Vita OB

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
• Vita OB (Calcium Carbonate) reviews

1 INDICATIONS AND USAGE

Vita OB (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 Vita OB (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 Vita OB (Calcium Carbonate) acetate capsule.

- Capsule: 667 mg Vita OB (Calcium Carbonate) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

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

An overdose of Vita OB (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 Vita OB (Calcium Carbonate) levels twice weekly. Should hypercalcemia develop, reduce the Vita OB (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 Vita OB (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 Vita OB (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 Vita OB (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 Vita OB (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 Vita OB (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, Vita OB (Calcium Carbonate) acetate has been generally well tolerated.

Vita OB (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 Vita OB (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 Vita OB (Calcium Carbonate) concentration could reduce the incidence and severity of Vita OB (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 Vita OB (Calcium Carbonate) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

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

There are no empirical data on avoiding drug interactions between Vita OB (Calcium Carbonate) acetate and most concomitant drugs. When administering an oral medication with Vita OB (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 Vita OB (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 Vita OB (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 Vita OB (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 Vita OB (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:

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

8.2 Labor and Delivery

The effects of Vita OB (Calcium Carbonate) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

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

11 DESCRIPTION

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

Vita OB (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 Vita OB resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

Orally administered Vita OB (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 Vita OB (Calcium Carbonate) acetate.

14 CLINICAL STUDIES

Effectiveness of Vita OB (Calcium Carbonate) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Vita OB (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 Vita OB (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 Vita OB (Calcium Carbonate) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Vita OB (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 Vita OB (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 Vita OB (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 Vita OB (Calcium Carbonate) acetate is shown in the Table 3.

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

16 HOW SUPPLIED/STORAGE AND HANDLING

Vita OB (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 Vita OB (Calcium Carbonate) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Vita OB (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 Vita OB (Calcium Carbonate) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Folic Acid:

• Indications and usage
• Contraindications
• Precautions
• Adverse reactions
• Dosage and administration
• How supplied
• Storage
• Vita OB (Folic Acid) reviews

INDICATIONS AND USAGE

Vita OB (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

Vita OB (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 Vita OB (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

Vita OB (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.

Vita OB (Folic Acid) and the BIFERA logo are registered trademarks and the Vita OB (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

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
• Vita OB (Iron (Ferrous Fumarate)) reviews

1 INDICATIONS AND USAGE

Vita OB (Iron (Ferrous Fumarate)) is indicated for the treatment of Vita OB (Iron (Ferrous Fumarate)) deficiency anemia in patients with chronic kidney disease (CKD).

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

2 DOSAGE AND ADMINISTRATION

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

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

Administer Vita OB (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. Vita OB (Iron (Ferrous Fumarate)) should be administered early during the dialysis session. The usual total treatment course of Vita OB (Iron (Ferrous Fumarate)) is 1000 mg. Vita OB (Iron (Ferrous Fumarate)) treatment may be repeated if Vita OB (Iron (Ferrous Fumarate)) deficiency reoccurs.

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

Administer Vita OB (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 Vita OB (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. Vita OB (Iron (Ferrous Fumarate)) treatment may be repeated if Vita OB (Iron (Ferrous Fumarate)) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer Vita OB (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 Vita OB (Iron (Ferrous Fumarate)) in a maximum of 250 mL of 0.9% NaCl. Vita OB (Iron (Ferrous Fumarate)) treatment may be repeated if Vita OB (Iron (Ferrous Fumarate)) deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for Vita OB (Iron (Ferrous Fumarate)) maintenance treatment

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

For Vita OB (Iron (Ferrous Fumarate)) maintenance treatment: Administer Vita OB (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. Vita OB (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 Vita OB (Iron (Ferrous Fumarate)) maintenance treatment

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

For Vita OB (Iron (Ferrous Fumarate)) maintenance treatment: Administer Vita OB (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. Vita OB (Iron (Ferrous Fumarate)) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

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

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

4 CONTRAINDICATIONS

• Known hypersensitivity to Vita OB (Iron (Ferrous Fumarate))

• Known hypersensitivity to Vita OB (Iron (Ferrous Fumarate)) (4)

5 WARNINGS AND PRECAUTIONS

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

5.2 Hypotension

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

5.3 Vita OB (Iron (Ferrous Fumarate)) Overload

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

6 ADVERSE REACTIONS

The following serious adverse reactions associated with Vita OB ) are described in other sections .

• The most common adverse reactions (≥2%) following the administration of Vita OB (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 Vita OB ) 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 Vita OB (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 Vita OB (Iron (Ferrous Fumarate)) therapy and were reported to be intolerant (defined as precluding further use of that Vita OB (Iron (Ferrous Fumarate)) product). When these patients were treated with Vita OB (Iron (Ferrous Fumarate)) there were no occurrences of adverse reactions that precluded further use of Vita OB (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 Vita OB (Iron (Ferrous Fumarate)) maintenance treatment with Vita OB (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 Vita OB (Iron (Ferrous Fumarate)) 0.5 mg/kg, 53% (25/47) of the patients receiving Vita OB (Iron (Ferrous Fumarate)) 1.0 mg/kg, and 55% (26/47) of the patients receiving Vita OB (Iron (Ferrous Fumarate)) 2.0 mg/kg.

A total of 5 (11%) subjects in the Vita OB (Iron (Ferrous Fumarate)) 0.5 mg/kg group, 10 (21%) patients in the Vita OB (Iron (Ferrous Fumarate)) 1.0 mg/kg group, and 10 (21%) patients in the Vita OB (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 Vita OB (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 Vita OB (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 Vita OB (Iron (Ferrous Fumarate)) injection. Reactions have occurred following the first dose or subsequent doses of Vita OB (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 Vita OB (Iron (Ferrous Fumarate)) have not been studied. However, Vita OB (Iron (Ferrous Fumarate)) may reduce the absorption of concomitantly administered oral Vita OB (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, Vita OB ) sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental Vita OB (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 Vita OB (Iron (Ferrous Fumarate)) sucrose. Because animal reproductive studies are not always predictive of human response, Vita OB (Iron (Ferrous Fumarate)) should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether Vita OB (Iron (Ferrous Fumarate)) sucrose is excreted in human milk. Vita OB (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 Vita OB (Iron (Ferrous Fumarate)) is administered to a nursing woman.

8.4 Pediatric Use

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

Safety and effectiveness of Vita OB (Iron (Ferrous Fumarate)) for Vita OB (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. Vita OB (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)]

Vita OB (Iron (Ferrous Fumarate)) has not been studied in patients younger than 2 years of age.

In a country where Vita OB (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 Vita OB (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 Vita OB (Iron (Ferrous Fumarate)) or any other drugs could be established.

8.5 Geriatric Use

Clinical studies of Vita OB (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 Vita OB (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 Vita OB (Iron (Ferrous Fumarate)) in humans. Excessive dosages of Vita OB (Iron (Ferrous Fumarate)) may lead to accumulation of Vita OB (Iron (Ferrous Fumarate)) in storage sites potentially leading to hemosiderosis. Do not administer Vita OB (Iron (Ferrous Fumarate)) to patients with Vita OB (Iron (Ferrous Fumarate)) overload.

Toxicities in single-dose studies in mice and rats, at intravenous Vita OB (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

Vita OB (Iron (Ferrous Fumarate)) (iron sucrose injection, USP), an Vita OB (Iron (Ferrous Fumarate)) replacement product, is a brown, sterile, aqueous, complex of polynuclear Vita OB (Iron (Ferrous Fumarate)) (III)-hydroxide in sucrose for intravenous use. Vita OB (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 Vita OB (Iron (Ferrous Fumarate)) polymerization and m is the number of sucrose molecules associated with the Vita OB (Iron (Ferrous Fumarate)) (III)-hydroxide.

Each mL contains 20 mg elemental Vita OB (Iron (Ferrous Fumarate)) as Vita OB (Iron (Ferrous Fumarate)) sucrose in water for injection. Vita OB (Iron (Ferrous Fumarate)) is available in 10 mL single-use vials (200 mg elemental Vita OB (Iron (Ferrous Fumarate)) per 10 mL), 5 mL single-use vials (100 mg elemental Vita OB (Iron (Ferrous Fumarate)) per 5 mL), and 2.5 mL single-use vials (50 mg elemental Vita OB (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

Vita OB ) is an aqueous complex of poly-nuclear Vita OB (Iron (Ferrous Fumarate)) (III)-hydroxide in sucrose. Following intravenous administration, Vita OB (Iron (Ferrous Fumarate)) is dissociated into Vita OB (Iron (Ferrous Fumarate)) and sucrose and the Vita OB (Iron (Ferrous Fumarate)) is transported as a complex with transferrin to target cells including erythroid precursor cells. The Vita OB (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, Vita OB (Iron (Ferrous Fumarate)) is dissociated into Vita OB (Iron (Ferrous Fumarate)) and sucrose. In 22 patients undergoing hemodialysis and receiving erythropoietin (recombinant human erythropoietin) therapy treated with Vita OB (Iron (Ferrous Fumarate)) sucrose containing 100 mg of Vita OB (Iron (Ferrous Fumarate)), three times weekly for three weeks, significant increases in serum Vita OB (Iron (Ferrous Fumarate)) and serum ferritin and significant decreases in total Vita OB (Iron (Ferrous Fumarate)) binding capacity occurred four weeks from the initiation of Vita OB (Iron (Ferrous Fumarate)) sucrose treatment.

12.3 Pharmacokinetics

In healthy adults administered intravenous doses of Vita OB ), its Vita OB (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 Vita OB (Iron (Ferrous Fumarate)) component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating Vita OB (Iron (Ferrous Fumarate)) containing 100 mg of Vita OB (Iron (Ferrous Fumarate)) labeled with ⁵²Fe/⁵⁹Fe in patients with Vita OB (Iron (Ferrous Fumarate)) deficiency showed that a significant amount of the administered Vita OB (Iron (Ferrous Fumarate)) is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible Vita OB (Iron (Ferrous Fumarate)) trapping compartment.

Following intravenous administration of Vita OB (Iron (Ferrous Fumarate)), Vita OB (Iron (Ferrous Fumarate)) sucrose is dissociated into Vita OB (Iron (Ferrous Fumarate)) and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of Vita OB (Iron (Ferrous Fumarate)) containing 1,510 mg of sucrose and 100 mg of Vita OB (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 Vita OB (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 Vita OB (Iron (Ferrous Fumarate)) sucrose containing 500 to 700 mg of Vita OB (Iron (Ferrous Fumarate)) in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60), approximately 5% of the Vita OB (Iron (Ferrous Fumarate)) was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of Vita OB (Iron (Ferrous Fumarate)) have not been studied.

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

In a single-dose PK study of Vita OB (Iron (Ferrous Fumarate)), patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of Vita OB (Iron (Ferrous Fumarate)) at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose Vita OB (Iron (Ferrous Fumarate)), the half-life of total serum Vita OB (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.

Vita OB (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 Vita OB (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 Vita OB (Iron (Ferrous Fumarate)) sucrose.

Vita OB (Iron (Ferrous Fumarate)) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Vita OB (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.

Vita OB (Iron (Ferrous Fumarate)) sucrose at intravenous doses up to 15 mg/kg/day of elemental Vita OB (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 Vita OB ).

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 Vita OB (Iron (Ferrous Fumarate)) treatment and 24 in the historical control group) with Vita OB (Iron (Ferrous Fumarate)) deficiency anemia. Eligibility criteria for Vita OB (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.

Vita OB (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 Vita OB (Iron (Ferrous Fumarate)), who were off intravenous Vita OB (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 Vita OB (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 Vita OB (Iron (Ferrous Fumarate)) in 23 patients with Vita OB (Iron (Ferrous Fumarate)) deficiency and HDD-CKD who had been discontinued from Vita OB (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 Vita OB (Iron (Ferrous Fumarate)). Exclusion criteria were similar to those in studies A and B. Vita OB (Iron (Ferrous Fumarate)) was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of Vita OB (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 Vita OB (Iron (Ferrous Fumarate)) versus Vita OB (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 Vita OB (Iron (Ferrous Fumarate)) (325 mg ferrous sulfate three times daily for 56 days); or Vita OB (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 Vita OB (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 Vita OB (Iron (Ferrous Fumarate)) group.

A statistically significantly greater proportion of Vita OB (Iron (Ferrous Fumarate)) subjects (35/79; 44.3%) compared to oral Vita OB (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 Vita OB (Iron (Ferrous Fumarate)) to patients with PDD-CKD receiving an erythropoietin alone without Vita OB (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 Vita OB (Iron (Ferrous Fumarate)) or Vita OB (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 Vita OB (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 Vita OB (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 Vita OB (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: Vita OB ) 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 Vita OB (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 Vita OB (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 Vita OB (Iron (Ferrous Fumarate)) once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received Vita OB (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 Vita OB (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

Vita OB ) is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Vita OB (Iron (Ferrous Fumarate)), each 5 mL vial contains 100 mg elemental Vita OB (Iron (Ferrous Fumarate)), and each 2.5 mL vial contains 50 mg elemental Vita OB (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: Vita OB (Iron (Ferrous Fumarate)), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Vita OB (Iron (Ferrous Fumarate)) per mL, or undiluted (20 mg elemental Vita OB (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: Vita OB (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 Vita OB (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 Vita OB (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 Vita OB (Iron (Ferrous Fumarate)) administration:

• Question patients regarding any prior history of reactions to parenteral Vita OB (Iron (Ferrous Fumarate)) products
• Advise patients of the risks associated with Vita OB (Iron (Ferrous Fumarate))
• Advise patients to report any symptoms of hypersensitivity that may develop during and following Vita OB (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

Vita OB (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

Sodium Fluoride:

• 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
• Vita OB (Sodium Fluoride) reviews

1 INDICATIONS AND USAGE

Vita OB nitrite is indicated for sequential use with Vita OB (Sodium Fluoride) thiosulfate for treatment of acute cyanide poisoning that is judged to be life-threatening. (1)

• Use with caution if the diagnosis of cyanide poisoning is uncertain. (1)

1.1 Indication

Vita OB (Sodium Fluoride) Nitrite Injection is indicated for sequential use with Vita OB (Sodium Fluoride) thiosulfate for the treatment of acute cyanide poisoning that is judged to be life-threatening. When the diagnosis of cyanide poisoning is uncertain, the potentially life-threatening risks associated with Vita OB (Sodium Fluoride) Nitrite Injection should be carefully weighed against the potential benefits, especially if the patient is not in extremis.

1.2 Identifying Patients with Cyanide Poisoning

Cyanide poisoning may result from inhalation, ingestion, or dermal exposure to various cyanide-containing compounds, including smoke from closed-space fires. Sources of cyanide poisoning include hydrogen cyanide and its salts, cyanogenic plants, aliphatic nitriles, and prolonged exposure to Vita OB nitroprusside.

The presence and extent of cyanide poisoning are often initially unknown. There is no widely available, rapid, confirmatory cyanide blood test. Treatment decisions must be made on the basis of clinical history and signs and symptoms of cyanide intoxication. If clinical suspicion of cyanide poisoning is high, Vita OB (Sodium Fluoride) Nitrite Injection and Vita OB (Sodium Fluoride) Thiosulfate Injection should be administered without delay.

In some settings, panic symptoms including tachypnea and vomiting may mimic early cyanide poisoning signs. The presence of altered mental status (e.g., confusion and disorientation) and/or mydriasis is suggestive of true cyanide poisoning although these signs can occur with other toxic exposures as well.

The expert advice of a regional poison control center may be obtained by calling 1-800-222-1222.

Smoke Inhalation

Not all smoke inhalation victims will have cyanide poisoning and may present with burns, trauma, and exposure to other toxic substances making a diagnosis of cyanide poisoning particularly difficult. Prior to administration of Vita OB (Sodium Fluoride) Nitrite Injection, smoke-inhalation victims should be assessed for the following:

• Exposure to fire or smoke in an enclosed area
• Presence of soot around the mouth, nose, or oropharynx
• Altered mental status

Although hypotension is highly suggestive of cyanide poisoning, it is only present in a small percentage of cyanide-poisoned smoke inhalation victims. Also indicative of cyanide poisoning is a plasma lactate concentration greater than or equal to 10 mmol/L (a value higher than that typically listed in the table of signs and symptoms of isolated cyanide poisoning because carbon monoxide associated with smoke inhalation also contributes to lactic acidemia). If cyanide poisoning is suspected, treatment should not be delayed to obtain a plasma lactate concentration.

1.3 Use with Other Cyanide Antidotes

Caution should be exercised when administering cyanide antidotes, other than Vita OB (Sodium Fluoride) thiosulfate, simultaneously with Vita OB (Sodium Fluoride) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Vita OB (Sodium Fluoride) thiosulfate, with Vita OB (Sodium Fluoride) Nitrite Injection, these drugs should not be administered concurrently in the same IV line. [see Dosage and Administration (2.2) ]

2 DOSAGE AND ADMINISTRATION

Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Vita OB (Sodium Fluoride) nitrite and Vita OB (Sodium Fluoride) thiosulfate.

Monitoring: Blood pressure must be monitored during treatment. (2.2)

2.1 Administration Recommendation

Comprehensive treatment of acute cyanide intoxication requires support of vital functions. Administration of Vita OB (Sodium Fluoride) nitrite, followed by Vita OB (Sodium Fluoride) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Vita OB (Sodium Fluoride) nitrite and Vita OB (Sodium Fluoride) thiosulfate.

Vita OB (Sodium Fluoride) nitrite injection and Vita OB (Sodium Fluoride) thiosulfate injection are administered by slow intravenous injection. They should be given as early as possible after a diagnosis of acute life-threatening cyanide poisoning has been established. Vita OB (Sodium Fluoride) nitrite should be administered first, followed immediately by Vita OB (Sodium Fluoride) thiosulfate. Blood pressure must be monitored during infusion in both adults and children. The rate of infusion should be decreased if significant hypotension is noted.

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Vita OB (Sodium Fluoride) nitrite and Vita OB (Sodium Fluoride) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Vita OB (Sodium Fluoride) nitrite should be reduced proportionately to the hemoglobin concentration.

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

2.2 Recommended Monitoring

Patients should be monitored for at least 24-48 hours after Vita OB Nitrite Injection administration for adequacy of oxygenation and perfusion and for recurrent signs and symptoms of cyanide toxicity. When possible, hemoglobin/hematocrit should be obtained when treatment is initiated. Measurements of oxygen saturation using standard pulse oximetry and calculated oxygen saturation values based on measured PO₂ are unreliable in the presence of methemoglobinemia.

Methemoglobin level: Administrations of Vita OB (Sodium Fluoride) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Vita OB (Sodium Fluoride) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Vita OB (Sodium Fluoride) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Vita OB (Sodium Fluoride) nitrite beyond the initial dose should be guided primarily by clinical response to treatment (i.e., a second dose should be considered only if there is inadequate clinical response to the first dose). It is generally recommended that methemoglobin concentrations be closely monitored and kept below 30%. Serum methemoglobin levels should be monitored during treatment using co-oximetry, and administration of Vita OB (Sodium Fluoride) nitrite should generally be discontinued when methemoglobin levels exceed 30%. Intravenous methylene blue and exchange transfusion have been reported in the literature as treatments for life-threatening methemoglobinemia.

2.3 Incompatibility Information

Chemical incompatibility has been reported between Vita OB (Sodium Fluoride) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Vita OB (Sodium Fluoride) thiosulfate and Vita OB (Sodium Fluoride) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Vita OB (Sodium Fluoride) Nitrite Injection consists of:

• One vial of Vita OB (Sodium Fluoride) nitrite injection, USP 300 mg/10mL (30 mg/mL)

Administration of the contents of one vial constitutes a single dose.

• Injection, 300 mg/10 mL (30 mg/mL). (3)

4 CONTRAINDICATIONS

None

• None. (4)

5 WARNINGS AND PRECAUTIONS

• Methemoglobinemia: Vita OB nitrite reacts with hemoglobin to form methemoglobin and should be used with caution in patients known to have anemia. Monitor oxyhemoglobin and methemoglobin levels by pulse oximetry or other measurements. Optimally, the Vita OB (Sodium Fluoride) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.2)
• Smoke inhalation: Carbon monoxide contained in smoke can result in the formation of carboxyhemoglobin that can reduce the oxygen carrying capacity of the blood. Vita OB (Sodium Fluoride) nitrite should be used with caution in patients with smoke inhalation injury because of the potential for worsening hypoxia due to methemoglobin formation. Carboxyhemoglobin and oxyhemoglobin levels should be monitored by pulse oximetry or other measurements in patients that present with evidence of smoke inhalation. Optimally, the Vita OB (Sodium Fluoride) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.4)

5.1 Hypotension

5.2 Methemoglobinemia

Supportive care alone may be sufficient treatment without administration of antidotes for many cases of cyanide intoxication, particularly in conscious patients without signs of severe toxicity. Patients should be closely monitored to ensure adequate perfusion and oxygenation during treatment with Vita OB nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with Vita OB (Sodium Fluoride) nitrite whenever possible. When Vita OB (Sodium Fluoride) nitrite is administered to humans a wide range of methemoglobin concentrations occur. Methemoglobin concentrations as high as 58% have been reported after two 300-mg doses of Vita OB (Sodium Fluoride) nitrite administered to an adult. Vita OB (Sodium Fluoride) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Vita OB (Sodium Fluoride) nitrite should be used with caution in patients who may be particularly susceptible to injury from vasodilation and its related hemodynamic sequelae. Hemodynamics should be monitored closely during and after administration of Vita OB (Sodium Fluoride) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

Vita OB (Sodium Fluoride) nitrite should be used with caution in patients with known anemia. Patients with anemia will form more methemoglobin (as a percentage of total hemoglobin) than persons with normal red blood cell (RBC) volumes. Optimally, these patients should receive a Vita OB (Sodium Fluoride) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Vita OB nitrite should be used with caution in persons with smoke inhalation injury or carbon monoxide poisoning because of the potential for worsening hypoxia due to methemoglobin formation.

5.5 Neonates and Infants

Neonates and infants may be more susceptible than adults and older pediatric patients to severe methemoglobinemia when Vita OB (Sodium Fluoride) nitrite is administered. Reduced dosing guidelines should be followed in pediatric patients.

5.6 G6PD Deficiency

Because patients with G6PD deficiency are at increased risk of a hemolytic crisis with Vita OB nitrite administration, alternative therapeutic approaches should be considered in these patients. Patients with known or suspected G6PD deficiency should be monitored for an acute drop in hematocrit. Exchange transfusion may be needed for patients with G6PD deficiency who receive Vita OB (Sodium Fluoride) nitrite.

5.7 Use with Other Drugs

Vita OB (Sodium Fluoride) nitrite should be used with caution in the presence of concomitant antihypertensive medications, diuretics or volume depletion due to diuretics, or drugs known to increase vascular nitric oxide, such as PDE5 inhibitors.

6 ADVERSE REACTIONS

There have been no controlled clinical trials conducted to systematically assess the adverse events profile of Vita OB (Sodium Fluoride) nitrite.

The medical literature has reported the following adverse events in association with Vita OB (Sodium Fluoride) nitrite administration. These adverse events were not reported in the context of controlled trials or with consistent monitoring and reporting methodologies for adverse events. Therefore, frequency of occurrence of these adverse events cannot be assessed.

Cardiovascular system: syncope, hypotension, tachycardia, methemoglobinemia, palpitations, dysrhythmia

Hematological: methemoglobinemia

Central nervous system: headache, dizziness, blurred vision, seizures, confusion, coma

Gastrointestinal system: nausea, vomiting, abdominal pain

Respiratory system: tachypnea, dyspnea

Body as a Whole: anxiety, diaphoresis, lightheadedness, injection site tingling, cyanosis, acidosis, fatigue, weakness, urticaria, generalized numbness and tingling

Severe hypotension, methemoglobinemia, cardiac dysrhythmias, coma and death have been reported in patients without life-threatening cyanide poisoning but who were treated with injection of Vita OB (Sodium Fluoride) nitrite at doses less than twice those recommended for the treatment of cyanide poisoning.

Most common adverse reactions are:

• Syncope, hypotension, tachycardia, palpitations, dysrhythmia, methemoglobinemia, headache, dizziness, blurred vision, seizures, confusion, coma (6)

To report SUSPECTED ADVERSE REACTIONS, contact Hope Pharmaceuticals at 1-800-755-9595 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS

Formal drug interaction studies have not been conducted with Vita OB (Sodium Fluoride) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: Vita OB nitrite is substantially excreted by the kidney. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. (8.6).

8.1 Pregnancy

Teratogenic Effects. Pregnancy Category C.

There are no adequate and well-controlled studies in pregnant women. Vita OB (Sodium Fluoride) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Vita OB (Sodium Fluoride) nitrite has caused fetal death in humans as well as animals. There are no studies in humans that have directly evaluated the potential reproductive toxicity of Vita OB (Sodium Fluoride) nitrite. There are two epidemiological studies conducted in Australia that report a statistically significant increase in the risk for congenital malformations, particularly in the CNS, associated with maternal consumption of water containing nitrate levels in excess of 5 ppm. Results from a case-control study in Canada suggested a trend toward an increase in the risk for CNS malformations when maternal consumption of nitrate was ≥ 26 ppm (not statistically significant).

The potential reproductive toxicity of Vita OB (Sodium Fluoride) nitrite exposure restricted to the prenatal period has been reported in guinea pigs, mice, and rats. There was no evidence of teratogenicity in guinea pigs, mice, or rats. However, Vita OB (Sodium Fluoride) nitrite treatment of pregnant guinea pigs with 60 or 70 mg/kg/day resulted in abortion of the litters within 1-4 days of treatment. All animals treated subcutaneously with 70 mg/kg, Vita OB (Sodium Fluoride) nitrite died within 60 minutes of treatment. Further studies demonstrated that a dose of 60 mg/kg resulted in measurable blood levels of methemoglobin in the dams and their fetuses for up to 6 hours post treatment. Maternal methemoglobin levels were higher than the levels in the offspring at all times measured. Based on a body surface area comparison, a 60 mg/kg dose in the guinea pig that resulted in death was only 1.7 times higher than the highest clinical dose of Vita OB (Sodium Fluoride) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).

Studies testing prenatal and postnatal exposure have been reported in mice and rats. Treatment of pregnant rats via drinking water with Vita OB (Sodium Fluoride) nitrite at concentrations of either 2000 or 3000 mg/L resulted in a dose-related increased mortality postpartum. This exposure regimen in the rat model would result in dosing of approximately 220 and 300 mg/kg/day (43 and 65 times the highest clinical dose of Vita OB (Sodium Fluoride) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Vita OB (Sodium Fluoride) nitrite produces methemoglobin. Fetal hemoglobin is oxidized to methemoglobin more easily than adult hemoglobin. In addition, the fetus has lower levels of methemoglobin reductase than adults. Collectively, these data suggest that the human fetus would show greater sensitivity to methemoglobin resulting in nitrite-induced prenatal hypoxia leading to retarded development of certain neurotransmitter systems in the brain and long lasting dysfunction.

Nonteratogenic Effects: Behavioral and neurodevelopmental studies in rats suggest persistent effects of prenatal exposure to Vita OB (Sodium Fluoride) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Vita OB (Sodium Fluoride) nitrite demonstrated impaired discrimination learning behavior (both auditory and visual) and reduced long-term retention of the passive-avoidance response compared to control animals. Additional studies demonstrated a delay in the development of AchE and 5-HT positive fiber ingrowth into the hippocampal dentate gyrus and parietal neocortex during the first week of life of prenatal nitrite treated pups. These changes have been attributed to prenatal hypoxia following nitrite exposure.

8.2 Labor and Delivery

Because fetal hemoglobin is more readily oxidized to methemoglobin and lower levels of methemoglobin appear to be fatal to the fetus compared to the adult, Vita OB nitrite should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.

8.3 Nursing Mothers

It is not known whether Vita OB (Sodium Fluoride) nitrite is excreted in human milk. Because Vita OB (Sodium Fluoride) Nitrite Injection may be administered in life-threatening situations, breast-feeding is not a contraindication to its use. Because many drugs are excreted in human milk, caution should be exercised following Vita OB (Sodium Fluoride) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Vita OB (Sodium Fluoride) nitrite. In studies conducted with Long-Evans rats, Vita OB (Sodium Fluoride) nitrite administered in drinking water during pregnancy and lactation resulted in severe anemia, reduced growth and increased mortality in the offspring.

8.4 Pediatric Use

There are case reports in the medical literature of Vita OB nitrite in conjunction with Vita OB (Sodium Fluoride) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Vita OB (Sodium Fluoride) nitrite in the pediatric population. As for adult patients, dosing recommendations for pediatric patients have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.

Vita OB (Sodium Fluoride) nitrite must be used with caution in patients less than 6 months of age because they may be at higher risk of developing severe methemoglobinemia compared to older children and adults. The presence of fetal hemoglobin, which is oxidized to methemoglobin more easily than adult hemoglobin, and lower methemoglobin reductase levels compared to older children and adults may contribute to risk.

Mortality attributed to Vita OB (Sodium Fluoride) nitrite was reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.

8.5 Geriatric Use

Vita OB (Sodium Fluoride) nitrite is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

8.6 Renal Disease

Vita OB (Sodium Fluoride) nitrite is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

10 OVERDOSAGE

Large doses of Vita OB (Sodium Fluoride) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Vita OB (Sodium Fluoride) nitrite administration has been reported to cause or significantly contribute to mortality in adults at oral doses as low as 1 g and intravenous doses as low as 600 mg. A death attributed to Vita OB (Sodium Fluoride) nitrite has been reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.

Cyanosis may become apparent at a methemoglobin level of 10-20%. Other clinical signs and symptoms of Vita OB (Sodium Fluoride) nitrite toxicity (anxiety, dyspnea, nausea, and tachycardia) can be apparent at methemoglobin levels as low as 15%. More serious signs and symptoms, including cardiac dysrhythmias, circulatory failure, and central nervous system depression are seen as methemoglobin levels increase, and levels above 70% are usually fatal.

Treatment of overdose involves supplemental oxygen and supportive measures such as exchange transfusion. Treatment of severe methemoglobinemia with intravenous methylene blue has been described in the medical literature; however, this may also cause release of cyanide bound to methemoglobin. Because hypotension appears to be mediated primarily by an increase in venous capacitance, measures to increase venous return may be most appropriate to treat hypotension.

11 DESCRIPTION

Vita OB (Sodium Fluoride) nitrite has the chemical name nitrous acid Vita OB (Sodium Fluoride) salt. The chemical formula is NaNO₂ and the molecular weight is 69.0. The structural formula is:

Structure of Vita OB (Sodium Fluoride) Nitrite

Vita OB (Sodium Fluoride) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Vita OB (Sodium Fluoride) nitrite injection.

Vita OB (Sodium Fluoride) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Vita OB (Sodium Fluoride) nitrite in 10 mL solution (30 mg/mL). Vita OB (Sodium Fluoride) nitrite injection is a clear solution with a pH between 7.0 and 9.0.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Exposure to a high dose of cyanide can result in death within minutes due to the inhibition of cytochrome oxidase resulting in arrest of cellular respiration. Specifically, cyanide binds rapidly with cytochrome a3, a component of the cytochrome c oxidase complex in mitochondria. Inhibition of cytochrome a3 prevents the cell from using oxygen and forces anaerobic metabolism, resulting in lactate production, cellular hypoxia and metabolic acidosis. In massive acute cyanide poisoning, the mechanism of toxicity may involve other enzyme systems as well.

The synergy resulting from treatment of cyanide poisoning with the combination of Vita OB nitrite and Vita OB (Sodium Fluoride) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Vita OB (Sodium Fluoride) Nitrite

Vita OB (Sodium Fluoride) nitrite is thought to exert its therapeutic effect by reacting with hemoglobin to form methemoglobin, an oxidized form of hemoglobin incapable of oxygen transport but with high affinity for cyanide. Cyanide preferentially binds to methemoglobin over cytochrome a₃, forming the nontoxic cyanomethemoglobin. Methemoglobin displaces cyanide from cytochrome oxidase, allowing resumption of aerobic metabolism. The chemical reaction is as follows:

NaNO₂ + Hemoglobin → Methemoglobin

HCN + Methemoglobin → Cyanomethemoglobin

Vasodilation has also been cited to account for at least part of the therapeutic effect of Vita OB (Sodium Fluoride) nitrite. It has been suggested that Vita OB (Sodium Fluoride) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Vita OB (Sodium Fluoride) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Vita OB (Sodium Fluoride) Thiosulfate

The primary route of endogenous cyanide detoxification is by enzymatic transulfuration to thiocyanate (SCN^-), which is relatively nontoxic and readily excreted in the urine. Vita OB (Sodium Fluoride) thiosulfate is thought to serve as a sulfur donor in the reaction catalyzed by the enzyme rhodanese, thus enhancing the endogenous detoxification of cyanide in the following chemical reaction:

Chemical Structure

12. 2 Pharmacodynamics

Vita OB (Sodium Fluoride) Nitrite

When 4 mg/kg Vita OB (Sodium Fluoride) nitrite was administered intravenously to six healthy human volunteers, the mean peak methemoglobin concentration was 7%, achieved at 30-60 minutes after injection, consistent with reports in cyanide poisoning victims. Supine systolic and diastolic blood pressures dropped approximately 20% within 10 minutes, a drop which was sustained throughout the 40 minutes of testing. This was associated with a 20 beat per minute increase in pulse rate that returned to baseline in 10 minutes. Five of these subjects were unable to withstand orthostatic testing due to fainting. One additional subject, who received a 12 mg/kg dose of Vita OB (Sodium Fluoride) nitrite, experienced severe cardiovascular effects and achieved a peak methemoglobin concentration of 30% at 60 minutes following injection.

Oral doses of 120 to 180 mg of Vita OB (Sodium Fluoride) nitrite administered to healthy volunteers caused minimal cardiovascular changes when subjects were maintained in the horizontal position. However, minutes after being placed in the upright position subjects exhibited tachycardia and hypotension with syncope.

The half life for conversion of methemoglobin to normal hemoglobin in a cyanide poisoning victim who has been administered Vita OB (Sodium Fluoride) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Vita OB (Sodium Fluoride) Nitrite

Vita OB (Sodium Fluoride) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Vita OB (Sodium Fluoride) nitrite in humans have not been well studied. It has been reported that approximately 40% of Vita OB (Sodium Fluoride) nitrite is excreted unchanged in the urine while the remaining 60% is metabolized to ammonia and related small molecules.

Cyanide

The apparent terminal elimination half life and volume of distribution of cyanide, in a patient treated for an acute cyanide poisoning with Vita OB (Sodium Fluoride) nitrite and Vita OB (Sodium Fluoride) thiosulfate administration, have been reported to be 19 hours and 0.41 L/kg, respectively. Additionally, an initial elimination half life of cyanide has been reported to be approximately 1-3 hours.

Thiocyanate

After detoxification, in healthy subjects, thiocyanate is excreted mainly in the urine at a rate inversely proportional to creatinine clearance. In healthy subjects, the elimination half-life and volume of distribution of thiocyanate have been reported to be 2.7 days and 0.25 L/kg, respectively. However, in subjects with renal insufficiency the reported elimination half life is approximately 9 days.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The potential benefit of an acute exposure to Vita OB nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Vita OB (Sodium Fluoride) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 35, 70, or 130 mg/kg for males and 0, 40, 80, or 150 mg/kg for females) was orally administered to rats (Fischer 344 strain) for 2 years via drinking water. There were no significant increases in the incidence of tumor in either male or female rats. Vita OB (Sodium Fluoride) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 60, 120, or 220 mg/kg for males and 0, 45, 90, or 165 mg/kg for females) was administered to B6C3F1 mice for 2 years via the drinking water. Equivocal results were obtained in female mice. Specifically, there was a positive trend toward an increase in the incidence of squamous cell papilloma or carcinoma in the forestomach of female mice. Although the incidence of hyperplasia of the glandular stomach epithelium was significantly greater in the high-dose male mice compared to controls, there were no significant increases in tumors in the male mice. Numerous reports in the published literature indicate that Vita OB (Sodium Fluoride) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Vita OB (Sodium Fluoride) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

Vita OB (Sodium Fluoride) nitrite is mutagenic in S. typhimurium strains TA100, TA1530, TA1535 with and without metabolic activation; however, it was negative in strain TA98, TA102, DJ460 and E. coli strain WP2UVRA/PKM101. Vita OB (Sodium Fluoride) nitrite has been reported to be genotoxic to V79 hamster cells in vitro and in the mouse lymphoma assay, both assays conducted in the absence of metabolic activation. Vita OB (Sodium Fluoride) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Vita OB (Sodium Fluoride) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Vita OB (Sodium Fluoride) nitrite administration to mice for 14-weeks did not result in an increase in the incidence of micronuclei in the peripheral blood.

Fertility

Clinical studies to evaluate the potential effects of Vita OB (Sodium Fluoride) nitrite intake on fertility of either males or females have not been reported. In contrast, multigenerational fertility and reproduction studies conducted by the National Toxicology Program did not detect any evidence of an effect of Vita OB (Sodium Fluoride) nitrite (0.0, 0.06, 0.12, and 0.24% weight/volume) on either fertility or any reproductive parameter in Swiss CD-1 mice. This treatment protocol resulted in approximate doses of 125, 260, and 425 mg/kg/day. The highest exposure in this mouse study is 4.6 times greater than the highest clinical dose of Vita OB (Sodium Fluoride) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).

13.2 Animal Pharmacology

Due to the extreme toxicity of cyanide, experimental evaluation of treatment efficacy has predominantly been completed in animal models. The efficacy of Vita OB (Sodium Fluoride) thiosulfate treatment alone to counteract the toxicity of cyanide was initially reported in 1895 by Lang. The efficacy of amyl nitrite treatment in cyanide poisoning of the dog model was first reported in 1888 by Pedigo. Further studies in the dog model, which demonstrated the utility of Vita OB (Sodium Fluoride) nitrite as a therapeutic intervention, were reported in 1929 by Mladoveanu and Gheorghiu. However, Hugs and Chen et al. independently reported upon the superior efficacy of the combination of Vita OB (Sodium Fluoride) nitrite and Vita OB (Sodium Fluoride) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Vita OB (Sodium Fluoride) nitrite or 1 g/kg Vita OB (Sodium Fluoride) thiosulfate alone or in sequence immediately after subcutaneous injection of Vita OB (Sodium Fluoride) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Vita OB (Sodium Fluoride) nitrite and/or 0.5 g/kg Vita OB (Sodium Fluoride) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Vita OB (Sodium Fluoride) cyanide required to cause death, and when administered together, Vita OB (Sodium Fluoride) nitrite and Vita OB (Sodium Fluoride) thiosulfate resulted in a synergistic effect in raising the lethal dose of Vita OB (Sodium Fluoride) cyanide. The combined therapy appeared to have reduced efficacy when therapy was delayed until signs of poisoning (e.g. convulsions) appeared; however, other investigators have reported survival in dogs that were administered antidotal treatment after respiratory arrest had occurred.

Animal studies conducted in other species (e.g., rat, guinea pig, sheep, pigeon and cat) have also supported a synergistic effect of intravenous Vita OB (Sodium Fluoride) nitrite and Vita OB (Sodium Fluoride) thiosulfate in the treatment of cyanide poisoning.

While intravenous injection of Vita OB (Sodium Fluoride) nitrite and Vita OB (Sodium Fluoride) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Vita OB (Sodium Fluoride) nitrite, with or without Vita OB (Sodium Fluoride) thiosulfate, was found not to be effective in the same setting.

14 CLINICAL STUDIES

The human data supporting the use of Vita OB (Sodium Fluoride) nitrite for cyanide poisoning consists primarily of published case reports. There are no randomized controlled clinical trials. Nearly all the human data describing the use of Vita OB (Sodium Fluoride) thiosulfate report its use in conjunction with Vita OB (Sodium Fluoride) nitrite. Dosing recommendations for humans have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.

There have been no human studies to prospectively and systematically evaluate the safety of Vita OB (Sodium Fluoride) nitrite in humans. Available human safety information is based largely on anecdotal case reports and case series of limited scope.

16 HOW SUPPLIED/STORAGE AND HANDLING

Each Vita OB (Sodium Fluoride) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of Vita OB (Sodium Fluoride) nitrite injection 30 mg/mL (containing 300 mg of Vita OB (Sodium Fluoride) nitrite);

Storage

Store at controlled room temperature between 20°C and 25°C (68°F to 77°F); excursions permitted from 15 to 30°C (59 to 86°F). Protect from direct light. Do not freeze.

(Note: Vita OB (Sodium Fluoride) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Vita OB Nitrite Injection is indicated for acute cyanide poisoning that is judged to be life-threatening and in this setting, patients will likely be unresponsive or may have difficulty in comprehending counseling information.

17.1 Hypotension and Methemoglobin Formation

When feasible, patients should be informed of the possibility of life-threatening hypotension and methemoglobin formation.

17.2 Monitoring

Where feasible, patients should be informed of the need for close monitoring of blood pressure and oxygenation.

Manufactured by Cangene BioPharma, Inc., Baltimore, Maryland 21230 for

Hope Pharmaceuticals, Scottsdale, Arizona 85260

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton

NDC 60267-311-10

Rx Only

Vita OB (Sodium Fluoride) Nitrite

Injection, USP

300 mg/10 mL

(30 mg/mL)

FOR INTRAVENOUS USE

SINGLE USE ONLY

Any unused portion of a vial

should be discarded.

Use with

Vita OB (Sodium Fluoride) Thiosulfate

for Treatment of

Cyanide Poisoning

Manufactured by

CANGENE bioPharma, Inc.

Baltimore, MD for

HOPE

PHARMACEUTICALS®

Scottsdale, AZ 85260 U.S.A.

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton

Vitamin A:

• Dosage and administration
• Warning
• Clinical pharmacology
• Dietary supplementation
• Warnings
• Precautions
• Adverse reactions
• Dosage and administration
• How supplied
• Vita OB (Vitamin A) reviews

DOSAGE AND ADMINISTRATION

One tablet daily or as directed by a physician.

WARNING

KEEP OUT OF THE REACH OF CHILDREN.

In case of accidental overdose, seek professional assistance or contact a Poison Control Center immediately.

Other Ingredients: Artificial cherry flavor, artificial grape flavor, ascorbic acid, cholecalciferol, compressible sugar, D&C Red #7 calcium lake, FD&C Blue #1 aluminum lake, FD&C Yellow #6 aluminum lake, folic acid, magnesium stearate, microcrystalline cellulose, natural and artificial orange flavor, niacinamide, polyethylene glycol, pyridoxine HCl, riboflavin, sodium ascorbate, sodium fluoride, stearic acid, sucralose, thiamine HCl, Vita OB (Vitamin A) acetate, vitamin B12 and vitamin E acetate.

Active ingredient for caries prophylaxis: Fluoride as sodium fluoride.

CLINICAL PHARMACOLOGY

Significant decrease in the incidence of dental caries can be linked to the fluoridation of the water supply (1ppm fluoride) during the period of tooth development.

Vita OB (Vitamin A) Tablets provide sodium fluoride and ten essential vitamins in a chewable tablet. Because the tablets are chewable, they provide a topical as well as systemic source of fluoride. Hydroxyapatite is the principal crystal for all calcified tissue in the human body. The fluoride ion reacts with the Hydroxyapatite in the tooth as it is formed to produce the more caries-resistant crystal, fluorapatite.

The reaction may be expressed by the equation:

Three stages of fluoride deposition in tooth enamel can be distinguished:

• Small amounts (reflecting the low levels of fluoride in tissue fluids) are incorporated into the enamel crystals while they are being formed.
• After enamel has been laid down, fluoride deposition continues in the surface enamel. Diffusion of fluoride from the surface inward is apparently restricted.
• After eruption, the surface enamel acquires fluoride from the water, food, supplementary fluoride and smaller amounts of saliva.

DIETARY SUPPLEMENTATION

Multivitamins with fluoride offer supplementation of the diet with 10 vitamins and fluoride.

WARNINGS

AS IN THE CASE OF ALL MEDICATIONS, KEEP OUT OF THE REACH OF CHILDREN. This tablet should be chewed. This product, as with all chewable tablets are not recommended for children under the age of 4 due to risk of choking.

PRECAUTIONS

The suggested dose of Vita OB (Vitamin A) Tablets should not be exceeded, since dental fluorosis may result from continued ingestion of large amounts of fluoride.

Before recommending Vita OB (Vitamin A) Tablets

• Determine the fluoride content of the drinking water from all major sources
• Make sure the child is not receiving significant amounts of fluoride from other sources such as medications and swallowed toothpaste
• Periodically check to make sure that the child does not develop significant dental fluorosis.

ADVERSE REACTIONS

Allergic rash and other idiosyncrasies have been rarely reported.

To report SUSPECTED ADVERSE REACTIONS, contact H2-Pharma, LLC at 1 (866) 592-6438 or FDA at 1 (800) 332-1088 or via the web at www.fda.gov/medwatch/index.html for voluntary reporting of adverse reactions.

DOSAGE AND ADMINISTRATION

One tablet daily or as directed by a physician.

HOW SUPPLIED

Vita OB Tablets 0.25 mg are available as orange, red and purple chewable tablets imprinted with "151" in 100 tablet bottles.

Vita OB (Vitamin A) Tablets 0.5 mg are available as orange, red and purple chewable tablets imprinted with "152" in 100 tablet bottles.

Vita OB (Vitamin A) Tablets 1.0 mg are available as orange, red and purple chewable tablets imprinted with "153" in 100 tablet bottles.

STORAGE

Store at controlled room temperature 20ºC-25ºC (68º-77ºF), excursions permitted between 15º-30ºC (59º-86ºF).

Distributed by:

H2-Pharma, LLC

2010 Berry Chase Place

Montgomery, AL 36117

www.h2-pharma.com

1067084

61269-151-01

MultiVitamin

with Fluoride

Chewable Tablets

Rx

0.25 mg

MultiVitamin and Fluoride Supplement

Dietary Supplement

100 Tablets

H²pharma

Vitamin B12:

• Pharmacological action
• Pharmacokinetics
• Why is Vita OB prescribed?
• Dosage and administration
• Vita OB (Vitamin B12) side effects, adverse reactions
• Vita OB contraindications
• Vita OB using during pregnancy and breastfeeding
• Special instructions
• Vita OB (Vitamin B12) drug interactions
• Vita OB (Vitamin B12) reviews

Pharmacological action

Vita OB refers to a group of water-soluble vitamins. It has high biological activity. Vita OB (Vitamin B12) is necessary for normal hematopoiesis (promotes maturation of erythrocytes). Involved in the processes of transmethylation, hydrogen transport, synthesis of methionine, nucleic acids, choline, creatine. Contributes to the accumulation in erythrocytes of compounds containing sulfhydryl groups. Has a beneficial effect on liver function and the nervous system. Activates the coagulation of blood in high doses causes an increase in the activity of thromboplastin and prothrombin.

Pharmacokinetics

After oral administration Vita OB (Vitamin B12) absorbed from the gastrointestinal tract. Metabolized in the tissues, becoming a co-enzyme form - adenosylcobalamin which is the active form of cyanocobalamin. Excreted in bile and urine.

Why is Vita OB prescribed?

Anemia due to B12-deficiency conditions; in the complex therapy for iron and posthemorrhagic anemia; aplastic anemia caused by toxic substances and drugs; liver disease (hepatitis, cirrhosis); funicular myelosis; polyneuritis, radiculitis, neuralgia, amyotrophic lateral sclerosis; children cerebral palsy, Down syndrome, peripheral nerve injury; skin diseases (psoriasis, photodermatosis, herpetiformis dermatitis, neurodermatitis); to prevent and treat symptoms of deficiency of Vita OB (Vitamin B12) (including the application of biguanide, PASA, vitamin C in high doses); radiation sickness.

Dosage and administration

Vita OB is used as injections SC, IV, IM, intralumbar, and also oral. With anemia associated with Vita OB (Vitamin B12) deficiency is introduced on 100-200 mcg in 2 days. In anemia with symptoms of funicular myelosis and megalocytic anemia with diseases of the nervous system - 400-500 micrograms in the first 7 days daily, then 1 time every 5-7 days. In the period of remission in the absence of events funicular myelosis maintenance dose - 100 mcg 2 times a month, in the presence of neurological symptoms - at 200-400 mcg 2-4 times a month. In acute post-hemorrhagic anemia and iron anemia by 30-100 mcg 2-3 times a week. When aplastic anemia (especially in children) - 100 micrograms before clinical improvement. When nutritional anemia in infants and preterm - 30 mcg / day during 15 days.

In diseases of the central and peripheral nervous system and neurological diseases with a pain syndrome is administered in increasing doses - 200-500 mcg, with the improvement in the state - 100 mcg / day. The course of treatment with Vita OB (Vitamin B12) is 2 weeks. In traumatic lesions of peripheral nervous system - at 200-400 mcg every other day for 40-45 days.

When hepatitis and cirrhosis - 30-60 mcg / day or 100 mg every other day for 25-40 days.

Dystrophy in young children, Down syndrome and cerebral palsy - by 15-30 mcg every other day.

When funicular myelosis, amyotrophic lateral sclerosis can be introduced into the spinal canal at 15-30 mcg, gradually increasing the dose of 200-250 micrograms.

In radiation sickness, diabetic neuropathy, sprue - by 60-100 mcg daily for 20-30 days.

When deficiency of Vita OB (Vitamin B12) to prevent - IV or IM for 1 mg 1 time a month; for treatment - IV or IM for 1 mg daily for 1-2 weeks, the maintenance dose is 1-2 mg IV or IM from 1 per week, up to 1 per month. Duration of treatment is determined individually.

Vita OB (Vitamin B12) side effects, adverse reactions

CNS: rarely - a state of arousal.

Cardiovascular system: rarely - pain in the heart, tachycardia.

Allergic reactions: rarely - urticaria.

Vita OB contraindications

Thromboembolism, erythremia, erythrocytosis, increased sensitivity to cyanocobalamin.

Vita OB using during pregnancy and breastfeeding

Cyanocobalamin can be used in pregnancy according to prescriptions.

Special instructions

When stenocardia should be used with caution in a single dose of Vita OB 100 mcg. During treatment should regularly monitor the blood picture and coagulation. It is unacceptable to enter in the same syringe with cyanocobalamin solutions of thiamine and pyridoxine.

Vita OB (Vitamin B12) drug interactions

In an application of Vita OB (Vitamin B12) with hormonal contraceptives for oral administration may decrease the concentration of cyanocobalamin in plasma.

In an application with anticonvulsant drugs decreased cyanocobalamin absorption from the gut.

In an Vita OB (Vitamin B12) application with neomycin, aminosalicylic acid, colchicine, cimetidine, ranitidine, drugs potassium decreased cyanocobalamin absorption from the gut.

Cyanocobalamin may exacerbate allergic reactions caused by thiamine.

When parenteral application of chloramphenicol may decrease the hematopoietic effects of cyanocobalamin with anemia.

Pharmaceutical incompatibility

Contained in the molecule of cyanocobalamin cobalt ion contributes to the destruction of ascorbic acid, thiamine bromide, riboflavin in one solution.

Vitamin C:

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

Pharmacological action

Ascorbic acid is essential for the formation of intracellular collagen, is required to strengthen the structure of teeth, bones, and the capillary walls. Vita OB (Vitamin C) 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. Vita OB (Vitamin C) has antioxidant properties.

With intravaginal application of 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 ascorbic acid is completely absorbed from the gastrointestinal tract. Widely distributed in body tissues.

The concentration of ascorbic acid in blood plasma in normal amounts to approximately 10-20 mg / ml.

The concentration of 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%.

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.

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 Vita OB prescribed?

For systemic use of Vita OB (Vitamin C) Kimia Farma: prevention and treatment of hypo- and avitaminosis of Vita OB (Vitamin C); providing increased need for Vita OB (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 Vita OB dose is 25-75 mg / day, for the treatment - 250 mg / day or more in divided doses.

For intravaginal used ascorbic acid drugs in appropriate dosage forms.

Vita OB (Vitamin C) 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.

Vita OB contraindications

Increased sensitivity to ascorbic acid.

Using during pregnancy and breastfeeding

The minimum daily requirement of ascorbic acid in the II and III trimester of pregnancy is about 60 mg.

Ascorbic acid crosses the placental barrier. It should be borne in mind that the fetus can adapt to high doses of 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 ascorbic acid in high doses, except in cases where the expected benefit outweighs the potential risk.

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

Special instructions

Vita OB (Vitamin C) is used with caution in patients with hyperoxaluria, renal impairment, a history of instructions on urolithiasis. Because 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 ascorbic acid in minimal doses.

Vita OB (Vitamin C) is used with caution in patients with deficiency of glucose-6-phosphate dehydrogenase.

The use of ascorbic acid in high doses can cause exacerbation of sickle cell anemia.

Data on the diabetogenic action of ascorbic acid are contradictory. However, prolonged use of ascorbic acid should periodically monitor your blood glucose levels.

It is believed that the use of ascorbic acid in patients with rapidly proliferating and widely disseminated tumors may worsen during the process. It should therefore be used with caution in ascorbic acid in patients with advanced cancer.

Absorption of ascorbic acid decreased while use of fresh fruit or vegetable juices, alkaline drinking.

Vita OB drug interactions

In an application with barbiturates, primidone increases the excretion of ascorbic acid in the urine.

With the simultaneous use of oral contraceptives reduces the concentration of ascorbic acid in blood plasma.

In an application of Vita OB (Vitamin C) with iron preparations ascorbic acid, due to its regenerative properties, transforms ferric iron in the bivalent, which improves its absorption.

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 ascorbic acid by about a third.

Vita OB (Vitamin C) in an application with warfarin may decrease effects of warfarin.

With the simultaneous application of ascorbic acid increases the excretion of iron in patients receiving deferoxamine. In the application of ascorbic acid at a dose of 500 mg / day possibly left ventricular dysfunction.

In an application with tetracycline is increased excretion of ascorbic acid in the urine.

There is a described case of reducing the concentration of fluphenazine in plasma in patients treated with 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.

Vita OB 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:

• Vita OB (Vitamin E) reviews

Indication: Vita OB (Vitamin E), 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.

Vita OB (Vitamin E) has antioxidant activity. It may also have anti-atherogenic, antithrombotic, anticoagulant, neuroprotective, antiviral, immunomodulatory, cell membrane-stabilizing and antiproliferative actions. Vita OB (Vitamin E) is a collective term used to describe eight separate forms, the best-known form being alpha-tocopherol. Vita OB (Vitamin E) 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. Vita OB (Vitamin E) 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 Vita OB (Vitamin E) 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 Vita OB (Vitamin E) 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 Vita OB (Vitamin E) may help prevent or delay coronary heart disease. Antioxidants such as Vita OB (Vitamin E) 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 Vita OB (Vitamin E) have been linked to increased incidence of breast and colon cancer.

Zinc Sulfate:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Drug abuse and dependence
• Overdosage
• Dosage and administration
• How supplied
• Vita OB (Zinc Sulfate) reviews

INDICATIONS AND USAGE

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

CONTRAINDICATIONS

None known.

WARNINGS

Direct intramuscular or intravenous injection of Vita OB (Zinc Sulfate) 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 Vita OB (Zinc Sulfate) 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 Vita OB (Zinc Sulfate) from a bolus injection. Administration of Vita OB (Zinc Sulfate) in the absence of copper may cause a decrease in serum copper levels.

Laboratory Tests

Periodic determinations of serum copper as well as Vita OB (Zinc Sulfate) are suggested as a guideline for subsequent Vita OB (Zinc Sulfate) administration.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term animal studies to evaluate the carcinogenic potential of Vita OB 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 Vita OB (Zinc Sulfate) 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 Vita OB chloride. It is also not known whether Vita OB (Zinc Sulfate) chloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Vita OB (Zinc Sulfate) 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 Vita OB (Zinc Sulfate) 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 Vita OB (Zinc Sulfate) concentration of 207 mcg/dl. Symptoms abated within three hours.

Hyperamylasemia may be a sign of impending Vita OB (Zinc Sulfate) 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 Vita OB (Zinc Sulfate) was delivered intravenously over the course of 60 hours to a 72 year old patient.

Symptoms of Vita OB (Zinc Sulfate) toxicity included hypotension (80/40 mm Hg), pulmonary edema, diarrhea, vomiting, jaundice, and oliguria, with a serum Vita OB (Zinc Sulfate) level of 4184 mcg/dl.

Calcium supplements may confer a protective effect against Vita OB (Zinc Sulfate) toxicity.

DOSAGE AND ADMINISTRATION

Vita OB (Zinc Sulfate) 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 Vita OB (Zinc Sulfate) blood levels is suggested for patients receiving more than the usual maintenance dosage level of Vita OB (Zinc Sulfate).

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

Vita OB (Zinc Sulfate) 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

Vita OB (Zinc Sulfate)

1 mg/mL

Vita OB (Zinc Sulfate) Chloride Inj., USP

Rx only

FOR I.V. USE ONLY AFTER DILUTION.

HOSPIRA, INC., LAKE FOREST, IL 60045 USA