Calcium Acetate

6 ADVERSE REACTIONS Hypercalcemia is discussed elsewhere [see Warnings and Precautions (5.1) ]. 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 Hikma Pharmaceuticals USA Inc. 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, 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 an alternate liquid formulation of calcium 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. Table 1: Adverse Reactions in Patients with End-Stage Renal Disease Undergoing Hemodialysis Preferred Term Total adverse reactions reported for calcium acetate N=167 N (%) 3 month, open label study of calcium acetate N=98 N (%) Double blind, placebo-controlled, cross-over study of liquid calcium acetate N=69 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 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.

4 CONTRAINDICATIONS Patients with hypercalcemia. Hypercalcemia. ( 4 )

11 DESCRIPTION Calcium acetate acts as a phosphate binder. Its chemical name is calcium acetate. Its molecular formula is C 4 H 6 CaO 4 , and its molecular weight is 158.17. Its structural formula is: Each white opaque/blue opaque capsule contains 667 mg of calcium acetate, USP (anhydrous; Ca(CH 3 COO) 2 ; MW=158.17 grams) equal to 169 mg (8.45 mEq) calcium, 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. Calcium Acetate Capsules, USP are administered orally for the control of hyperphosphatemia in end-stage renal failure. Structural Formula

2 DOSAGE AND ADMINISTRATION The recommended initial dose of calcium 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 )

1 INDICATIONS AND USAGE Calcium 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 )

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

7 DRUG INTERACTIONS The drug interaction of calcium acetate is characterized by the potential of calcium to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Calcium acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism. There are no empirical data on avoiding drug interactions between calcium acetate and most concomitant drugs. When administering an oral medication with calcium 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 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 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 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 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

12 CLINICAL PHARMACOLOGY Patients with ESRD retain phosphorus and can develop hyperphosphatemia. High serum phosphorus can precipitate serum calcium resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD. 12.1 Mechanism of Action Calcium acetate, 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. 12.2 Pharmacodynamics Orally administered calcium 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.

12.1 Mechanism of Action Calcium acetate, 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.

12.2 Pharmacodynamics Orally administered calcium 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.

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

Calcium Acetate Calcium Acetate POLYETHYLENE GLYCOL 8000 MAGNESIUM STEARATE FD&C BLUE NO. 1 FD&C RED NO. 3 GELATIN, UNSPECIFIED TITANIUM DIOXIDE AMMONIA FERROSOFERRIC OXIDE ISOPROPYL ALCOHOL BUTYL ALCOHOL PROPYLENE GLYCOL SHELLAC CALCIUM ACETATE CALCIUM CATION Opaque Opaque 54;215;54;215

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity, mutagenicity, or fertility studies have been conducted with calcium acetate.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity, mutagenicity, or fertility studies have been conducted with calcium acetate.

ANDA077728

Calcium Acetate

Calcium Acetate

68084-479

HUMAN PRESCRIPTION DRUG

ORAL

Package/Label Display Panel – Carton – 667 mg NDC 68084- 479 -01 Calcium Acetate Capsules, USP 667 mg 100 Capsules (10 x 10) Rx Only Each capsule contains 667 mg calcium acetate, USP equivalent to 169 mg calcium. Directions: SWALLOW CAPSULES: DO NOT CHEW. Take as directed by your physician. Usual Dosage: See package insert for full prescribing information. Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep this and all drugs out of reach of children. FOR YOUR PROTECTION: Do not use if blister is torn or broken. The drug product contained in this package is from NDC # 0054-0088, Hikma Pharmaceuticals USA Inc. Distributed by: American Health Packaging Columbus, Ohio 43217 047901 0247901/0121 667 mg Calcium Acetate Capsules Carton

PACKAGING INFORMATION American Health Packaging unit dose blisters (see How Supplied section) contain drug product from Hikma Pharmaceuticals USA Inc. as follows: (667 mg / 100 UD) NDC 68084-479-01 packaged from NDC 0054-0088 Distributed by: American Health Packaging Columbus, OH 43217 8247901/0121

17 PATIENT COUNSELING INFORMATION Inform patients to take calcium acetate capsules with meals, adhere to their prescribed diets, and avoid the use of calcium supplements including non-prescription 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 calcium acetate capsules. FOR YOUR PROTECTION: Do not use if blister is torn or broken.

14 CLINICAL STUDIES Effectiveness of calcium acetate in decreasing serum phosphorus has been demonstrated in two studies of the calcium 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 calcium 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 calcium acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum calcium levels are also presented. Table 2: Average Serum Phosphorous and Calcium Levels at Pre-Study, Interim, and Study Completion Time Points Parameter Pre-Study Week 4 Ninety-one patients completed at least 6 weeks of the study. Week 8 Week 12 p-value ANOVA of difference in values at pre-study and study completion. Phosphorus (mg/dL) Values expressed as mean ± SE. 7.4 ± 0.17 5.9 ± 0.16 5.6 ± 0.17 5.2 ± 0.17 ≤0.01 Calcium (mg/dL) 8.9 ± 0.09 9.5 ± 0.10 9.7 ± 0.10 9.7 ± 0.10 ≤0.01 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 calcium 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 calcium 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 calcium acetate is shown in the Table 3. Table 3: Serum Phosphorous and Calcium Levels at Study Initiation and After Completion of Each Treatment Arm Parameter Pre-Study Post-Treatment p-value ANOVA of calcium acetate vs. placebo after 2 weeks of treatment. Calcium Acetate Placebo Phosphorus (mg/dL) Values expressed as mean ± SEM. 7.3 ± 0.18 5.9 ± 0.24 7.8 ± 0.22 <0.01 Calcium (mg/dL) 8.9 ± 0.11 9.5 ± 0.13 8.8 ± 0.12 <0.01 Overall, 2 weeks of treatment with calcium acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum calcium by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

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 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.

8.2 Labor and Delivery The effects of calcium acetate on labor and delivery are unknown.

8.3 Nursing Mothers Calcium acetate capsules contains calcium acetate and is excreted in human milk. Human milk feeding by a mother receiving calcium acetate 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.

8.1 Pregnancy Pregnancy Category C : Calcium acetate capsules contains calcium acetate. Animal reproduction studies have not been conducted with calcium acetate, and there are no adequate and well controlled studies of calcium acetate 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 treatment, as recommended, is not expected to harm a fetus if maternal calcium levels are properly monitored during and following treatment.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C : Calcium acetate capsules contains calcium acetate. Animal reproduction studies have not been conducted with calcium acetate, and there are no adequate and well controlled studies of calcium acetate 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 treatment, as recommended, is not expected to harm a fetus if maternal calcium levels are properly monitored during and following treatment. 8.2 Labor and Delivery The effects of calcium acetate on labor and delivery are unknown. 8.3 Nursing Mothers Calcium acetate capsules contains calcium acetate and is excreted in human milk. Human milk feeding by a mother receiving calcium acetate 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 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Calcium Acetate Capsules, USP 667 mg capsule is supplied as a white opaque/blue opaque capsule imprinted with “54 215” on the cap and body. Unit dose packages of 100 (10 x 10) NDC 68084-479-01 Storage Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]