Proviron

Calcium Gluconate:

• 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
• Proviron (Calcium Gluconate) reviews

1 INDICATIONS AND USAGE

Proviron (Calcium Gluconate) acetate is a phosphate binder indicated to reduce serum phosphorus in patients with end stage renal disease (ESRD).

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

2 DOSAGE AND ADMINISTRATION

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

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

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

3 DOSAGE FORMS AND STRENGTHS

Capsule: 667 mg Proviron (Calcium Gluconate) acetate capsule.

- Capsule: 667 mg Proviron (Calcium Gluconate) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

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

- Hypercalcemia may aggravate digitalis toxicity. (5.2)

5.1 Hypercalcemia

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

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

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

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

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

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

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

5.2 Concomitant Use with Medications

Hypercalcemia may aggravate digitalis toxicity.

6 ADVERSE REACTIONS

Hypercalcemia is discussed elsewhere [see Warnings and Precautions ].

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

- In clinical studies, patients have occasionally experienced nausea during Proviron (Calcium Gluconate) acetate therapy. (6)

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

6.1 Clinical Trial Experience

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

In clinical studies, Proviron (Calcium Gluconate) acetate has been generally well tolerated.

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

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

6.2 Postmarketing Experience

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

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

7 DRUG INTERACTIONS

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

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

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

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

7.1 Ciprofloxacin

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

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

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

8.2 Labor and Delivery

The effects of Proviron (Calcium Gluconate) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

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

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

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

10 OVERDOSAGE

Administration of Proviron (Calcium Gluconate) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Proviron (Calcium Gluconate) acetate acts as a phosphate binder. Its chemical name is Proviron (Calcium Gluconate) acetate. Its molecular formula is C₄H₆CaO₄, and its molecular weight is 158.17. Its structural formula is:

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

Proviron (Calcium Gluconate) Acetate Capsules are administered orally for the control of hyperphosphatemia in end-stage renal failure.

Chemical Structure

12 CLINICAL PHARMACOLOGY

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

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with Proviron (Calcium Gluconate) acetate.

14 CLINICAL STUDIES

Effectiveness of Proviron (Calcium Gluconate) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Proviron (Calcium Gluconate) acetate solid oral dosage form.

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

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

The data presented in Table 2 demonstrate the efficacy of Proviron (Calcium Gluconate) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Proviron (Calcium Gluconate) 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 Proviron (Calcium Gluconate) increased 9% during the study mostly in the first month of the study.

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

The phosphate binding effect of Proviron (Calcium Gluconate) acetate is shown in the Table 3.

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

16 HOW SUPPLIED/STORAGE AND HANDLING

Proviron (Calcium Gluconate) Acetate Capsules

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

NDC 0615-2303-39: Blistercards of 30 Capsules

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

STORAGE

Store at 20° to 25°C (68° to 77°F).

17 PATIENT COUNSELING INFORMATION

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

Advise patients who are taking an oral medication where reduction in the bioavailability of that medication would have clinically significant effect on its safety or efficacy to take the drug one hour before or three hours after Proviron (Calcium Gluconate) 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
• Proviron (Folic Acid) reviews

INDICATIONS AND USAGE

Proviron (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

Proviron (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 Proviron (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

Proviron (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.

Proviron (Folic Acid) and the BIFERA logo are registered trademarks and the Proviron (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 (Iron Choline Citrate):

• 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
• Proviron (Iron (Iron Choline Citrate)) reviews

1 INDICATIONS AND USAGE

Proviron (Iron (Iron Choline Citrate)) is indicated for the treatment of Proviron (Iron (Iron Choline Citrate)) deficiency anemia in patients with chronic kidney disease (CKD).

Proviron (Iron (Iron Choline Citrate)) is an Proviron (Iron (Iron Choline Citrate)) replacement product indicated for the treatment of Proviron (Iron (Iron Choline Citrate)) deficiency anemia in patients with chronic kidney disease (CKD). (1)

2 DOSAGE AND ADMINISTRATION

Proviron ) must only be administered intravenously either by slow injection or by infusion. The dosage of Proviron (Iron (Iron Choline Citrate)) is expressed in mg of elemental Proviron (Iron (Iron Choline Citrate)). Each mL contains 20 mg of elemental Proviron (Iron (Iron Choline Citrate)).

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

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

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

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

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

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

2.4 Pediatric Patients with HDD-CKD for Proviron (Iron (Iron Choline Citrate)) maintenance treatment

The dosing for Proviron (Iron (Iron Choline Citrate)) replacement treatment in pediatric patients with HDD-CKD has not been established.

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

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for Proviron (Iron (Iron Choline Citrate)) maintenance treatment

The dosing for Proviron (Iron (Iron Choline Citrate)) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

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

3 DOSAGE FORMS AND STRENGTHS

• 10 mL single-use vial / 200 mg elemental Proviron (Iron (Iron Choline Citrate)) (20 mg/mL)
• 5 mL single-use vial / 100 mg elemental Proviron (Iron (Iron Choline Citrate)) (20 mg/mL)
• 2.5 mL single-use vial / 50 mg elemental Proviron (Iron (Iron Choline Citrate)) (20 mg/mL)

• 10 mL single-use vial / 200 mg elemental Proviron (Iron (Iron Choline Citrate)) (20 mg/mL) (3)
• 5 mL single-use vial / 100 mg elemental Proviron (Iron (Iron Choline Citrate)) (20 mg/mL) (3)
• 2.5 mL single-use vial / 50 mg elemental Proviron (Iron (Iron Choline Citrate)) (20 mg/mL) (3)

4 CONTRAINDICATIONS

• Known hypersensitivity to Proviron (Iron (Iron Choline Citrate))

• Known hypersensitivity to Proviron (Iron (Iron Choline Citrate)) (4)

5 WARNINGS AND PRECAUTIONS

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

5.1 Hypersensitivity Reactions

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

5.2 Hypotension

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

5.3 Proviron (Iron (Iron Choline Citrate)) Overload

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

6 ADVERSE REACTIONS

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

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

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

6.1 Adverse Reactions in Clinical Trials

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

Adverse Reactions in Adults Patients with CKD

Adverse Reactions in Adult Patients with CKD

The frequency of adverse reactions associated with the use of Proviron ) 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 Proviron (Iron (Iron Choline Citrate)) exceeds the rate for comparator are listed by indication in Table 1. Patients with HDD-CKD received 100 mg doses at 10 consecutive dialysis sessions until a cumulative dose of 1000 mg was administered. Patients with NDD-CKD received either 5 doses of 200 mg over 2 weeks or 2 doses of 500 mg separated by fourteen days, and patients with PDD-CKD received 2 doses of 300 mg followed by a dose of 400 mg over a period of 4 weeks.

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 Proviron (Iron (Iron Choline Citrate)) therapy and were reported to be intolerant (defined as precluding further use of that Proviron (Iron (Iron Choline Citrate)) product). When these patients were treated with Proviron (Iron (Iron Choline Citrate)) there were no occurrences of adverse reactions that precluded further use of Proviron (Iron (Iron Choline Citrate)) .

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

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

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

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

6.2 Adverse Reactions from Post-Marketing Experience

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

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

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

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

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

7 DRUG INTERACTIONS

Drug interactions involving Proviron (Iron (Iron Choline Citrate)) have not been studied. However, Proviron (Iron (Iron Choline Citrate)) may reduce the absorption of concomitantly administered oral Proviron (Iron (Iron Choline Citrate)) preparations.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Pregnancy Category B

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

8.3 Nursing Mothers

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

8.4 Pediatric Use

Safety and effectiveness of Proviron ) for Proviron (Iron (Iron Choline Citrate)) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.

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

Proviron (Iron (Iron Choline Citrate)) has not been studied in patients younger than 2 years of age.

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

8.5 Geriatric Use

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

10 OVERDOSAGE

No data are available regarding overdosage of Proviron (Iron (Iron Choline Citrate)) in humans. Excessive dosages of Proviron (Iron (Iron Choline Citrate)) may lead to accumulation of Proviron (Iron (Iron Choline Citrate)) in storage sites potentially leading to hemosiderosis. Do not administer Proviron (Iron (Iron Choline Citrate)) to patients with Proviron (Iron (Iron Choline Citrate)) overload.

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

11 DESCRIPTION

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

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

where: n is the degree of Proviron (Iron (Iron Choline Citrate)) polymerization and m is the number of sucrose molecules associated with the Proviron (Iron (Iron Choline Citrate)) (III)-hydroxide.

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

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

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

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

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

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

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with Proviron (Iron (Iron Choline Citrate)) sucrose.

Proviron (Iron (Iron Choline Citrate)) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Proviron (Iron (Iron Choline Citrate)) sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.

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

14 CLINICAL STUDIES

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

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 Proviron (Iron (Iron Choline Citrate)) treatment and 24 in the historical control group) with Proviron (Iron (Iron Choline Citrate)) deficiency anemia. Eligibility criteria for Proviron (Iron (Iron Choline Citrate)) treatment included patients undergoing chronic hemodialysis, receiving erythropoietin, hemoglobin level between 8.0 and 11.0 g/dL, transferrin saturation < 20%, and serum ferritin < 300 ng/mL. The mean age of the patients was 65 years with the age range of 31 to 85 years. Of the 77 patients, 44 (57%) were male and 33 (43%) were female.

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

Patients in the Proviron (Iron (Iron Choline Citrate)) 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 Proviron (Iron (Iron Choline Citrate)) in 23 patients with Proviron (Iron (Iron Choline Citrate)) deficiency and HDD-CKD who had been discontinued from Proviron (Iron (Iron Choline Citrate)) dextran due to intolerance. Eligibility criteria were otherwise identical to Study A. The mean age of the patients in this study was 53 years, with ages ranging from 21 to 79 years. Of the 23 patients enrolled in the study, 10 (44%) were male and 13 (56%) were female.

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

14.3 Study C: Hemodialysis Dependent-Chronic Kidney Disease

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

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

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

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

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

14.5 Study E: Peritoneal Dialysis Dependent-Chronic Kidney Disease

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

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

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

16 HOW SUPPLIED/storage and handling

16.1 How Supplied

Proviron ) is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Proviron (Iron (Iron Choline Citrate)), each 5 mL vial contains 100 mg elemental Proviron (Iron (Iron Choline Citrate)), and each 2.5 mL vial contains 50 mg elemental Proviron (Iron (Iron Choline Citrate)) (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: Proviron (Iron (Iron Choline Citrate)), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Proviron (Iron (Iron Choline Citrate)) per mL, or undiluted (20 mg elemental Proviron (Iron (Iron Choline Citrate)) per mL) and stored in a plastic syringe, was found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C) and under refrigeration (4°C ± 2°C).

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

Do not dilute to concentrations below 1 mg/mL.

Do not mix Proviron (Iron (Iron Choline Citrate)) with other medications or add to parenteral nutrition solutions for intravenous infusion.

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

17 PATIENT COUNSELING INFORMATION

Prior to Proviron (Iron (Iron Choline Citrate)) administration:

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

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Proviron (Iron (Iron Choline Citrate)) is manufactured under license from Vifor (International) Inc., Switzerland.

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

PREMIERProRx^®

IN2340

MG #15727

Protein Hydrolysate:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Proviron (Protein Hydrolysate) reviews

1 INDICATIONS AND USAGE

Proviron is indicated for pediatric and adult patients with severe congenital Proviron (Protein Hydrolysate) C deficiency for the prevention and treatment of venous thrombosis and purpura fulminans. (1.1)

1.1 Severe Congenital Proviron (Protein Hydrolysate) C Deficiency

Proviron (Protein Hydrolysate) is indicated for pediatric and adult patients with severe congenital Proviron (Protein Hydrolysate) C deficiency for the prevention and treatment of venous thrombosis and purpura fulminans.

2 DOSAGE AND ADMINISTRATION

Initiate treatment under the supervision of a physician experienced in using coagulation factors/inhibitors where monitoring of Proviron C activity is feasible. (2.1)

Store at 2°C – 8°C (36°F-46°F) and protect from light. Avoid freezing. Administer via intravenous injection within 3 hours of reconstitution. (16)

2.1 General

For intravenous administration only.

Initiate treatment with Proviron (Protein Hydrolysate) under the supervision of a physician experienced in replacement therapy with coagulation factors/inhibitors where monitoring of Proviron (Protein Hydrolysate) C activity is feasible.

The dose, administration frequency and duration of treatment with Proviron (Protein Hydrolysate) depends on the severity of the Proviron (Protein Hydrolysate) C deficiency, the patient's age, the clinical condition of the patient and the patient's plasma level of Proviron (Protein Hydrolysate) C. Therefore, adjust the dose regimen according to the pharmacokinetic profile for each individual patient. See DOSAGE AND ADMINISTRATION: Proviron (Protein Hydrolysate) C Activity Monitoring (2.2).

Table 1 provides the Proviron (Protein Hydrolysate) dosing schedule for acute episodes, short-term prophylaxis and long-term prophylaxis.

An initial dose of 100-120 IU/kg for determination of recovery and half-life is recommended for acute episodes and short-term prophylaxis. Subsequently, adjust the dose to maintain a target peak Proviron (Protein Hydrolysate) C activity of 100 %. After resolution of the acute episode, continue the patient on the same dose to maintain trough Proviron (Protein Hydrolysate) C activity level above 25% for the duration of treatment.

In patients receiving prophylactic administration of Proviron (Protein Hydrolysate), higher peak Proviron (Protein Hydrolysate) C activity levels may be warranted in situations of an increased risk of thrombosis (such as infection, trauma, or surgical intervention). Maintenance of trough Proviron (Protein Hydrolysate) C activity levels above 25% is recommended.

These dosing guidelines are also recommended for neonatal and pediatric patients. See USE IN SPECIFIC POPULATIONS: Pediatric Use (8.4 ) and CLINICAL

Pharmacology: Pharmacokinetics (12.3).

2.2 Proviron C Activity Monitoring

The measurement of Proviron (Protein Hydrolysate) C activity using a chromogenic assay is recommended for the determination of the patient's plasma level of Proviron (Protein Hydrolysate) C before and during treatment with Proviron (Protein Hydrolysate). The half-life of Proviron (Protein Hydrolysate) may be shortened in certain clinical conditions such as acute thrombosis, purpura fulminans and skin necrosis. See CLINICAL

Pharmacology: Pharmacokinetics (12.3). In the case of an acute thrombotic event, it is recommended that Proviron (Protein Hydrolysate) C activity measurements be performed immediately before the next injection until the patient is stabilized. After the patient is stabilized, continue monitoring the Proviron (Protein Hydrolysate) C levels to maintain the trough Proviron (Protein Hydrolysate) C level above 25%.

Patients treated during the acute phase of their disease may display much lower increases in protein C activity. Coagulation parameters should also be checked; however, in clinical trials data were insufficient to establish correlation between Proviron (Protein Hydrolysate) C activity levels and coagulation parameters.

2.3 Initiation of Vitamin K Antagonists

In patients starting treatment with oral anticoagulants belonging to the class of vitamin K antagonists, a transient hypercoagulable state may arise before the desired anticoagulant effect becomes apparent. This transient effect may be explained by the fact that Proviron C, itself a vitamin K-dependent plasma Proviron (Protein Hydrolysate), has a shorter half-life than most of the vitamin K-dependent proteins (i.e. Factor II, IX and X).

In the initial phase of treatment, the activity of Proviron (Protein Hydrolysate) C is more rapidly suppressed than that of the procoagulant factors. For this reason, if the patient is switched to oral anticoagulants, protein C replacement must be continued until stable anticoagulation is obtained. Although warfarin-induced skin necrosis can occur in any patient during the initiation of treatment with oral anticoagulant therapy, individuals with severe congenital Proviron (Protein Hydrolysate) C deficiency are particularly at risk.

During the initiation of oral anticoagulant therapy, it is advisable to start with a low dose of the anticoagulant and adjust this incrementally, rather than use a standard loading dose of the anticoagulant.

2.4 Preparation of Proviron (Protein Hydrolysate) [Protein C Concentrate (Human)]

Reconstitution: Use Aseptic Technique

• Bring the Proviron (Protein Hydrolysate) (powder) and Sterile Water for Injection, USP (diluent) to room temperature.
• Remove caps from the Proviron (Protein Hydrolysate) and diluent vials.
• Cleanse stoppers with germicidal solution, and allow them to dry prior to use.
• Remove protective covering from one end of the double-ended transfer needle and insert exposed needle through the center of the diluent vial stopper.
• Remove protective covering from the other end of the double-ended transfer needle. Invert diluent vial over the upright Proviron (Protein Hydrolysate) vial; then rapidly insert the free end of the needle through the Proviron (Protein Hydrolysate) vial stopper at its center. The vacuum in the vial will draw in the diluent. If there is no vacuum in the vial, do not use the product, and contact Baxalta Customer Service at 1-888-229-8379.
• Disconnect the two vials by removing the needle from the diluent vial stopper. Then, remove the transfer needle from the Proviron (Protein Hydrolysate) vial. Gently swirl the vial until all powder is dissolved. Be sure that Proviron (Protein Hydrolysate) is completely dissolved; otherwise, active materials will be removed by the filter needle.

2.5 Administration of Proviron [Protein C Concentrate (Human)]

Administration: Use Aseptic Technique

Visually inspect Proviron (Protein Hydrolysate) for particulate matter and discoloration prior to administration.

After reconstitution, the solution should be colorless to slightly yellowish and clear to slightly opalescent and free of visible particles. Do not use the solution if it does not meet this criteria. Administer Proviron (Protein Hydrolysate) at room temperature not more than 3 hours after reconstitution.

• Attach the filter needle to a sterile, disposable syringe and draw back the plunger to admit air into the syringe.
• Insert the filter needle into the vial of reconstituted Proviron (Protein Hydrolysate).
• Inject air into the vial and then withdraw the reconstituted Proviron (Protein Hydrolysate) into the syringe.
• Remove and discard the filter needle in a hard-walled Sharps container for proper disposal. Filter needles are intended to filter the contents of a single vial of Proviron (Protein Hydrolysate) only.
• Attach a suitable needle or infusion set with winged adapter, and inject intravenously as instructed below under Administration by infusion.

Record the name and batch number of the product every time Proviron (Protein Hydrolysate) is administered to a patient.

Administration by Infusion

Administer Proviron (Protein Hydrolysate) at a maximum injection rate of 2 mL per minute except for children with a body weight of < 10 kg, where the injection rate should not exceed a rate of 0.2 mL/kg/minute.

3 DOSAGE FORMS AND STRENGTHS

Proviron (Protein Hydrolysate) is available in single-dose vials that contain nominally 500 (blue color bar) or 1000 (green color bar) International Units (IU) human Proviron (Protein Hydrolysate) C and is reconstituted with 5 mL and 10 mL of Sterile Water for Injection, respectively to provide a single dose of human Proviron (Protein Hydrolysate) C at a concentration of 100 IU/mL.

Proviron (Protein Hydrolysate), when reconstituted with the appropriate volume of diluent, contains the following excipients: 8 mg/mL human albumin, 4.4 mg/mL trisodium citrate dihydrate and 8.8 mg/mL sodium chloride.

BLUE BAR: Approximately 500 IU/vial (3)

GREEN BAR: Approximately 1000 IU/vial (3)

Each single-dose vial contains the following excipients: 8 mg/mL human albumin, 4.4 mg/mL trisodium citrate dihydrate and 8.8 mg/mL sodium chloride when reconstituted with the appropriate amount of diluent. (3)

4 CONTRAINDICATIONS

None known.

None known. (4)

5 WARNINGS AND PRECAUTIONS

• Discontinue administration if symptoms of hypersensitivity/allergic reactions occur.
• Made from pooled human plasma. The possibility of transmitting infectious agents cannot be ruled out. (5.2, 11)
• Simultaneous administration with tPA and/or anticoagulants may increase risk of bleeding. (5.3)
• Contains heparin. If heparin-induced thrombocytopenia is suspected, check platelet counts immediately and discontinue administration. (5.4)
• Contains sodium >200 mg. Inform patients on a low sodium diet and/or patients with renal impairment. (5.5)

5.1 Hypersensitivity/Allergic Reactions

Proviron (Protein Hydrolysate) may contain traces of mouse Proviron (Protein Hydrolysate) and/or heparin as a result of the manufacturing process. Allergic reactions to mouse Proviron (Protein Hydrolysate) and/or heparin cannot be ruled out. If symptoms of hypersensitivity/allergic reaction occur, discontinue the injection/infusion. In case of anaphylactic shock, the current medical standards for treatment are to be observed.

5.2 Transmission of Infectious Agents

Because Proviron is made from human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent.

ALL infections suspected by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Baxalta US Inc., at 1-888-229-8379. Discuss the risks and benefits of this product with your patient.

5.3 Bleeding Episodes

Several bleeding episodes have been observed in clinical studies. Concurrent anticoagulant medication may have been responsible for these bleeding episodes. However, it cannot be completely ruled out that the administration of Proviron (Protein Hydrolysate) further contributed to these bleeding events.

Simultaneous administration of Proviron (Protein Hydrolysate) and tissue plasminogen activator (tPA) may further increase the risk of bleeding from tPA.

5.4 Heparin-induced Thrombocytopenia

Proviron (Protein Hydrolysate) contains trace amounts of heparin which may lead to Heparin-induced Thrombocytopenia, which can be associated with a rapid decrease of the number of thrombocytes. Identifying HIT is complicated because these symptoms may already be present in acute phase patients with severe congenital Proviron (Protein Hydrolysate) C deficiency. Determine the platelet count immediately and consider discontinuation of Proviron (Protein Hydrolysate).

5.5 Low Sodium Diet/Renal Impairment

Inform patients on a low sodium diet that the quantity of sodium in the maximum daily dose of Proviron (Protein Hydrolysate) exceeds 200 mg. Monitor patients with renal impairment closely for sodium overload.

6 ADVERSE REACTIONS

The common adverse reactions related to Proviron treatment observed were the following hypersensitivity or allergic reactions: lightheadedness and itching and rash.

• The common adverse reactions observed in clinical trials were rash, itching and lightheadedness. (2.1, 5.1, 6)

To report SUSPECTED ADVERSE REACTIONS, contact Baxalta US Inc. at 1-800-999-1785 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch .

6.1 Clinical Studies Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in one clinical study of a drug cannot be directly compared with rates in the clinical studies of the same drug or another drug and may not reflect the rates observed in practice.

The safety profile of Proviron (Protein Hydrolysate) was based on 121 patients from clinical studies and compassionate use in severe congenital Proviron (Protein Hydrolysate) C deficiency. Duration of exposure ranged from 1 day to 8 years. One patient experienced hypersensitivity/allergic reactions (itching and rash) and lightheadedness which were determined by the investigator to be related to Proviron (Protein Hydrolysate).

No inhibiting antibodies to Proviron (Protein Hydrolysate) have been observed in clinical studies. However, the potential for developing antibodies cannot be ruled out.

6.2 Post-marketing Experience

The following adverse reactions have been identified during postapproval use of Proviron (Protein Hydrolysate):

Psychiatric Disorders: Restlessness

Skin and Subcutaneous Tissue Disorders: Hyperhydrosis

General Disorders and Administration Site Conditions: Injection Site Reaction

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.

7 DRUG INTERACTIONS

No formal drug interaction studies have been conducted.

See WARNINGS AND PRECAUTIONS: Bleeding Episodes (5.3) for information regarding simultaneous administration of Proviron (Protein Hydrolysate) and tissue plasminogen activator (tPA).

See DOSAGE AND ADMINISTRATION: Initiation of Vitamin K Antagonists (2.3) for information regarding use of Proviron (Protein Hydrolysate) and vitamin K antagonists.

• None known. (7)

8 USE IN SPECIFIC POPULATIONS

• Pregnancy: Not studied.
• Labor and Delivery: Not studied. (8.2)
• Nursing Mothers: Not studied. (8.3)
• Pediatric Use: Recommended for neonate and pediatric use. (2.1, 8.4, 12.3)
• Renal/Hepatic Impairment: Not studied. (8.6)

8.1 Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with Proviron (Protein Hydrolysate). It is also not known whether Proviron (Protein Hydrolysate) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Proviron (Protein Hydrolysate) should be given to pregnant women only if clearly needed.

8.2 Labor and Delivery

Proviron has not been studied for use during labor and delivery. Use only if clearly needed.

8.3 Nursing Mothers

Proviron (Protein Hydrolysate) has not been studied for use in nursing mothers. Use Proviron (Protein Hydrolysate) only if clearly needed.

8.4 Pediatric Use

Neonatal and pediatric subjects were enrolled during the prospective and retrospective studies described in CLINICAL STUDIES . Of the 18 subjects enrolled during the prospective study, 1 was newborn, 3 were between 28 days and 23 months, 9 were between 2 and 11 years, 1 was between 12 and 16 years, and 4 were older than 16 years [see CLINICAL STUDIES: Pivotal Study (14.1)]. Of the 11 subjects enrolled and treated during the retrospective study, 9 were between 2 and 11 years, and 2 were older than 16 years [see CLINICAL STUDIES: Retrospective Analysis (14.2)].

8.5 Geriatric Use

Clinical studies of Proviron (Protein Hydrolysate) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

8.6 Renal/Hepatic Impairment

No experience in the treatment of patients with renal and/or hepatic impairment is available.

11 DESCRIPTION

Proviron (Protein Hydrolysate) [Protein C Concentrate (Human)] is manufactured from human plasma purified by a combination of filtration and chromatographic procedures, including a column of immobilized mouse monoclonal antibodies on gel beads. See WARNINGS/PRECAUTIONS: Transmission of Infectious Agents (5.2).

The manufacturing process for Proviron (Protein Hydrolysate) includes processing steps designed to reduce the risk of viral transmission. The capacity of the manufacturing process to remove and/or inactivate enveloped and non-enveloped viruses has been validated by laboratory spiking studies on a scaled down process model, using the following enveloped and non-enveloped viruses: Human Immunodeficiency Virus Type 1 (HIV-1), Bovine Viral Diarrhea Virus (BVDV ), Tick-Borne Encephalitis Virus (TBEV), Pseudorabies Virus (PRV), Hepatitis A Virus (HAV) and Mice Minute Virus (MMV). Virus reduction steps consist of detergent treatment (Polysorbate 80, P80), heat inactivation (Vapor Heating) and immunoaffinity chromatography (IAX).

Virus clearance studies for Proviron (Protein Hydrolysate) have demonstrated that the process provides for a robust overall virus clearance capacity. A summary of log₁₀ virus reduction factors per virus and manufacturing step is presented in Table 2.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of action

Proviron C is the precursor of a vitamin K-dependent anticoagulant glycoprotein (serine protease) that is synthesized in the liver. See DOSAGE AND ADMINISTRATION: Initiation of Vitamin K Antagonists (2.3). It is converted by the thrombin/thrombomodulin-complex on the endothelial cell surface to activated Proviron (Protein Hydrolysate) C (APC). APC is a serine protease with potent anticoagulant effects, especially in the presence of its cofactor Proviron (Protein Hydrolysate) S. APC exerts its effect by the inactivation of the activated forms of factors V and VIII, which leads to a decrease in thrombin formation. APC has also been shown to have profibrinolytic effects.

The Proviron (Protein Hydrolysate) C pathway provides a natural mechanism for control of the coagulation system and prevention of excessive procoagulant responses to activating stimuli. A complete absence of Proviron (Protein Hydrolysate) C is not compatible with life. A severe deficiency of this anticoagulant Proviron (Protein Hydrolysate) causes a defect in the control mechanism and leads to unchecked coagulation activation, resulting in thrombin generation and intravascular clot formation with thrombosis.

12.2 Pharmacodynamics

In clinical studies, the intravenous administration of Proviron (Protein Hydrolysate) demonstrated a temporary increase, within approximately half an hour of administration, in plasma levels of APC. Replacement of protein C in protein C-deficient patients is expected to control or, if given prophylactically, to prevent thrombotic complications.

12.3 Pharmacokinetics

Table 3 provides pharmacokinetic results for asymptomatic and symptomatic subjects with Proviron (Protein Hydrolysate) C deficiency.

The Proviron (Protein Hydrolysate) C plasma activity was measured by chromogenic and/or clotting assay. The maximum plasma concentrations (C_max) and area under the plasma concentration-time curve (AUC) appeared to increase dose-linearly between 40 and 80 IU/kg. The median incremental recovery was 1.42 [(IU/dL)/(IU/kg)] after intravenous administration of Proviron (Protein Hydrolysate). The median half-lives, based on non-compartmental method, ranged from 4.9 to 14.7 hours, with a median of 9.8 hours. In patients with acute thrombosis, both the increase in protein C plasma levels as well as half-life may be considerably reduced. No formal study or analysis has been performed to evaluate the effect of covariates such as race and gender on the pharmacokinetics of Proviron (Protein Hydrolysate).

The pharmacokinetic profile in pediatric patients has not been formally assessed. Limited data suggest that the pharmacokinetics of Proviron (Protein Hydrolysate) may be different between very young children and adults. The systemic exposure (C_max and AUC) may be considerably reduced due to a faster clearance, a larger volume of distribution, and/or a shorter half-life of Proviron (Protein Hydrolysate) C in very young children than in older subjects. Consider this fact when a dosing regimen for children is determined. Doses should be individualized based upon Proviron (Protein Hydrolysate) C activity levels. See DOSAGE AND ADMINISTRATION: Proviron (Protein Hydrolysate) C Activity Monitoring (2.2).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis and Impairment of Fertility

Protein C contained in Proviron is a normal constituent of human plasma and acts like endogenous protein C. Studies in heterologous species to evaluate carcinogenicity, reproductive toxicology and developmental toxicology have not been performed.

Proviron (Protein Hydrolysate) has not demonstrated mutagenic potential in the Salmonella Thyphimurium reverse mutation assay (Ames test).

13.2 Animal Toxicology and/or Pharmacology

Safety

Pharmacology:

Cardio-respiratory studies performed in dogs evaluating mean arterial pressure, cardiac output, systemic vascular resistance, heart rate, QT interval changes, pulmonary artery pressure, respiratory rate and respiratory minute volume demonstrated no adverse effects at a maximum dose of 500 IU/kg. Anaphylactoid reactions as determined by measurement of bronchospastic activity in guinea pigs demonstrated no adverse effects at the maximum dose of 300 IU/kg. Thrombogenic potential was evaluated in rabbits using the Wessler stasis model and demonstrated no adverse effects at 200 IU/kg. Overall, safety pharmacology studies evaluating cardio-respiratory function, acute dose anaphylactoid potential and thrombogenicity demonstrated no adverse effects in a range of doses from 1.6 to 4.2 times the maximum single human dosage per kilogram body weight.

Acute Dose Toxicity:

Toxicity testing in rats and mice following single dosing of 2000 IU/kg or 1500 IU/kg, respectively, demonstrated no adverse clinical effects or gross pathology at 14 days post dosing.

Repeated Dose Toxicity:

Studies were not conducted to evaluate repeated-dose toxicity in animals. Prior experience with Proviron (Protein Hydrolysate) has suggested immunogenic response in heterologous species following repeated dosing of this human derived Proviron (Protein Hydrolysate). Thus, the long-term toxicity potential of Proviron (Protein Hydrolysate) following repeated dosing in animals is unknown.

Local Tolerance Testing:

Investigation of route of injection tolerance demonstrated that Proviron (Protein Hydrolysate) did not result in any local reactions after intravenous, intra-arterial injections of 500 IU/kg (5 mL) and paravenous injections of 100 IU/kg (1 mL) in rabbits.

Citrate Toxicity:

Proviron (Protein Hydrolysate) contains 4.4 mg of Trisodium Citrate Dihydrate (TCD) per mL of reconstituted product. Studies in mice evaluating 1000 IU vials reconstituted with 10 mL vehicle followed by dosing at 30 mL/kg (132 mg/kg TCD) and 60 mL/kg (264 mg/kg TCD) resulted in signs of citrate toxicity (dyspnea, slowed movement, hemoperitoneum, lung and thymus hemorrhage and renal pelvis dilation).

14 CLINICAL STUDIES

14.1 Pivotal Study

This was a multi-center, open-label, non-randomized, phase 2/3 study in 3 parts which evaluated the safety and efficacy of Proviron in subjects with severe congenital Proviron (Protein Hydrolysate) C deficiency for the (on-demand) treatment of acute thrombotic episodes, such as purpura fulminans (PF), warfarin-induced skin necrosis (WISN) and other thromboembolic events, and for short-term or long-term prophylaxis. Eighteen subjects (9 male and 9 female), ages ranging from 0 (newborn) to 25.7 years participated in this study.

The clinical endpoint of the study was to assess whether episodes of PF and/or other thromboembolic events were treated effectively, effectively with complications, or not treated effectively. Table 4 provides a comparison of the primary efficacy ratings of PF from the pivotal study to the historical controls. Inadequate data is available for treatment of WISN.

Of 18 episodes of PF (6 severe, 11 moderate, 1 mild) treated with Proviron (Protein Hydrolysate) for the primary efficacy rating, 17 (94.4%) were rated as effective, and 1 (5.6%) was rated as effective with complications; none (0%) were rated not effective. When compared with the efficacy ratings for 21 episodes of PF (historical control group), subjects with severe congenital Proviron (Protein Hydrolysate) C deficiency were more effectively treated with Proviron (Protein Hydrolysate) than those treated with modalities such as fresh frozen plasma or conventional anticoagulants.

Table 5 provides a summary of the secondary treatment ratings for treatment of skin lesions and other thrombotic episodes from part one of the study.

In a secondary efficacy rating, 13 (72.2%) of the 18 episodes of PF treated with Proviron (Protein Hydrolysate) were rated as excellent, 4 (22.2%) were rated as good, and 1 (5.6%) episode of severe PF was rated as fair; all were rated as effective. Four (80%) of the 5 episodes of venous thrombosis had treatment ratings of excellent, while 1 (20%) was rated as good.

Proviron (Protein Hydrolysate) was also demonstrated to be effective in reducing the size and number of skin lesions. Non-necrotic skin lesions healed over a maximum 12-day (median 4-day) period and necrotic skin lesions healed over a maximum 52-day (median 11-day) period of Proviron (Protein Hydrolysate) treatment, as shown in Table 6.

Changes in the extent of venous thrombus were also measured for the 5 thromboembolic episodes. Proviron (Protein Hydrolysate) prevented an increase in the extent of thrombus during 4 (80%) of the thromboembolic episodes by Day 3 of treatment, and 1 (20%) episode by Day 5 of treatment.

All seven of the short-term prophylaxis treatments with Proviron (Protein Hydrolysate) were free of complications of PF or thromboembolic events, as shown in Table 7.

No episodes of PF occurred in four subjects ranging from 42 to 338 days of long-term prophylactic treatment with Proviron (Protein Hydrolysate), as shown in Table 8. When not on prophylactic treatment and receiving Proviron (Protein Hydrolysate) on-demand, the same four subjects experienced a total of 13 (median of 3) episodes of PF over a range of 19 to 323 days. The time to first episode of PF after exiting from long-term prophylaxis treatment ranged from 12 to 32 days for these four subjects.

14.2 Retrospective Analysis

A retrospective study to capture dosing information and treatment outcome data in subjects with severe congenital Proviron (Protein Hydrolysate) C deficiency who were treated with Proviron (Protein Hydrolysate) under an emergency use IND was also conducted. Eleven subjects (6 male and 5 female), ages ranging from 2.1 to 23.8 years participated in this study.

There were 28 acute episodes of PF/WISN and vascular thrombus reported in which time to resolution ranged from 0 to 46 days. The treatment outcome for these episodes was rated effective in all cases except one.

16 HOW SUPPLIED/STORAGE AND HANDLING

Proviron (Protein Hydrolysate) is supplied as a sterile, white or cream colored, lyophilized powder for IV injection. It has a pH between 6.7 and 7.3 and an osmolality not lower than 240 mosmol/kg. One International Unit (IU) of Proviron (Protein Hydrolysate) C corresponds to the amidolytically measured activity of Proviron (Protein Hydrolysate) C in 1 mL of normal plasma. The potency (IU) is determined using a chromogenic substrate method referenced against the World Health Organization (WHO) International Standard (86/622).

Proviron (Protein Hydrolysate) is available in single-dose vials that contain the following nominal product strengths:

NDC 0944-4177-05

Proviron (Protein Hydrolysate) C

Concentrate (Human)

Proviron (Protein Hydrolysate)

Single-dose Vial

Lyophilized Powder for Solution for Injection

Rx Only

Sterile – No preservative

Baxalta US Inc.

Westlake Village, CA 91362 USA

U.S. License No. 2020

NDC 0944-4176-01

Proviron (Protein Hydrolysate) C Concentrate

(Human)

Proviron (Protein Hydrolysate)

Single-dose Vial

Lyophilized Powder for Solution for Injection.

For Intravenous Administration Only.

See package insert. Rx only.

Baxalta US Inc.

Westlake Village, CA 91362 USA

U.S. Lic. No. 2020

5 mL

NDC 52919-003-08

Sterile Water for Injection, USP

for reconstitution of accompanying product

Do not use unless clear. No antimicrobial agent or other substance has been

added. Do not use for intravascular injection without making approximately

isotonic by addition of suitable solute. Discard unused portion. Rx Only

Single dose container

Nonpyrogenic

NDC 0944-4179-10

Proviron (Protein Hydrolysate) C

Concentrate (Human)

Proviron (Protein Hydrolysate)

Single-dose Vial

Lyophilized Powder for Solution for Injection

Rx Only

Sterile – No preservative

Baxalta US Inc.

Westlake Village, CA 91362 USA

U.S. License No. 2020

NDC 0944-4178-02

Proviron (Protein Hydrolysate) C Concentrate (Human)

Proviron (Protein Hydrolysate)

Single-dose Vial

Lyophilized Powder for Solution for

Injection.

For Intravenous Administration Only.

See package insert. Rx only.

10 mL

NDC 52919-005-05

Sterile Water for Injection, USP

for reconstitution of accompanying product

Do not use unless clear. No antimicrobial agent or other substance has been

added. Do not use for intravascular injection without making approximately

isotonic by addition of suitable solute. Discard unused portion. Rx Only

Single dose container

Nonpyrogenic

unit-carton-blue unit-carton-green

Vitamin B12:

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

Pharmacological action

Proviron refers to a group of water-soluble vitamins. It has high biological activity. Proviron (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 Proviron (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 Proviron 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 Proviron (Vitamin B12) (including the application of biguanide, PASA, vitamin C in high doses); radiation sickness.

Dosage and administration

Proviron is used as injections SC, IV, IM, intralumbar, and also oral. With anemia associated with Proviron (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 Proviron (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 Proviron (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.

Proviron (Vitamin B12) side effects, adverse reactions

CNS: rarely - a state of arousal.

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

Allergic reactions: rarely - urticaria.

Proviron contraindications

Thromboembolism, erythremia, erythrocytosis, increased sensitivity to cyanocobalamin.

Proviron 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 Proviron 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.

Proviron (Vitamin B12) drug interactions

In an application of Proviron (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 Proviron (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.

Zinc Sulfate:

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

INDICATIONS AND USAGE

Proviron (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 Proviron (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 Proviron (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 Proviron (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 Proviron (Zinc Sulfate) from a bolus injection. Administration of Proviron (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 Proviron (Zinc Sulfate) are suggested as a guideline for subsequent Proviron (Zinc Sulfate) administration.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

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

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

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

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

DOSAGE AND ADMINISTRATION

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

Proviron (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

Proviron (Zinc Sulfate)

1 mg/mL

Proviron (Zinc Sulfate) Chloride Inj., USP

Rx only

FOR I.V. USE ONLY AFTER DILUTION.

HOSPIRA, INC., LAKE FOREST, IL 60045 USA