ADVERSE REACTIONS SECTION.


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 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). 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 3-month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of calcium acetate was studied in 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 HemodialysisPreferred TermTotal advers reactions reported for calcium acetate n=167n (%)3-mo, open-label study ofcalcium acetate n=98n (%)Double blind, placebo-controlled,cross-over study of liquid calciumacetaten=69Calcium acetaten (%)Placebon (%)Nausea6 (3.6)6 (6.1)0 (0)0 (0)Vomiting4 (2.4)4 (4.1)0 (0)0 (0)Hypercalcemia21 (12.6)16 (16.3)5 (7.2)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 population of uncertain size, it is not always possible to estimate their frequency or to establish causal relationship to drug exposure.The following additional adverse reactions have been identified during post-approval of calcium acetate: dizziness, edema, and weakness.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


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

CLINICAL PHARMACOLOGY SECTION.


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 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.

CLINICAL STUDIES SECTION.


6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 3-month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of calcium acetate was studied in 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 HemodialysisPreferred TermTotal advers reactions reported for calcium acetate n=167n (%)3-mo, open-label study ofcalcium acetate n=98n (%)Double blind, placebo-controlled,cross-over study of liquid calciumacetaten=69Calcium acetaten (%)Placebon (%)Nausea6 (3.6)6 (6.1)0 (0)0 (0)Vomiting4 (2.4)4 (4.1)0 (0)0 (0)Hypercalcemia21 (12.6)16 (16.3)5 (7.2)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.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS Patients with hypercalcemia.. Patients with hypercalcemia.. Hype rcalcemia. (4). Hype rcalcemia. (4).

DESCRIPTION SECTION.


11 DESCRIPTION Calcium acetate, USP acts as phosphate binder. Its chemical name is calcium acetate. Its molecular formula is C4H6CaO4, and its molecular weight is 158.17. Its structural formula is:Each capsule has light-blue cap imprinted with ECI and white body imprinted with 825 with black ink. Each capsule contains 667 mg calcium acetate, USP (anhydrous; Ca(CH3COO)2; MW=158 .17 grams) equal to 169 mg (8.45 mEq) calcium and magnesium stearate. Each capsule also contains the following inactive ingredients: FD&C Blue 1, FD&C Red 3, gelatin and titanium dioxide.Calcium acetate capsules are administered orally for the control of hyperphosphatemia in end-stage renal failure.. The structural formula for Calcium acetate, USP acts as phosphate binder. Its chemical name is calcium acetate. Its molecular formula is C4H6CaO4, and its molecular weight is 158.17.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION The recommended initial dose of calcium acetate, USP for the adult dialysis patient is 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 to capsules with each meal.. Starting dose is capsules with each meal. (2) Titrate the dose every to weeks until acceptable serum phosphorus level is reached. Most patients require to capsules with each meal. (2). Starting dose is capsules with each meal. (2) Titrate the dose every to weeks until acceptable serum phosphorus level is reached. Most patients require to capsules with each meal. (2).

DOSAGE FORMS & STRENGTHS SECTION.


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

DRUG INTERACTIONS SECTION.


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 or calcium acetate capsules and most concomitant drugs. When administering an oral medication with calcium acetate capsules where reduction in the bioavailability of that medication would have 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 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 tetracycline or fluoroquinolone s. (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). Calcium acetate may decrease the bioavailability of tetracycline or fluoroquinolone s. (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 study of 15 healthy subjects, co-administered single dose of calcium acetate tablets, approximately 2.7 g, decreased the bioavailability of ciprofloxacin by approximately 50%.

GERIATRIC USE SECTION.


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.

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/ST ORAGE AND HANDLING Calcium Acetate Capsules, 667 mg are hard gelatin capsules with white opaque body imprinted with 825 and blue opaque cap imprinted with ECI with black ink. Each capsule contains 667 mg calcium acetate, USP (anhydrous; Ca(CH3COO)2; MW=158 .17 grams) equal to 169 mg (8.45 mEq) calcium.They are available as follows:Bottles of 200: NDC 10135-0629-02STORAGE: Store at 20 to 25C (68 to 77F); excursions permitted to 15 to 30C (59 to 86F) [See USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE Calcium acetate, USP is phosphate binder indicated to reduce serum phosphorus in patients with end stage renal disease (ESRD).. Calcium acetate, USP is phosphate binder indicated for the reduction of serum phosphorus in patients with end stage renal disease. (1). Calcium acetate, USP is phosphate binder indicated for the reduction of serum phosphorus in patients with end stage renal disease. (1).

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION Inform patients to take calcium acetate with meals, adhere to their prescribed diets, and avoid the use of calcium 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 calcium acetate.Manufactured For and Distributed By: Marlex Pharmaceuticals, Inc. New Castle, DE 19720Rev.1 12/17ECI.

LABOR & DELIVERY SECTION.


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

MECHANISM OF ACTION SECTION.


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.

NONCLINICAL TOXICOLOGY SECTION.


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

NURSING MOTHERS SECTION.


8.3 Nursing Mothers Calcium acetate capsules contain calcium acetate and is excreted in human milk. Human milk feeding by mother receiving calcium acetate is not expected to harm an infant, provided maternal serum calcium levels are appropriately monitored.

OVERDOSAGE SECTION.


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

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PACKAGE LABEL PRINCIPAL DISPLAY PANELNDC 10135-0629-02Calcium Acetate Capsules667 mgRx Only200 Capsules. PACKAGE LABEL PRINCIPAL DISPLAY PANELNDC 10135-0629-02Calcium Acetate Capsules667 mgRx Only200 Capsules.

PEDIATRIC USE SECTION.


8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

PHARMACODYNAMICS SECTION.


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.

POSTMARKETING EXPERIENCE SECTION.


6.2 Postmarketing Experience Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to estimate their frequency or to establish causal relationship to drug exposure.The following additional adverse reactions have been identified during post-approval of calcium acetate: dizziness, edema, and weakness.

PREGNANCY SECTION.


8.1 Pregnancy Pregnancy Category CCalcium acetate capsules contain 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 fetus if maternal calcium levels are properly monitored during and following treatment.

SPL UNCLASSIFIED SECTION.


5.1 Hypercalcemia Patients with end stage renal disease may develop hypercalcemia when treated with calcium, including calcium acetate. Avoid the use of calcium supplements, including calcium-based nonprescription antacids, concurrently with calcium acetate.An overdose of calcium acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum calcium levels twice weekly. Should hypercalcemia develop, reduce the calcium 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 calcium 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 calcium acetate dose or temporarily discontinuing therapy. Decreasing or discontinuing Vitamin 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 calcium 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 3-month study of solid dose formulation of calcium acetate; all cases resolved upon lowering the dose or discontinuing treatment.Maintain the serum calcium-phosphorus (Ca P) product below 55 mg2/dL2.

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category CCalcium acetate capsules contain 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 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 contain calcium acetate and is excreted in human milk. Human milk feeding by 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.

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS Treat mild hypercalcemia by reducing or interrupting calcium acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of calcium acetate. (5.1) Hype rcalcemia may aggravate digitalis toxicity. (5.2). Treat mild hypercalcemia by reducing or interrupting calcium acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of calcium acetate. (5.1) Hype rcalcemia may aggravate digitalis toxicity. (5.2). 5.1 Hypercalcemia Patients with end stage renal disease may develop hypercalcemia when treated with calcium, including calcium acetate. Avoid the use of calcium supplements, including calcium-based nonprescription antacids, concurrently with calcium acetate.An overdose of calcium acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum calcium levels twice weekly. Should hypercalcemia develop, reduce the calcium 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 calcium 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 calcium acetate dose or temporarily discontinuing therapy. Decreasing or discontinuing Vitamin 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 calcium 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 3-month study of solid dose formulation of calcium acetate; all cases resolved upon lowering the dose or discontinuing treatment.Maintain the serum calcium-phosphorus (Ca P) product below 55 mg2/dL2.. 5.2 Concomitant Use with Medications Hypercalcemia may aggravate digitalis toxicity.