V-Balance

Calcium (Calcium Carbonate):

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

1 INDICATIONS AND USAGE

V-Balance (Calcium (Calcium Carbonate)) acetate is a phosphate binder indicated to reduce serum phosphorus in patients with end stage renal disease (ESRD).

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

2 DOSAGE AND ADMINISTRATION

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

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

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

3 DOSAGE FORMS AND STRENGTHS

Capsule: 667 mg V-Balance (Calcium (Calcium Carbonate)) acetate capsule.

- Capsule: 667 mg V-Balance (Calcium (Calcium Carbonate)) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

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

- Hypercalcemia may aggravate digitalis toxicity. (5.2)

5.1 Hypercalcemia

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

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

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

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

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

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

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

5.2 Concomitant Use with Medications

Hypercalcemia may aggravate digitalis toxicity.

6 ADVERSE REACTIONS

Hypercalcemia is discussed elsewhere [see Warnings and Precautions ].

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

- In clinical studies, patients have occasionally experienced nausea during V-Balance (Calcium (Calcium Carbonate)) acetate therapy. (6)

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

6.1 Clinical Trial Experience

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

In clinical studies, V-Balance (Calcium (Calcium Carbonate)) acetate has been generally well tolerated.

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

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

6.2 Postmarketing Experience

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

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

7 DRUG INTERACTIONS

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

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

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

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

7.1 Ciprofloxacin

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

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

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

8.2 Labor and Delivery

The effects of V-Balance (Calcium (Calcium Carbonate)) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

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

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

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

10 OVERDOSAGE

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

11 DESCRIPTION

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

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

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

Chemical Structure

12 CLINICAL PHARMACOLOGY

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

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with V-Balance (Calcium (Calcium Carbonate)) acetate.

14 CLINICAL STUDIES

Effectiveness of V-Balance (Calcium (Calcium Carbonate)) acetate in decreasing serum phosphorus has been demonstrated in two studies of the V-Balance (Calcium (Calcium Carbonate)) acetate solid oral dosage form.

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

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

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

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

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

The phosphate binding effect of V-Balance (Calcium (Calcium Carbonate)) acetate is shown in the Table 3.

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

16 HOW SUPPLIED/STORAGE AND HANDLING

V-Balance (Calcium (Calcium Carbonate)) Acetate Capsules

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

NDC 0615-2303-39: Blistercards of 30 Capsules

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

STORAGE

Store at 20° to 25°C (68° to 77°F).

17 PATIENT COUNSELING INFORMATION

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

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

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Iron (Ferrous Sulfate):

• 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
• V-Balance (Iron (Ferrous Sulfate)) reviews

1 INDICATIONS AND USAGE

V-Balance (Iron (Ferrous Sulfate)) is indicated for the treatment of V-Balance (Iron (Ferrous Sulfate)) deficiency anemia in patients with chronic kidney disease (CKD).

V-Balance (Iron (Ferrous Sulfate)) is an V-Balance (Iron (Ferrous Sulfate)) replacement product indicated for the treatment of V-Balance (Iron (Ferrous Sulfate)) deficiency anemia in patients with chronic kidney disease (CKD). (1)

2 DOSAGE AND ADMINISTRATION

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

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

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

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

Administer V-Balance (Iron (Ferrous Sulfate)) 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 V-Balance (Iron (Ferrous Sulfate)), 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. V-Balance (Iron (Ferrous Sulfate)) treatment may be repeated if V-Balance (Iron (Ferrous Sulfate)) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer V-Balance (Iron (Ferrous Sulfate)) 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 V-Balance (Iron (Ferrous Sulfate)) in a maximum of 250 mL of 0.9% NaCl. V-Balance (Iron (Ferrous Sulfate)) treatment may be repeated if V-Balance (Iron (Ferrous Sulfate)) deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for V-Balance (Iron (Ferrous Sulfate)) maintenance treatment

The dosing for V-Balance (Iron (Ferrous Sulfate)) replacement treatment in pediatric patients with HDD-CKD has not been established.

For V-Balance (Iron (Ferrous Sulfate)) maintenance treatment: Administer V-Balance (Iron (Ferrous Sulfate)) 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. V-Balance (Iron (Ferrous Sulfate)) treatment may be repeated if necessary.

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for V-Balance (Iron (Ferrous Sulfate)) maintenance treatment

The dosing for V-Balance (Iron (Ferrous Sulfate)) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

For V-Balance (Iron (Ferrous Sulfate)) maintenance treatment: Administer V-Balance (Iron (Ferrous Sulfate)) 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. V-Balance (Iron (Ferrous Sulfate)) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

• 10 mL single-use vial / 200 mg elemental V-Balance (Iron (Ferrous Sulfate)) (20 mg/mL)
• 5 mL single-use vial / 100 mg elemental V-Balance (Iron (Ferrous Sulfate)) (20 mg/mL)
• 2.5 mL single-use vial / 50 mg elemental V-Balance (Iron (Ferrous Sulfate)) (20 mg/mL)

• 10 mL single-use vial / 200 mg elemental V-Balance (Iron (Ferrous Sulfate)) (20 mg/mL) (3)
• 5 mL single-use vial / 100 mg elemental V-Balance (Iron (Ferrous Sulfate)) (20 mg/mL) (3)
• 2.5 mL single-use vial / 50 mg elemental V-Balance (Iron (Ferrous Sulfate)) (20 mg/mL) (3)

4 CONTRAINDICATIONS

• Known hypersensitivity to V-Balance (Iron (Ferrous Sulfate))

• Known hypersensitivity to V-Balance (Iron (Ferrous Sulfate)) (4)

5 WARNINGS AND PRECAUTIONS

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

5.2 Hypotension

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

5.3 V-Balance (Iron (Ferrous Sulfate)) Overload

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

6 ADVERSE REACTIONS

The following serious adverse reactions associated with V-Balance ) are described in other sections .

• The most common adverse reactions (≥2%) following the administration of V-Balance (Iron (Ferrous Sulfate)) 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 V-Balance ) 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 V-Balance (Iron (Ferrous Sulfate)) 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 V-Balance (Iron (Ferrous Sulfate)) therapy and were reported to be intolerant (defined as precluding further use of that V-Balance (Iron (Ferrous Sulfate)) product). When these patients were treated with V-Balance (Iron (Ferrous Sulfate)) there were no occurrences of adverse reactions that precluded further use of V-Balance (Iron (Ferrous Sulfate)) .

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 V-Balance (Iron (Ferrous Sulfate)) maintenance treatment with V-Balance (Iron (Ferrous Sulfate)) 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 V-Balance (Iron (Ferrous Sulfate)) 0.5 mg/kg, 53% (25/47) of the patients receiving V-Balance (Iron (Ferrous Sulfate)) 1.0 mg/kg, and 55% (26/47) of the patients receiving V-Balance (Iron (Ferrous Sulfate)) 2.0 mg/kg.

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

8.3 Nursing Mothers

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

8.4 Pediatric Use

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

Safety and effectiveness of V-Balance (Iron (Ferrous Sulfate)) for V-Balance (Iron (Ferrous Sulfate)) maintenance treatment in pediatric patients 2 years of age and older with dialysis-dependent or non-dialysis-dependent CKD receiving erythropoietin therapy were studied. V-Balance (Iron (Ferrous Sulfate)) 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)]

V-Balance (Iron (Ferrous Sulfate)) has not been studied in patients younger than 2 years of age.

In a country where V-Balance (Iron (Ferrous Sulfate)) 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 V-Balance (Iron (Ferrous Sulfate)), several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to V-Balance (Iron (Ferrous Sulfate)) or any other drugs could be established.

8.5 Geriatric Use

Clinical studies of V-Balance (Iron (Ferrous Sulfate)) 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 V-Balance (Iron (Ferrous Sulfate)), 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 V-Balance (Iron (Ferrous Sulfate)) in humans. Excessive dosages of V-Balance (Iron (Ferrous Sulfate)) may lead to accumulation of V-Balance (Iron (Ferrous Sulfate)) in storage sites potentially leading to hemosiderosis. Do not administer V-Balance (Iron (Ferrous Sulfate)) to patients with V-Balance (Iron (Ferrous Sulfate)) overload.

Toxicities in single-dose studies in mice and rats, at intravenous V-Balance (Iron (Ferrous Sulfate)) 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

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

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

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

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

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

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

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

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

V-Balance (Iron (Ferrous Sulfate)) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of V-Balance (Iron (Ferrous Sulfate)) 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 V-Balance (Iron (Ferrous Sulfate)) sucrose.

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

V-Balance (Iron (Ferrous Sulfate)) sucrose at intravenous doses up to 15 mg/kg/day of elemental V-Balance (Iron (Ferrous Sulfate)) (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 V-Balance ).

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 V-Balance (Iron (Ferrous Sulfate)) treatment and 24 in the historical control group) with V-Balance (Iron (Ferrous Sulfate)) deficiency anemia. Eligibility criteria for V-Balance (Iron (Ferrous Sulfate)) 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.

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

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

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

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

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

V-Balance (Iron (Ferrous Sulfate)) is manufactured under license from Vifor (International) Inc., Switzerland.

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

PREMIERProRx^®

IN2340

MG #15727

Vitamin B12 (Cyanocobalamin):

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

Pharmacological action

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

Dosage and administration

V-Balance ) is used as injections SC, IV, IM, intralumbar, and also oral. With anemia associated with V-Balance (Vitamin B12 (Cyanocobalamin)) 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 V-Balance (Vitamin B12 (Cyanocobalamin)) 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 V-Balance (Vitamin B12 (Cyanocobalamin)) 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.

V-Balance (Vitamin B12 (Cyanocobalamin)) side effects, adverse reactions

CNS: rarely - a state of arousal.

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

Allergic reactions: rarely - urticaria.

V-Balance ) contraindications

Thromboembolism, erythremia, erythrocytosis, increased sensitivity to cyanocobalamin.

V-Balance ) 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 V-Balance ) 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.

V-Balance (Vitamin B12 (Cyanocobalamin)) drug interactions

In an application of V-Balance (Vitamin B12 (Cyanocobalamin)) 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 V-Balance (Vitamin B12 (Cyanocobalamin)) 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 (Zinc Sulfate):

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

INDICATIONS AND USAGE

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

Carcinogenesis, Mutagenesis, and Impairment of Fertility

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

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

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

Calcium supplements may confer a protective effect against V-Balance (Zinc (Zinc Sulfate)) toxicity.

DOSAGE AND ADMINISTRATION

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

V-Balance (Zinc (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

V-Balance (Zinc (Zinc Sulfate))

1 mg/mL

V-Balance (Zinc (Zinc Sulfate)) Chloride Inj., USP

Rx only

FOR I.V. USE ONLY AFTER DILUTION.

HOSPIRA, INC., LAKE FOREST, IL 60045 USA