous Fumarate)) reviews

1 INDICATIONS AND USAGE

Pre-Natal Supplement (Iron (Ferrous Fumarate)) is indicated for the treatment of Pre-Natal Supplement (Iron (Ferrous Fumarate)) deficiency anemia in patients with chronic kidney disease (CKD).

Pre-Natal Supplement (Iron (Ferrous Fumarate)) is an Pre-Natal Supplement (Iron (Ferrous Fumarate)) replacement product indicated for the treatment of Pre-Natal Supplement (Iron (Ferrous Fumarate)) deficiency anemia in patients with chronic kidney disease (CKD). (1)

2 DOSAGE AND ADMINISTRATION

Pre-Natal Supplement ) must only be administered intravenously either by slow injection or by infusion. The dosage of Pre-Natal Supplement (Iron (Ferrous Fumarate)) is expressed in mg of elemental Pre-Natal Supplement (Iron (Ferrous Fumarate)). Each mL contains 20 mg of elemental Pre-Natal Supplement (Iron (Ferrous Fumarate)).

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

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

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

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

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

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

2.4 Pediatric Patients with HDD-CKD for Pre-Natal Supplement (Iron (Ferrous Fumarate)) maintenance treatment

The dosing for Pre-Natal Supplement (Iron (Ferrous Fumarate)) replacement treatment in pediatric patients with HDD-CKD has not been established.

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

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for Pre-Natal Supplement (Iron (Ferrous Fumarate)) maintenance treatment

The dosing for Pre-Natal Supplement (Iron (Ferrous Fumarate)) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

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

3 DOSAGE FORMS AND STRENGTHS

• 10 mL single-use vial / 200 mg elemental Pre-Natal Supplement (Iron (Ferrous Fumarate)) (20 mg/mL)
• 5 mL single-use vial / 100 mg elemental Pre-Natal Supplement (Iron (Ferrous Fumarate)) (20 mg/mL)
• 2.5 mL single-use vial / 50 mg elemental Pre-Natal Supplement (Iron (Ferrous Fumarate)) (20 mg/mL)

• 10 mL single-use vial / 200 mg elemental Pre-Natal Supplement (Iron (Ferrous Fumarate)) (20 mg/mL) (3)
• 5 mL single-use vial / 100 mg elemental Pre-Natal Supplement (Iron (Ferrous Fumarate)) (20 mg/mL) (3)
• 2.5 mL single-use vial / 50 mg elemental Pre-Natal Supplement (Iron (Ferrous Fumarate)) (20 mg/mL) (3)

4 CONTRAINDICATIONS

• Known hypersensitivity to Pre-Natal Supplement (Iron (Ferrous Fumarate))

• Known hypersensitivity to Pre-Natal Supplement (Iron (Ferrous Fumarate)) (4)

5 WARNINGS AND PRECAUTIONS

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

5.1 Hypersensitivity Reactions

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

5.2 Hypotension

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

5.3 Pre-Natal Supplement (Iron (Ferrous Fumarate)) Overload

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

6 ADVERSE REACTIONS

The following serious adverse reactions associated with Pre-Natal Supplement ) are described in other sections .

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

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

6.1 Adverse Reactions in Clinical Trials

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

Adverse Reactions in Adults Patients with CKD

Adverse Reactions in Adult Patients with CKD

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

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

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

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

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

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

6.2 Adverse Reactions from Post-Marketing Experience

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

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

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

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

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

7 DRUG INTERACTIONS

Drug interactions involving Pre-Natal Supplement (Iron (Ferrous Fumarate)) have not been studied. However, Pre-Natal Supplement (Iron (Ferrous Fumarate)) may reduce the absorption of concomitantly administered oral Pre-Natal Supplement (Iron (Ferrous Fumarate)) preparations.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Pregnancy Category B

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

8.3 Nursing Mothers

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

8.4 Pediatric Use

Safety and effectiveness of Pre-Natal Supplement ) for Pre-Natal Supplement (Iron (Ferrous Fumarate)) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.

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

Pre-Natal Supplement (Iron (Ferrous Fumarate)) has not been studied in patients younger than 2 years of age.

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

8.5 Geriatric Use

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

10 OVERDOSAGE

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

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

11 DESCRIPTION

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

[Na₂Fe₅O₈(OH) ·3(H₂O)]_n ·m(C₁₂H₂₂O₁₁)

where: n is the degree of Pre-Natal Supplement (Iron (Ferrous Fumarate)) polymerization and m is the number of sucrose molecules associated with the Pre-Natal Supplement (Iron (Ferrous Fumarate)) (III)-hydroxide.

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

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

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

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

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

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

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with Pre-Natal Supplement (Iron (Ferrous Fumarate)) sucrose.

Pre-Natal Supplement (Iron (Ferrous Fumarate)) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Pre-Natal Supplement (Iron (Ferrous Fumarate)) sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.

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

14 CLINICAL STUDIES

Five clinical trials involving 647 adult patients and one clinical trial involving 131 pediatric patients were conducted to assess the safety and efficacy of Pre-Natal Supplement ).

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

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

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

Patients in the Pre-Natal Supplement (Iron (Ferrous Fumarate)) treated population showed a greater increase in hemoglobin and hematocrit than did patients in the historical control population. See Table 2.

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

14.2 Study B: Hemodialysis Dependent-Chronic Kidney Disease

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

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

14.3 Study C: Hemodialysis Dependent-Chronic Kidney Disease

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

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

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

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

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

14.5 Study E: Peritoneal Dialysis Dependent-Chronic Kidney Disease

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

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

14.6 Study F: Pre-Natal Supplement ) Maintenance Treatment Dosing in Pediatric Patients Ages 2 years and Older with Chronic Kidney Disease

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

16 HOW SUPPLIED/storage and handling

16.1 How Supplied

Pre-Natal Supplement ) is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Pre-Natal Supplement (Iron (Ferrous Fumarate)), each 5 mL vial contains 100 mg elemental Pre-Natal Supplement (Iron (Ferrous Fumarate)), and each 2.5 mL vial contains 50 mg elemental Pre-Natal Supplement (Iron (Ferrous Fumarate)) (20 mg/mL).

16.2 Stability and Storage

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

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

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

Do not dilute to concentrations below 1 mg/mL.

Do not mix Pre-Natal Supplement (Iron (Ferrous Fumarate)) with other medications or add to parenteral nutrition solutions for intravenous infusion.

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

17 PATIENT COUNSELING INFORMATION

Prior to Pre-Natal Supplement (Iron (Ferrous Fumarate)) administration:

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

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Pre-Natal Supplement (Iron (Ferrous Fumarate)) is manufactured under license from Vifor (International) Inc., Switzerland.

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

PREMIERProRx^®

IN2340

MG #15727

Iron (Ferrous HVP Chelate):

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Pre-Natal Supplement (Iron (Ferrous HVP Chelate)) reviews

1 INDICATIONS AND USAGE

Pre-Natal Supplement (Iron (Ferrous HVP Chelate)) is indicated for the treatment of Pre-Natal Supplement (Iron (Ferrous HVP Chelate)) deficiency anemia in patients with chronic kidney disease (CKD).

Pre-Natal Supplement (Iron (Ferrous HVP Chelate)) is an Pre-Natal Supplement (Iron (Ferrous HVP Chelate)) replacement product indicated for the treatment of Pre-Natal Supplement (Iron (Ferrous HVP Chelate)) deficiency anemia in patients with chronic kidney disease (CKD). (1)

2 DOSAGE AND ADMINISTRATION

Pre-Natal Supplement ) must only be administered intravenously either by slow injection or by infusion. The dosage of Pre-Natal Supplement (Iron (Ferrous HVP Chelate)) is expressed in mg of elemental Pre-Natal Supplement (Iron (Ferrous HVP Chelate)). Each mL contains 20 mg of elemental Pre-Natal Supplement (Iron (Ferrous HVP Chelate)).

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

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

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

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

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

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

2.4 Pediatric Patients with HDD-CKD for Pre-Natal Supplement (Iron (Ferrous HVP Chelate)) maintenance treatment

The dosing for Pre-Natal Supplement (Iron (Ferrous HVP Chelate)) replacement treatment in pediatric patients with HDD-CKD has not been established.

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

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for Pre-Natal Supplement (Iron (Ferrous HVP Chelate)) maintenance treatment

The dosing for Pre-Natal Supplement (Iron (Ferrous HVP Chelate)) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

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

3 DOSAGE FORMS AND STRENGTHS

• 10 mL single-use vial / 200 mg elemental Pre-Natal Supplement (Iron (Ferrous HVP Chelate)) (20 mg/mL)
• 5 mL single-use vial / 100 mg elemental Pre-Natal Supplement (Iron (Ferrous HVP Chelate)) (20 mg/mL)
• 2.5 mL single-use vial / 50 mg elemental Pre-Natal Supplement (Iron (Ferrous HVP Chelate)) (20 mg/mL)

• 10 mL single-use vial / 200 mg elemental Pre-Natal Supplement (Iron (Ferrous HVP Chelate)) (20 mg/mL) (3)
• 5 mL single-use vial / 100 mg elemental Pre-Natal Supplement (Iron (Ferrous HVP Chelate)) (20 mg/mL) (3)
• 2.5 mL single-use vial / 50 mg elemental Pre-Natal Supplement (Iron (Ferrous HVP Chelate)) (20 mg/mL) (3)

4 CONTRAINDICATIONS

• Known hypersensitivity to Pre-Natal Supplement (Iron (Ferrous HVP Chelate))

• Known hypersensitivity to Pre-Natal Supplement (Iron (Ferrous HVP Chelate)) (4)

5 WARNINGS AND PRECAUTIONS

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

5.1 Hypersensitivity Reactions

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

5.2 Hypotension

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

5.3 Pre-Natal Supplement (Iron (Ferrous HVP Chelate)) Overload

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

6 ADVERSE REACTIONS

The following serious adverse reactions associated with Pre-Natal Supplement ) are described in other sections .

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

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

6.1 Adverse Reactions in Clinical Trials

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

Adverse Reactions in Adults Patients with CKD

Adverse Reactions in Adult Patients with CKD

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

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

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

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

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

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

6.2 Adverse Reactions from Post-Marketing Experience

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

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

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

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

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

7 DRUG INTERACTIONS

Drug interactions involving Pre-Natal Supplement (Iron (Ferrous HVP Chelate)) have not been studied. However, Pre-Natal Supplement (Iron (Ferrous HVP Chelate)) may reduce the absorption of concomitantly administered oral Pre-Natal Supplement (Iron (Ferrous HVP Chelate)) preparations.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Pregnancy Category B

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

8.3 Nursing Mothers

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

8.4 Pediatric Use

Safety and effectiveness of Pre-Natal Supplement ) for Pre-Natal Supplement (Iron (Ferrous HVP Chelate)) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.

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

Pre-Natal Supplement (Iron (Ferrous HVP Chelate)) has not been studied in patients younger than 2 years of age.

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

8.5 Geriatric Use

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

10 OVERDOSAGE

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

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

11 DESCRIPTION

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

[Na₂Fe₅O₈(OH) ·3(H₂O)]_n ·m(C₁₂H₂₂O₁₁)

where: n is the degree of Pre-Natal Supplement (Iron (Ferrous HVP Chelate)) polymerization and m is the number of sucrose molecules associated with the Pre-Natal Supplement (Iron (Ferrous HVP Chelate)) (III)-hydroxide.

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

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

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

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

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

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

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with Pre-Natal Supplement (Iron (Ferrous HVP Chelate)) sucrose.

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

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

14 CLINICAL STUDIES

Five clinical trials involving 647 adult patients and one clinical trial involving 131 pediatric patients were conducted to assess the safety and efficacy of Pre-Natal Supplement ).

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

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

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

Patients in the Pre-Natal Supplement (Iron (Ferrous HVP Chelate)) treated population showed a greater increase in hemoglobin and hematocrit than did patients in the historical control population. See Table 2.

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

14.2 Study B: Hemodialysis Dependent-Chronic Kidney Disease

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

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

14.3 Study C: Hemodialysis Dependent-Chronic Kidney Disease

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

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

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

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

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

14.5 Study E: Peritoneal Dialysis Dependent-Chronic Kidney Disease

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

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

14.6 Study F: Pre-Natal Supplement ) Maintenance Treatment Dosing in Pediatric Patients Ages 2 years and Older with Chronic Kidney Disease

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

16 HOW SUPPLIED/storage and handling

16.1 How Supplied

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

16.2 Stability and Storage

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

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

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

Do not dilute to concentrations below 1 mg/mL.

Do not mix Pre-Natal Supplement (Iron (Ferrous HVP Chelate)) with other medications or add to parenteral nutrition solutions for intravenous infusion.

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

17 PATIENT COUNSELING INFORMATION

Prior to Pre-Natal Supplement (Iron (Ferrous HVP Chelate)) administration:

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

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Pre-Natal Supplement (Iron (Ferrous HVP Chelate)) is manufactured under license from Vifor (International) Inc., Switzerland.

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

PREMIERProRx^®

IN2340

MG #15727

Magnesium (Magnesium HVP Chelate):

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• References
• Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) reviews

Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) Sulfate

Injection, USP

Ansyr Plastic Syringe

Rx only

Hospira Logo

DESCRIPTION

Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) Sulfate Injection, USP is a sterile solution of Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) sulfate heptahydrate in Water for Injection, USP administered by the intravenous or intramuscular routes as an electrolyte replenisher or anticonvulsant. Must be diluted before intravenous use. May contain sulfuric acid and/or sodium hydroxide for pH adjustment. The pH is 5.5 to 7.0. The 50% concentration has an osmolarity of 4.06 mOsmol/mL (calc.).

The solution contains no bacteriostat, antimicrobial agent or added buffer (except for pH adjustment) and is intended only for use as a single-dose injection. When smaller doses are required the unused portion should be discarded with the entire unit.

Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) Sulfate, USP heptahydrate is chemically designated MgSO₄ - 7H₂O with molecular weight of 246.48 and occurs as colorless crystals or white powder freely soluble in water.

The plastic syringe is molded from a specially formulated polypropylene. Water permeates from inside the container at an extremely slow rate which will have an insignificant effect on solution concentration over the expected shelf life. Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the syringe material.

CLINICAL PHARMACOLOGY

Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) (Mg⁺⁺) is an important cofactor for enzymatic reactions and plays an important role in neurochemical transmission and muscular excitability.

As a nutritional adjunct in hyperalimentation, the precise mechanism of action for Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) is uncertain. Early symptoms of hypomagnesemia (less than 1.5 mEq/liter) may develop as early as three to four days or within weeks.

Predominant deficiency effects are neurological, e.g., muscle irritability, clonic twitching and tremors. Hypocalcemia and hypokalemia often follow low serum levels of Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)). While there are large stores of Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) present intracellularly and in the bones of adults, these stores often are not mobilized sufficiently to maintain plasma levels. Parenteral Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) therapy repairs the plasma deficit and causes deficiency symptoms and signs to cease.

Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) prevents or controls convulsions by blocking neuromuscular transmission and decreasing the amount of acetylcholine liberated at the end plate by the motor nerve impulse. Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) is said to have a depressant effect on the central nervous system (CNS), but it does not adversely affect the woman, fetus or neonate when used as directed in eclampsia or pre-eclampsia. Normal plasma Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) levels range from 1.5 to 2.5 mEq/liter.

As plasma Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) rises above 4 mEq/liter, the deep tendon reflexes are first decreased and then disappear as the plasma level approaches 10 mEq/liter. At this level respiratory paralysis may occur. Heart block also may occur at this or lower plasma levels of Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)). Serum Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) concentrations in excess of 12 mEq/L may be fatal.

Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) acts peripherally to produce vasodilation. With low doses only flushing and sweating occur, but larger doses cause lowering of blood pressure. The central and peripheral effects of Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) poisoning are antagonized to some extent by intravenous administration of calcium.

Pharmacokinetics

With intravenous administration the onset of anticonvulsant action is immediate and lasts about 30 minutes. Following intramuscular administration the onset of action occurs in about one hour and persists for three to four hours. Effective anticonvulsant serum levels range from 2.5 to 7.5 mEq/liter. Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) is excreted solely by the kidneys at a rate proportional to the plasma concentration and glomerular filtration.

INDICATIONS AND USAGE

Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) Sulfate Injection, USP is suitable for replacement therapy in Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) deficiency, especially in acute hypomagnesemia accompanied by signs of tetany similar to those observed in hypocalcemia. In such cases, the serum Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) (Mg⁺⁺) level is usually below the lower limit of normal (1.5 to 2.5 mEq/liter) and the serum calcium (Ca⁺⁺) level is normal (4.3 to 5.3 mEq/liter) or elevated.

In total parenteral nutrition (TPN), Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) sulfate may be added to the nutrient admixture to correct or prevent hypomagnesemia which can arise during the course of therapy.

Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) Sulfate Injection, USP is also indicated for the prevention and control of seizures (convulsions) in pre-eclampsia and eclampsia, respectively.

CONTRAINDICATIONS

Parenteral administration of the drug is contraindicated in patients with heart block or myocardial damage.

WARNINGS

FETAL HARM: Continuous administration of Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) sulfate beyond 5 to 7 days to pregnant women can lead to hypocalcemia and bone abnormalities in the developing fetus. These bone abnormalities include skeletal demineralization and osteopenia. In addition, cases of neonatal fracture have been reported. The shortest duration of treatment that can lead to fetal harm is not known. Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) sulfate should be used during pregnancy only if clearly needed. If Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) sulfate is given for treatment of preterm labor, the woman should be informed that the efficacy and safety of such use have not been established and that use of Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) sulfate beyond 5 to 7 days may cause fetal abnormalities.

ALUMINUM TOXICITY: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

Parenteral use in the presence of renal insufficiency may lead to Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) intoxication. Intravenous use in the eclampsia should be reserved for immediate control of life-threatening convulsions.

PRECAUTIONS

General

Administer with caution if flushing and sweating occurs. When barbiturates, narcotics or other hypnotics (or systemic anesthetics) are to be given in conjunction with Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)), their dosage should be adjusted with caution because of additive CNS depressant effects of Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)).

Because Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) is removed from the body solely by the kidneys, the drug should be used with caution in patients with renal impairment. Urine output should be maintained at a level of 100 mL or more during the four hours preceding each dose. Monitoring serum Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) levels and the patient's clinical status is essential to avoid the consequences of overdosage in toxemia. Clinical indications of a safe dosage regimen include the presence of the patellar reflex (knee jerk) and absence of respiratory depression (approximately 16 breaths or more/minute). When repeated doses of the drug are given parenterally, knee jerk reflexes should be tested before each dose and if they are absent, no additional Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) should be given until they return. Serum Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) levels usually sufficient to control convulsions range from 3 to 6 mg/100 mL (2.5 to 5 mEq/liter). The strength of the deep tendon reflexes begins to diminish when Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) levels exceed 4 mEq/liter. Reflexes may be absent at 10 mEq magnesium/liter, where respiratory paralysis is a potential hazard. An injectable calcium salt should be immediately available to counteract the potential hazards of Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) intoxication in eclampsia.

50% Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) Sulfate Injection, USP must be diluted to a concentration of 20% or less prior to intravenous infusion. Rate of administration should be slow and cautious, to avoid producing hypermagnesemia. The 50% solution also should be diluted to 20% or less for intramuscular injection in infants and children.

Laboratory Tests

Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) sulfate injection should not be given unless hypomagnesemia has been confirmed and the serum concentration of Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) is monitored. The normal serum level is 1.5 to 2.5 mEq/L.

Drug Interactions

CNS Depressants - When barbiturates, narcotics or other hypnotics (or systemic anesthetics), or other CNS depressants are to be given in conjunction with Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)), their dosage should be adjusted with caution because of additive CNS depressant effects of Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)). CNS depression and peripheral transmission defects produced by Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) may be antagonized by calcium.

Neuromuscular Blocking Agents - Excessive neuromuscular block has occurred in patients receiving parenteral Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) sulfate and a neuromuscular blocking agent; these drugs should be administered concomitantly with caution.

Cardiac Glycosides - Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) sulfate should be administered with extreme caution in digitalized patients, because serious changes in cardiac conduction which can result in heart block may occur if administration of calcium is required to treat Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) toxicity.

Pregnancy

Teratogenic Effects

Pregnancy Category D (See WARNINGS and PRECAUTIONS )

See WARNINGS and PRECAUTIONS .

Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) sulfate can cause fetal abnormalities when administered beyond 5 to 7 days to pregnant women. There are retrospective epidemiological studies and case reports documenting fetal abnormalities such as hypocalcemia, skeletal demineralization, osteopenia and other skeletal abnormalities with continuous maternal administration of Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) sulfate for more than 5 to 7 days.^1-10 Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) sulfate injection should be used during pregnancy only if clearly needed. If this drug is used during pregnancy, the woman should be apprised of the potential harm to the fetus.

Nonteratogenic Effects

When administered by continuous intravenous infusion (especially for more than 24 hours preceding delivery) to control convulsions in a toxemic woman, the newborn may show signs of Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) toxicity, including neuromuscular or respiratory depression (See OVERDOSAGE ).

Labor and Delivery

Continuous administration of Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) sulfate is an unapproved treatment for preterm labor. The safety and efficacy of such use have not been established. The administration of Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) sulfate outside of its approved indication in pregnant women should be by trained obstetrical personnel in a hospital setting with appropriate obstetrical care facilities.

Nursing Mothers

Since Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) is distributed into milk during parenteral Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) sulfate administration, the drug should be used with caution in nursing women.

Geriatrics

Geriatric patients often require reduced dosage because of impaired renal function. In patients with severe impairment, dosage should not exceed 20 grams in 48 hours. Serum Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) should be monitored in such patients.

ADVERSE REACTIONS

The adverse effects of parenterally administered Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) usually are the result of Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) intoxication. These include flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, cardiac and central nervous system depression proceeding to respiratory paralysis. Hypocalcemia with signs of tetany secondary to Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) sulfate therapy for eclampsia has been reported.

OVERDOSAGE

Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) intoxication is manifested by a sharp drop in blood pressure and respiratory paralysis. Disappearance of the patellar reflex is a useful clinical sign to detect the onset of Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) intoxication. In the event of overdosage, artificial ventilation must be provided until a calcium salt can be injected intravenously to antagonize the effects of Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)).

For Treatment of Overdose

Artificial respiration is often required. Intravenous calcium, 10 to 20 mL of a 5% solution (diluted if desirable with isotonic sodium chloride for injection) is used to counteract effects of hypermagnesemia. Subcutaneous physostigmine, 0.5 to 1 mg may be helpful.

Hypermagnesemia in the newborn may require resuscitation and assisted ventilation via endotracheal intubation or intermittent positive pressure ventilation as well as intravenous calcium.

DOSAGE AND ADMINISTRATION

Dosage of Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) sulfate must be carefully adjusted according to individual requirements and response, and administration of the drug should be discontinued as soon as the desired effect is obtained.

Both intravenous and intramuscular administration are appropriate. Intramuscular administration of the undiluted 50% solution results in therapeutic plasma levels in 60 minutes, whereas intravenous doses will provide a therapeutic level almost immediately. The rate of intravenous injection should generally not exceed 150 mg/minute (1.5 mL of a 10% concentration or its equivalent), except in severe eclampsia with seizures. Continuous maternal administration of Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

Solutions for intravenous infusion must be diluted to a concentration of 20% or less prior to administration. The diluents commonly used are 5% Dextrose Injection, USP and 0.9% Sodium Chloride Injection, USP. Deep intramuscular injection of the undiluted (50%) solution is appropriate for adults, but the solution should be diluted to a 20% or less concentration prior to such injection in children.

In Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) Deficiency

In the treatment of mild Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) deficiency, the usual adult dose is 1 gram, equivalent to 8.12 mEq of Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) (2 mL of the 50% solution) injected intramuscularly every six hours for four doses (equivalent to a total of 32.5 mEq of Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) per 24 hours). For severe hypomagnesemia, as much as 250 mg (approximately 2 mEq) per kg of body weight (0.5 mL of the 50% solution) may be given intramuscularly within a period of four hours if necessary. Alternatively, 5 grams, (approximately 40 mEq) can be added to one liter of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP for slow intravenous infusion over a three-hour period. In the treatment of deficiency states, caution must be observed to prevent exceeding the renal excretory capacity.

In Hyperalimentation

In total parenteral nutrition, maintenance requirements for Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) are not precisely known. The maintenance dose used in adults ranges from 8 to 24 mEq (1 gram to 3 grams) daily; for infants, the range is 2 to 10 mEq (0.25 gram to 1.25 grams) daily.

In Pre-eclampsia or Eclampsia

In severe pre-eclampsia or eclampsia, the total initial dose is 10 grams to 14 grams of Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) sulfate. Intravenously, a dose of 4 grams to 5 grams in 250 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP may be infused. Simultaneously, intramuscular doses of up to 10 grams (5 grams or 10 mL of the undiluted 50% solution in each buttock) are given. Alternatively, the initial intravenous dose of 4 grams may be given by diluting the 50% solution to a 10 or 20% concentration; the diluted fluid (40 mL of a 10% solution or 20 mL of a 20% solution) may then be injected intravenously over a period of three to four minutes. Subsequently, 4 grams to 5 grams (8 to 10 mL of the 50% solution) are injected intramuscularly into alternate buttocks every four hours as needed, depending on the continuing presence of the patellar reflex and adequate respiratory function. Alternatively, after the initial intravenous dose, some clinicians administer 1 gram to 2 grams/hour by constant intravenous infusion. Therapy should continue until paroxysms cease. A serum Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) level of 6 mg/100 mL is considered optimal for control of seizures. A total daily (24 hr) dose of 30 grams to 40 grams should not be exceeded. In the presence of severe renal insufficiency, the maximum dosage of Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) sulfate is 20 grams/48 hours and frequent serum Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) concentrations must be obtained. Continuous use of Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

Other Uses

In counteracting the muscle-stimulating effects of barium poisoning, the usual dose of Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) sulfate is 1 gram to 2 grams given intravenously.

For controlling seizures associated with epilepsy, glomerulonephritis or hypothyroidism, the usual adult dose is 1 gram administered intramuscularly or intravenously.

In paroxysmal atrial tachycardia, Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) should be used only if simpler measures have failed and there is no evidence of myocardial damage. The usual dose is 3 grams to 4 grams (30 to 40 mL of a 10% solution) administered intravenously over 30 seconds with extreme caution.

For reduction of cerebral edema, 2.5 grams (25 mL of a 10% solution) is given intravenously.

Incompatibilities

Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) sulfate in solution may result in a precipitate formation when mixed with solutions containing:

Alcohol (in high Heavy Metals

concentrations) Hydrocortisone sodium

Alkali carbonates and succinate

bicarbonates Phosphates

Alkali hydroxides Polymixin B sulfate

Arsenates Procaine hydrochloride

Barium Salicylates

Calcium Strontium

Clindamycin phosphate Tartrates

The potential incompatibility will often be influenced by the changes in the concentration of reactants and the pH of the solutions.

It has been reported that Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) may reduce the antibiotic activity of streptomycin, tetracycline and tobramycin when given together.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

HOW SUPPLIED

Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) Sulfate Injection, USP is supplied in single-dose containers as follows:

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 Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) administration and bone metabolism in neonates. Early Hum Dev. 2010;86(3):187-91. Epub 2010 Mar 12.
• Wedig KE, Kogan J, Schorry EK et al. Skeletal demineralization and fractures caused by fetal Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) toxicity. J. Perinatol. 2006; 26(6):371-4.
• Nassar AH, Sakhel K, Maarouf H, et al. Adverse maternal and neonatal outcome of prolonged course of Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) sulfate tocolysis. Acta Obstet Gynecol Scan. 2006;85(9):1099-103.
• Malaeb SN, Rassi A, Haddad MC. Bone mineralization in newborns whose mothers received Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) sulphate for tocolysis of premature labor. Pediatr Radiol. 2004;34(5):384-6. Epub 2004 Feb 18.
• Matsuda Y, Maeda Y, Ito M, et al. Effect of Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) sulfate treatment on neonatal bone abnormalities. Gynecol Obstet Invest. 1997;44(2):82-8.
• Schanler RJ, Smith LG, Burns PA. Effects of long-term maternal intravenous Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) sulfate therapy on neonatal calcium metabolism and bone mineral content. Gynecol Obstet Invest. 1997;43(4):236-41.
• Santi MD, Henry GW, Douglas GL. Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) sulfate treatment of preterm labor as a cause of abnormal neonatal bone mineralization. J Pediatr Orthrop. 1994;14(2):249-53.
• Holcomb WL, Shackelford GD, Petrie RH. Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) tocolysis and neonatal bone abnormalities; a controlled study. Obstet Gynecol. 1991; 78(4):611-4.
• Cumming WA, Thomas VJ. Hypermagnesemia: a cause of abnormal metaphyses in the neonate. Am J Roentgenol. 1989; 152(5):1071-2.
• Lamm CL, Norton KL, Murphy RJ. Congenital rickets associated with Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) sulfate infusion for tocolysis. J Pediatr. 1988; 113(6):1078-82.
• McGuinness GA, Weinstein MM, Cruikshank DP, et al. Effects of Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) sulfate treatment on perinatal calcium metabolism. II. Neonatal responses. Obstet Gynecol. 1980; 56(5): 595-600.
• Riaz M, Porat R, Brodsky NL, et al. The effects of maternal Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) sulfate treatment on newborns: a prospective controlled study. J. Perinatol. 1998;18(6 pt 1):449-54.

Hospira, Inc., Lake Forest, IL 60045 USA

LAB-1024-1.0

April 2017

Hospira Logo

50% Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) Sulfate 5 g/10 mL (500 mg/mL)

Rx only

NDC 0409-1754-10

10 mL Single-dose syringe

50% Pre-Natal Supplement (Magnesium (Magnesium HVP Chelate)) Sulfate Injection, USP

5 g/10 mL (500 mg/mL) (4 mEq Mg++/mL)

MUST BE DILUTED FOR INTRAVENOUS USE.

For Intravenous or Intramuscular Use. Sterile. 4.06 mOsmol/mL (calc.).

Contains no more than 75 mcg/L of aluminum.

Hospira, Inc., Lake Forest, IL 60045 USA

Hospira

RL-6891

Magnesium (Magnesium Oxide):

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• References
• Pre-Natal Supplement (Magnesium (Magnesium Oxide)) reviews

Pre-Natal Supplement (Magnesium (Magnesium Oxide)) Sulfate

Injection, USP

Ansyr Plastic Syringe

Rx only

Hospira Logo

DESCRIPTION

Pre-Natal Supplement (Magnesium (Magnesium Oxide)) Sulfate Injection, USP is a sterile solution of Pre-Natal Supplement (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.

Pre-Natal Supplement (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

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

Pre-Natal Supplement (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. Pre-Natal Supplement (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 Pre-Natal Supplement (Magnesium (Magnesium Oxide)) levels range from 1.5 to 2.5 mEq/liter.

As plasma Pre-Natal Supplement (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 Pre-Natal Supplement (Magnesium (Magnesium Oxide)). Serum Pre-Natal Supplement (Magnesium (Magnesium Oxide)) concentrations in excess of 12 mEq/L may be fatal.

Pre-Natal Supplement (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 Pre-Natal Supplement (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. Pre-Natal Supplement (Magnesium (Magnesium Oxide)) is excreted solely by the kidneys at a rate proportional to the plasma concentration and glomerular filtration.

INDICATIONS AND USAGE

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

Pre-Natal Supplement (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 Pre-Natal Supplement (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. Pre-Natal Supplement (Magnesium (Magnesium Oxide)) sulfate should be used during pregnancy only if clearly needed. If Pre-Natal Supplement (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 Pre-Natal Supplement (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 Pre-Natal Supplement (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 Pre-Natal Supplement (Magnesium (Magnesium Oxide)), their dosage should be adjusted with caution because of additive CNS depressant effects of Pre-Natal Supplement (Magnesium (Magnesium Oxide)).

Because Pre-Natal Supplement (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 Pre-Natal Supplement (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 Pre-Natal Supplement (Magnesium (Magnesium Oxide)) should be given until they return. Serum Pre-Natal Supplement (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 Pre-Natal Supplement (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 Pre-Natal Supplement (Magnesium (Magnesium Oxide)) intoxication in eclampsia.

50% Pre-Natal Supplement (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

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

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

Cardiac Glycosides - Pre-Natal Supplement (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 Pre-Natal Supplement (Magnesium (Magnesium Oxide)) toxicity.

Pregnancy

Teratogenic Effects

Pregnancy Category D (See WARNINGS and PRECAUTIONS )

See WARNINGS and PRECAUTIONS .

Pre-Natal Supplement (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 Pre-Natal Supplement (Magnesium (Magnesium Oxide)) sulfate for more than 5 to 7 days.^1-10 Pre-Natal Supplement (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 Pre-Natal Supplement (Magnesium (Magnesium Oxide)) toxicity, including neuromuscular or respiratory depression (See OVERDOSAGE ).

Labor and Delivery

Continuous administration of Pre-Natal Supplement (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 Pre-Natal Supplement (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 Pre-Natal Supplement (Magnesium (Magnesium Oxide)) is distributed into milk during parenteral Pre-Natal Supplement (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 Pre-Natal Supplement (Magnesium (Magnesium Oxide)) should be monitored in such patients.

ADVERSE REACTIONS

The adverse effects of parenterally administered Pre-Natal Supplement (Magnesium (Magnesium Oxide)) usually are the result of Pre-Natal Supplement (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 Pre-Natal Supplement (Magnesium (Magnesium Oxide)) sulfate therapy for eclampsia has been reported.

OVERDOSAGE

Pre-Natal Supplement (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 Pre-Natal Supplement (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 Pre-Natal Supplement (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 Pre-Natal Supplement (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 Pre-Natal Supplement (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 Pre-Natal Supplement (Magnesium (Magnesium Oxide)) Deficiency

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

Pre-Natal Supplement (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 Pre-Natal Supplement (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

Pre-Natal Supplement (Magnesium (Magnesium Oxide)) Sulfate Injection, USP is supplied in single-dose containers as follows:

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

Rx only

NDC 0409-1754-10

10 mL Single-dose syringe

50% Pre-Natal Supplement (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

Manganese (Manganese HVP Chelate):

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Drug abuse and dependence
• Overdosage
• Dosage and administration
• How supplied
• Rl-0104
• Pre-Natal Supplement (Manganese (Manganese HVP Chelate)) reviews

INDICATIONS AND USAGE

Pre-Natal Supplement (Manganese (Manganese HVP Chelate)) 0.1 mg/mL (Manganese Chloride Injection, USP) is indicated for use as a supplement to intravenous solutions given for total parenteral nutrition (TPN).

Administration helps to maintain Pre-Natal Supplement (Manganese (Manganese HVP Chelate)) serum levels and to prevent depletion of endogenous stores and subsequent deficiency symptoms.

CONTRAINDICATIONS

None known.

WARNINGS

Direct intramuscular or intravenous injection of Pre-Natal Supplement (Manganese (Manganese HVP Chelate)) 0.1 mg/mL (Manganese Chloride Injection, USP) is contraindicated as the acidic pH of the solution (pH 2.0) may cause considerable tissue irritation.

Liver and/or biliary tract dysfunction may require omission or reduction of copper and Pre-Natal Supplement (Manganese (Manganese HVP Chelate)) doses because these elements are primarily eliminated in the bile.

WARNING: 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.

PRECAUTIONS

General

Do not use unless solution is clear and seal is intact.

Pre-Natal Supplement ) 0.1 mg/mL (Manganese Chloride Injection, USP) should only be used in conjunction with a pharmacy directed admixture program using aseptic technique in a laminar flow environment; it should be used promptly and in a single operation without any repeated penetrations. Solution contains no preservatives; discard unused portion immediately after admixture procedure is completed.

Laboratory Tests

Serum Pre-Natal Supplement (Manganese (Manganese HVP Chelate)) levels can be measured periodically at the discretion of the investigator. Because of the low serum concentration normally present, samples will usually be analyzed by a reference laboratory.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term animal studies to evaluate the carcinogenic potential of Pre-Natal Supplement ) 0.1 mg/mL (Manganese Chloride Injection, USP) have not been performed, nor have studies been done to assess mutagenesis or impairment of fertility.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Pre-Natal Supplement (Manganese (Manganese HVP Chelate)) 0.1 mg/mL (Manganese Chloride Injection, USP) additive is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Pregnancy Category C.

Animal reproduction studies have not been conducted with Pre-Natal Supplement (Manganese (Manganese HVP Chelate)) chloride. It is also not known whether Pre-Natal Supplement (Manganese (Manganese HVP Chelate)) chloride can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Pre-Natal Supplement (Manganese (Manganese HVP Chelate)) chloride should be given to a pregnant woman only if clearly indicated.

Geriatric Use

An evaluation of current literature revealed no clinical experience identifying differences in response 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.

ADVERSE REACTIONS

None known.

DRUG ABUSE AND DEPENDENCE

None known.

OVERDOSAGE

Pre-Natal Supplement (Manganese (Manganese HVP Chelate)) toxicity in TPN patients has not been reported.

DOSAGE AND ADMINISTRATION

Pre-Natal Supplement (Manganese (Manganese HVP Chelate)) 0.1 mg/mL (Manganese Chloride Injection, USP) contains 0.1 mg manganese/mL and is administered intravenously only after dilution. The additive should be administered in a volume of fluid not less than 100 mL. For the adult receiving TPN, the suggested additive dosage for Pre-Natal Supplement (Manganese (Manganese HVP Chelate)) is 0.15 to 0.8 mg/day (1.5 to 8 mL/day). For pediatric patients, a dosage of 2 to 10 mcg manganese/kg/day (0.02 to 0.1 mL/kg/day) is recommended.

Periodic monitoring of Pre-Natal Supplement (Manganese (Manganese HVP Chelate)) plasma levels is suggested as a guideline for subsequent administration.

Parenteral products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. (See PRECAUTIONS .)

HOW SUPPLIED

Pre-Natal Supplement (Manganese (Manganese HVP Chelate)) 0.1 mg/mL (Manganese Chloride Injection, USP) is supplied in 10 mL Plastic Vials (NDC No. 0409-4091-01).

Store at 20 to 25°C (68 to 77°F)

Revised: November, 2009

Printed in USA EN-2320

Hospira, Inc., Lake Forest, IL 60045 USA

RL-0104

Vitamin C (Ascorbic Acid):

• Pharmacological action
• Pharmacokinetics
• Why is Pre-Natal Supplement ) prescribed?
• Dosage and administration
• Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) side effects, adverse reactions
• Pre-Natal Supplement ) contraindications
• Using during pregnancy and breastfeeding
• Special instructions
• Pre-Natal Supplement ) drug interactions
• Pre-Natal Supplement ) in case of emergency / overdose
• Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) reviews

Pharmacological action

Pre-Natal Supplement ) (vitamin c) is essential for the formation of intracellular collagen, is required to strengthen the structure of teeth, bones, and the capillary walls. Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) participates in redox reactions, the metabolism of tyrosine, converting folic acid into folinic acid, metabolism of carbohydrates, the synthesis of lipids and proteins, iron metabolism, processes of cellular respiration. Reduces the need for vitamins B1, B2, A, E, folic acid, pantothenic acid, enhances the body's resistance to infections; enhances iron absorption, contributing to its sequestration in reduced form. Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) has antioxidant properties.

With intravaginal application of Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) lowers the vaginal pH, inhibiting the growth of bacteria and helps to restore and maintain normal pH and vaginal flora (Lactobacillus acidophilus, Lactobacillus gasseri).

Pharmacokinetics

After oral administration Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) is completely absorbed from the gastrointestinal tract. Widely distributed in body tissues.

The concentration of Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) in blood plasma in normal amounts to approximately 10-20 mg / ml.

The concentration of Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) in white blood cells and platelets is higher than in erythrocytes and plasma. When deficient state of concentration in leucocytes is reduced later and more slowly and is regarded as the best criterion for evaluating the deficit than the concentration in plasma.

Plasma protein binding is about 25%.

Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) is reversibly oxidized to form dehydroascorbic acid, is metabolized with the formation of ascorbate-2-sulphate which is inactive and oxalic acid which is excreted in the urine.

Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) taken in excessive quantities is rapidly excreted unchanged in urine, it usually happens when exceeding a daily dose is 200 mg.

Why is Pre-Natal Supplement ) prescribed?

For systemic use of Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) RiteMED Phils: prevention and treatment of hypo- and avitaminosis of vitamin C; providing increased need for vitamin C during growth, pregnancy, lactation, with heavy loads, fatigue and during recovery after prolonged severe illness; in winter with an increased risk of infectious diseases.

For intravaginal use: chronic or recurrent vaginitis (bacterial vaginosis, nonspecific vaginitis) caused by the anaerobic flora (due to changes in pH of the vagina) in order to normalize disturbed vaginal microflora.

Dosage and administration

This medication administered orally, IM, IV, intravaginally.

For the prevention of deficiency conditions Pre-Natal Supplement ) dose is 25-75 mg / day, for the treatment - 250 mg / day or more in divided doses.

For intravaginal used Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) drugs in appropriate dosage forms.

Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) side effects, adverse reactions

CNS: headache, fatigue, insomnia.

Digestive system: stomach cramps, nausea and vomiting.

Allergic reaction: describes a few cases of skin reactions and manifestations of the respiratory system.

Urinary system: when used in high doses - hyperoxaluria and the formation of kidney stones of calcium oxalate.

Local reactions: with intravaginal application - a burning or itching in the vagina, increased mucous discharge, redness, swelling of the vulva. Other: sensation of heat.

Pre-Natal Supplement ) contraindications

Increased sensitivity to Pre-Natal Supplement (Vitamin C (Ascorbic Acid)).

Using during pregnancy and breastfeeding

The minimum daily requirement of Pre-Natal Supplement ) in the II and III trimester of pregnancy is about 60 mg.

Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) crosses the placental barrier. It should be borne in mind that the fetus can adapt to high doses of Pre-Natal Supplement (Vitamin C (Ascorbic Acid)), which takes a pregnant woman, and then a newborn baby may develop the ascorbic disease as the reaction of cancel. Therefore, during pregnancy should not to take Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) in high doses, except in cases where the expected benefit outweighs the potential risk.

The minimum daily requirement during lactation (breastfeeding) is 80 mg. Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) is excreted in breast milk. A mother's diet that contains adequate amounts of Pre-Natal Supplement (Vitamin C (Ascorbic Acid)), is sufficient to prevent deficiency in an infant. It is unknown whether dangerous to the child's mother use of Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) in high doses. Theoretically it is possible. Therefore, it is recommended not to exceed the maximum daily nursing mother needs to Pre-Natal Supplement (Vitamin C (Ascorbic Acid)), except when the expected benefit outweighs the potential risk.

Special instructions

Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) is used with caution in patients with hyperoxaluria, renal impairment, a history of instructions on urolithiasis. Because Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) increases iron absorption, its use in high doses can be dangerous in patients with hemochromatosis, thalassemia, polycythemia, leukemia, and sideroblastic anemia.

Patients with high content body iron should apply Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) in minimal doses.

Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) is used with caution in patients with deficiency of glucose-6-phosphate dehydrogenase.

The use of Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) in high doses can cause exacerbation of sickle cell anemia.

Data on the diabetogenic action of Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) are contradictory. However, prolonged use of Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) should periodically monitor your blood glucose levels.

It is believed that the use of Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) in patients with rapidly proliferating and widely disseminated tumors may worsen during the process. It should therefore be used with caution in Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) in patients with advanced cancer.

Absorption of Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) decreased while use of fresh fruit or vegetable juices, alkaline drinking.

Pre-Natal Supplement ) drug interactions

In an application with barbiturates, primidone increases the excretion of Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) in the urine.

With the simultaneous use of oral contraceptives reduces the concentration of Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) in blood plasma.

In an application of Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) with iron preparations Pre-Natal Supplement (Vitamin C (Ascorbic Acid)), due to its regenerative properties, transforms ferric iron in the bivalent, which improves its absorption.

Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) in high doses can decrease urine pH that while the application reduces the tubular reabsorption of amphetamine and tricyclic antidepressants.

With the simultaneous use of aspirin reduces the absorption of Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) by about a third.

Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) in an application with warfarin may decrease effects of warfarin.

With the simultaneous application of Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) increases the excretion of iron in patients receiving deferoxamine. In the application of Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) at a dose of 500 mg / day possibly left ventricular dysfunction.

In an application with tetracycline is increased excretion of Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) in the urine.

There is a described case of reducing the concentration of fluphenazine in plasma in patients treated with Pre-Natal Supplement (Vitamin C (Ascorbic Acid)) 500 mg 2 times / day.

May increase the concentration of ethinyl estradiol in the blood plasma in its simultaneous application in the oral contraceptives.

Pre-Natal Supplement ) in case of emergency / overdose

Symptoms: long-term use of large doses (more than 1 g) - headache, increased CNS excitability, insomnia, nausea, vomiting, diarrhea, gastritis giperatsidnyh, ultseratsiya gastrointestinal mucosa, inhibition of the function insular apparatus of the pancreas (hyperglycemia, glycosuria), hyperoxaluria, nephrolithiasis (calcium oxalate), damage to the glomerular apparatus of the kidneys, moderate thamuria (when receiving a dose of 600 mg / day).

Decrease capillary permeability (possibly deteriorating trophic tissues, increased blood pressure, hypercoagulability, the development of microangiopathy).

When IV administration in high doses - the threat of termination of pregnancy (due to estrogenemia), hemolysis of red blood cells.

Vitamin E (D-Alpha Tocopherol Acid Succinate):

• Pre-Natal Supplement (Vitamin E (D-Alpha Tocopherol Acid Succinate)) reviews

Indication: Pre-Natal Supplement (Vitamin E (D-Alpha Tocopherol Acid Succinate)), known for its antioxidant activities, is protective against cardiovascular disease and some forms of cancer and has also demonstrated immune-enhancing effects. It may be of limited benefit in some with asthma and rheumatoid arthritis. It may be helpful in some neurological diseases including Alzheimer's, some eye disorders including cataracts, and diabetes and premenstrual syndrome. It may also help protect skin from ultraviolet irradiation although claims that it reverses skin aging, enhances male fertility and exercise performance are poorly supported. It may help relieve some muscle cramps.

Pre-Natal Supplement (Vitamin E (D-Alpha Tocopherol Acid Succinate)) has antioxidant activity. It may also have anti-atherogenic, antithrombotic, anticoagulant, neuroprotective, antiviral, immunomodulatory, cell membrane-stabilizing and antiproliferative actions. Pre-Natal Supplement (Vitamin E (D-Alpha Tocopherol Acid Succinate)) is a collective term used to describe eight separate forms, the best-known form being alpha-tocopherol. Pre-Natal Supplement (Vitamin E (D-Alpha Tocopherol Acid Succinate)) is a fat-soluble vitamin and is an important antioxidant. It acts to protect cells against the effects of free radicals, which are potentially damaging by-products of the body's metabolism. Pre-Natal Supplement (Vitamin E (D-Alpha Tocopherol Acid Succinate)) is often used in skin creams and lotions because it is believed to play a role in encouraging skin healing and reducing scarring after injuries such as burns. There are three specific situations when a Pre-Natal Supplement (Vitamin E (D-Alpha Tocopherol Acid Succinate)) deficiency is likely to occur. It is seen in persons who cannot absorb dietary fat, has been found in premature, very low birth weight infants (birth weights less than 1500 grams, or 3½ pounds), and is seen in individuals with rare disorders of fat metabolism. A Pre-Natal Supplement (Vitamin E (D-Alpha Tocopherol Acid Succinate)) deficiency is usually characterized by neurological problems due to poor nerve conduction. Symptoms may include infertility, neuromuscular impairment, menstrual problems, miscarriage and uterine degradation. Preliminary research has led to a widely held belief that Pre-Natal Supplement (Vitamin E (D-Alpha Tocopherol Acid Succinate)) may help prevent or delay coronary heart disease. Antioxidants such as Pre-Natal Supplement (Vitamin E (D-Alpha Tocopherol Acid Succinate)) help protect against the damaging effects of free radicals, which may contribute to the development of chronic diseases such as cancer. It also protects other fat-soluble vitamins (A and B group vitamins) from destruction by oxygen. Low levels of Pre-Natal Supplement (Vitamin E (D-Alpha Tocopherol Acid Succinate)) have been linked to increased incidence of breast and colon cancer.

Zinc (Zinc HVP Chelate):

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Drug abuse and dependence
• Overdosage
• Dosage and administration
• How supplied
• Pre-Natal Supplement (Zinc (Zinc HVP Chelate)) reviews

INDICATIONS AND USAGE

Pre-Natal Supplement (Zinc (Zinc HVP Chelate)) 1 mg/mL (Zinc Chloride Injection, USP) is indicated for use as a supplement to intravenous solutions given for TPN. Administration helps to maintain Pre-Natal Supplement (Zinc (Zinc HVP Chelate)) serum levels and to prevent depletion of endogenous stores, and subsequent deficiency symptoms.

CONTRAINDICATIONS

None known.

WARNINGS

Direct intramuscular or intravenous injection of Pre-Natal Supplement (Zinc (Zinc HVP Chelate)) 1 mg/mL (Zinc Chloride Injection, USP) is contraindicated as the acidic pH of the solution (2) may cause considerable tissue irritation.

Severe kidney disease may make it necessary to reduce or omit chromium and Pre-Natal Supplement (Zinc (Zinc HVP Chelate)) doses because these elements are primarily eliminated in the urine.

WARNING: 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.

PRECAUTIONS

General

Do not use unless the solution is clear and the seal is intact.

Zinc 1 mg/mL should only be used in conjunction with a pharmacy directed admixture program using aseptic technique in a laminar flow environment; it should be used promptly and in a single operation without any repeated penetrations. Solution contains no preservatives; discard unused portion immediately after admixture procedure is completed.

Zinc should not be given undiluted by direct injection into a peripheral vein because of the likelihood of infusion phlebitis and the potential for increased excretory loss of Pre-Natal Supplement (Zinc (Zinc HVP Chelate)) from a bolus injection. Administration of Pre-Natal Supplement (Zinc (Zinc HVP Chelate)) in the absence of copper may cause a decrease in serum copper levels.

Laboratory Tests

Periodic determinations of serum copper as well as Pre-Natal Supplement (Zinc (Zinc HVP Chelate)) are suggested as a guideline for subsequent Pre-Natal Supplement (Zinc (Zinc HVP Chelate)) administration.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term animal studies to evaluate the carcinogenic potential of Pre-Natal Supplement ) 1 mg/mL (Zinc Chloride Injection, USP) have not been performed, nor have studies been done to assess mutagenesis or impairment of fertility.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Pre-Natal Supplement (Zinc (Zinc HVP Chelate)) 1 mg/mL (Zinc Chloride Injection, USP) is administered to a nursing woman.

Pediatric Use

Pregnancy Category C. Animal reproduction studies have not been conducted with Pre-Natal Supplement ) chloride. It is also not known whether Pre-Natal Supplement (Zinc (Zinc HVP Chelate)) chloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Pre-Natal Supplement (Zinc (Zinc HVP Chelate)) chloride should be given to a pregnant woman only if clearly needed.

Geriatric Use

An evaluation of current literature revealed no clinical experience identifying differences in response 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.

ADVERSE REACTIONS

None known.

DRUG ABUSE AND DEPENDENCE

None known.

OVERDOSAGE

Single intravenous doses of 1 to 2 mg zinc/kg body weight have been given to adult leukemic patients without toxic manifestations. However, acute toxicity was reported in an adult when 10 mg Pre-Natal Supplement (Zinc (Zinc HVP Chelate)) was infused over a period of one hour on each of four consecutive days. Profuse sweating, decreased level of consciousness, blurred vision, tachycardia (140/min), and marked hypothermia (94.2° F) on the fourth day were accompanied by a serum Pre-Natal Supplement (Zinc (Zinc HVP Chelate)) concentration of 207 mcg/dl. Symptoms abated within three hours.

Hyperamylasemia may be a sign of impending Pre-Natal Supplement (Zinc (Zinc HVP Chelate)) overdosage; patients receiving an inadvertent overdose (25 mg zinc/liter of TPN solution, equivalent to 50 to 70 mg zinc/day) developed hyperamylasemia (557 to 1850 Klein units; normal: 130 to 310).

Death resulted from an overdosage in which 1683 mg Pre-Natal Supplement (Zinc (Zinc HVP Chelate)) was delivered intravenously over the course of 60 hours to a 72 year old patient.

Symptoms of Pre-Natal Supplement (Zinc (Zinc HVP Chelate)) toxicity included hypotension (80/40 mm Hg), pulmonary edema, diarrhea, vomiting, jaundice, and oliguria, with a serum Pre-Natal Supplement (Zinc (Zinc HVP Chelate)) level of 4184 mcg/dl.

Calcium supplements may confer a protective effect against Pre-Natal Supplement (Zinc (Zinc HVP Chelate)) toxicity.

DOSAGE AND ADMINISTRATION

Pre-Natal Supplement (Zinc (Zinc HVP Chelate)) 1 mg/mL (Zinc Chloride Injection, USP) contains 1 mg zinc/mL and is administered intravenously only after dilution. The additive should be diluted prior to administration in a volume of fluid not less than 100 mL. For the metabolically stable adult receiving TPN, the suggested intravenous dosage is 2.5 to 4 mg zinc/day (2.5 to 4 mL/day). An additional 2 mg zinc/day (2 mL/day) is suggested for acute catabolic states. For the stable adult with fluid loss from the small bowel, an additional 12.2 mg zinc/liter of small bowel fluid lost (12.2 mL/liter of small bowel fluid lost), or an additional 17.1 mg zinc/kg of stool or ileostomy output (17.1 mL/kg of stool or ileostomy output) is recommended. Frequent monitoring of Pre-Natal Supplement (Zinc (Zinc HVP Chelate)) blood levels is suggested for patients receiving more than the usual maintenance dosage level of Pre-Natal Supplement (Zinc (Zinc HVP Chelate)).

For full term infants and children up to 5 years of age, 100 mcg zinc/kg/day (0.1 mL/kg/day) is recommended. For premature infants (birth weight less than 1500 g) up to 3 kg in body weight, 300 mcg zinc/kg/day (0.3 mL/kg/day) is suggested.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. See PRECAUTIONS.

HOW SUPPLIED

Pre-Natal Supplement (Zinc (Zinc HVP Chelate)) 1 mg/mL (Zinc Chloride Injection, USP) is supplied in 10 mL Plastic Vials (List No. 4090).

Store at 20 to 25°C (68 to 77°F).

Revised: October, 2004

© Hospira 2004 EN-0488 Printed in USA

HOSPIRA, INC., LAKE FOREST, IL 60045 USA

10 mL Vial

Pre-Natal Supplement (Zinc (Zinc HVP Chelate))

1 mg/mL

Pre-Natal Supplement (Zinc (Zinc HVP Chelate)) Chloride Inj., USP

Rx only

FOR I.V. USE ONLY AFTER DILUTION.

HOSPIRA, INC., LAKE FOREST, IL 60045 USA