Calcium Acetate

1. INDICATIONS & USAGE Calcium acetate capsules are a phosphate binder indicated to reduce serum phosphorus in patients with end stage renal disease (ESRD). • Calcium acetate capsules are a phosphate binder indicated for the reduction of serum phosphorus in patients with end stage renal disease. ( 1 )

2 DOSAGE AND ADMINISTRATION The recommended initial dose of calcium acetate capsules for the adult dialysis patient is 2 capsules with each meal. Increase the dose gradually to lower serum phosphorus levels to the target range, as long as hypercalcemia does not develop. Most patients require 3 to 4 capsules with each meal. Starting dose is 2 capsules with each meal. ( 2 ) Titrate the dose every 2 to 3 weeks until acceptable serum phosphorus level is reached. Most patients require 3 to 4 capsules with each meal. ( 2 )

3 DOSAGE FORMS AND STRENGTHS Capsule: 667 mg calcium acetate, USP per capsule. Capsule: 667 mg calcium acetate capsule. ( 3 )

4. CONTRAINDICATIONS Patients with hypercalcemia. • Hypercalcemia. ( 4 )

6 ADVERSE REACTIONS To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-362-3993 or drugsafety@avkare.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The most common (>10%) adverse reactions are hypercalcemia, nausea, and vomiting. ( 6.1 ). In clinical studies, patients have occasionally experienced nausea during calcium acetate therapy. ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-362-3993 or drugsafety@avkare.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Hypercalcemia is discussed elsewhere [see Warnings and Precautions (5.1) ]. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical studies, calcium acetate has been generally well tolerated. Calcium acetate was studied in a 3-month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and 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. Table 1: Adverse Reactions in Patients with End-Stage Renal Disease Undergoing Hemodialysis Preferred Term Total adverse reactions reported for calcium acetate 3 – mo , open-label study of calcium acetate n = 98 Double-blind , placebo-controlled , cross over study of calcium acetate n = 69 n = 167 n (%) n (%) Calcium acetate n (%) Placebo n (%) Nausea 6 (3.6) 6 (6.1) 0 (0.0) 0 (0.0) Vomiting 4 (2.4) 4 (4.1) 0 (0.0) 0 (0.0) Hypercalcemia 21 (12.6) 16 (16.3) 5 (7.2) 0 (0.0) Mild hypercalcemia may be asymptomatic or manifest itself as constipation, anorexia, nausea, and vomiting. More severe hypercalcemia is associated with confusion, delirium, stupor, and coma. Decreasing dialysate calcium concentration could reduce the incidence and severity of calcium acetate-induced hypercalcemia. Isolated cases of pruritus have been reported, which may represent allergic reactions. 6.2 Postmarketing Experience Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or to establish a causal relationship to drug exposure. The following additional adverse reactions have been identified during post-approval of calcium acetate: dizziness, edema, and weakness.

7. DRUG INTERACTIONS The drug interaction of calcium acetate capsules is characterized by the potential of calcium to bind to drugs with anionic functions (e.g., carboxyl and hydroxyl groups). Calcium acetate capsules may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism. There are no empirical data on avoiding drug interactions between calcium acetate or calcium acetate capsules and most concomitant drugs. When administering an oral medication with calcium acetate capsules where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, administer the drug one hour before or three hours after calcium acetate capsules or calcium acetate. Monitor blood levels of the concomitant drugs that have a narrow therapeutic range. Patients taking anti-arrhythmic medications for the control of arrhythmias and anti-seizure medications for the control of seizure disorders were excluded from the clinical trials with all forms of calcium acetate. • Calcium acetate capsules may decrease the bioavailability of tetracyclines or fluoroquinolones. ( 7 ) • When clinically significant drug interactions are expected, administer the drug at least one hour before or at least three hours after calcium acetate capsules, or consider monitorinG blood levels of the drug. ( 7 ) 7.1 Ciprofloxacin In a study of 15 healthy subjects, a co-administered single dose of 4 calcium acetate tablets approximately 2.7 g decreased the bioavailability of ciprofloxacin by approximately 50%.

8. USE IN SPECIFIC POPULATIONS 8.1 PREGNANCY Pregnancy Category C Calcium acetate capsules contain calcium acetate. Animal reproduction studies have not been conducted with calcium acetate capsules, and there are no adequate and well controlled studies of calcium acetate capsules use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with calcium acetate treatment [see Warnings and Precautions (5.1) ]. Maintenance of normal serum calcium levels is important for maternal and fetal well being. Hypercalcemia during pregnancy may increase the risk for maternal and neonatal complications such as stillbirth, preterm delivery, and neonatal hypocalcemia and hypoparathyroidism. Calcium acetate capsules treatment, as recommended, is not expected to harm a fetus if maternal calcium levels are properly monitored during and following treatment. 8.2 LABOR & DELIVERY The effects of calcium acetate capsules on labor and delivery are unknown. 8.3 NURSING MOTHERS Calcium acetate capsules contain calcium acetate and is excreted in human milk. Human milk feeding by a mother receiving calcium acetate capsules is not expected to harm an infant, provided maternal serum calcium levels are appropriately monitored. 8.4 PEDIATRIC USE Safety and effectiveness in pediatric patients have not been established. 8.5 GERIATRIC USE Clinical studies of calcium 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 the 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.

12.1 MECHANISM OF ACTION Calcium acetate (calcium acetate capsules) when taken with meals, combines with dietary phosphate to form an insoluble calcium phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

11 DESCRIPTION Calcium acetate, USP acts as a phosphate binder. Its chemical name is calcium acetate, USP. Its molecular formula is C 4 H 6 CaO 4 , and its molecular weight is 158.17. Its structural formula is: Each capsule has a light-blue cap imprinted with “AMNEAL” and white body imprinted with “590” with black ink. Each capsule contains 667 mg calcium acetate, USP (anhydrous; Ca(CH 3 COO) 2 ; MW=158.17 grams) equal to 169 mg (8.45 mEq) calcium. Each capsule also contains the following inactive ingredients: FD&C Blue #1, FD&C Red #3, gelatin, magnesium stearate, polyethylene glycol and titanium dioxide. In addition to the inactive ingredients listed above, each capsule contains Opacode (Black) monogramming ink. Opacode (Black) contains D&C Yellow #10, FD&C Blue #2, FD&C Red #40, iron oxide black and shellac. Opacode (Black) may also contain ethanol, methanol, n-butyl alcohol and propylene glycol. Calcium acetate capsules, USP are administered orally for the control of hyperphosphatemia in end-stage renal failure. Meets USP dissolution test 4. ab

10. OVERDOSAGE Administration of calcium acetate capsules in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1) ]

16. HOW SUPPLIED/STORAGE AND HANDLING Each calcium acetate capsule USP, for oral administration, contains 667 mg of Calcium Acetate, USP (anhydrous Ca (CH 3 COO) 2 ; MW=158.17 grams) equivalent to 169 mg (8.45 mEq) of calcium. The capsules are size 00EL with light green opaque cap and white opaque body with black imprint on cap "NC" above "667". NDC 82804-968-20 Bottles of 20 NDC 82804-968-30 Bottles of 30 NDC 82804-968-60 Bottles of 60 NDC 82804-968-90 Bottles of 90 NDC 82804-968-00 Bottles of 100 NDC 82804-968-72 Bottles of 120 NDC 82804-968-78 Bottles of 180 NDC 82804-968-64 Bottles of 240 NDC 82804-968-55 Bottles of 500 STORAGE: Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F) [See USP "Controlled Room Temperature"].