Calcium; Vitamin D3

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Calcium; Vitamin D3 uses

Calcium; Vitamin D3 consists of Calcium (Calcium Carbonate), Calcium (Calcium Citrate), Calcium (Calcium Fumarate), Calcium (Calcium Glutarate), Calcium (Calcium Malate), Calcium (Calcium Succinate), Vitamin D3.

Calcium (Calcium Carbonate):


1 INDICATIONS AND USAGE

Calcium; Vitamin D3 (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 Calcium; Vitamin D3 (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 Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate capsule.

- Capsule: 667 mg Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Calcium; Vitamin D3 ) acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Calcium; Vitamin D3 (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 Calcium; Vitamin D3 (Calcium (Calcium Carbonate)), including Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate. Avoid the use of Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) supplements, including Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) based nonprescription antacids, concurrently with Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate.

An overdose of Calcium; Vitamin D3 (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 Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) levels twice weekly. Should hypercalcemia develop, reduce the Calcium; Vitamin D3 (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 Calcium; Vitamin D3 (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 Calcium; Vitamin D3 (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 Calcium; Vitamin D3 (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 Calcium; Vitamin D3 (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.

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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 Calcium; Vitamin D3 (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, Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate has been generally well tolerated.

Calcium; Vitamin D3 (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 Calcium; Vitamin D3 (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.


Preferred Term


Total adverse reactions reported for Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate

N=167

N (%)


3 month, open label study of Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate

N=98

N (%)


Double blind, placebo-controlled, cross-over study of liquid Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate

N=69


Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate

N (%)


Placebo

N (%)


Nausea


6 (3.6)


6 (6.1)


0 (0)


0 (0)


Vomiting


4 (2.4)


4 (4.1)


0 (0)


0 (0)


Hypercalcemia


21 (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; Vitamin D3 (Calcium (Calcium Carbonate)) concentration could reduce the incidence and severity of Calcium; Vitamin D3 (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 Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate: dizziness, edema, and weakness.

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7 DRUG INTERACTIONS

The drug interaction of Calcium; Vitamin D3 ) acetate is characterized by the potential of Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Calcium; Vitamin D3 (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 Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate and most concomitant drugs. When administering an oral medication with Calcium; Vitamin D3 (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 Calcium; Vitamin D3 (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 Calcium; Vitamin D3 (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 Calcium; Vitamin D3 (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 Calcium; Vitamin D3 (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:

Calcium; Vitamin D3 ) acetate capsules contains Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate. Animal reproduction studies have not been conducted with Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate, and there are no adequate and well controlled studies of Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Calcium; Vitamin D3 (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. Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate treatment, as recommended, is not expected to harm a fetus if maternal Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Calcium; Vitamin D3 ) Acetate Capsules contains Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate and is excreted in human milk. Human milk feeding by a mother receiving Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate is not expected to harm an infant, provided maternal serum Calcium; Vitamin D3 (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 Calcium; Vitamin D3 (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.

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10 OVERDOSAGE

Administration of Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate acts as a phosphate binder. Its chemical name is Calcium; Vitamin D3 (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 Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate USP (anhydrous; Ca(CH3COO)2; MW=158.17 grams) equal to 169 mg (8.45 mEq) Calcium; Vitamin D3 (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.

Calcium; Vitamin D3 (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 Calcium; Vitamin D3 ) 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; Vitamin D3 (Calcium (Calcium Carbonate)) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Calcium; Vitamin D3 (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.

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13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate.

14 CLINICAL STUDIES

Effectiveness of Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Calcium; Vitamin D3 (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 Calcium; Vitamin D3 (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 Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) levels are also presented.


* Ninety-one patients completed at least 6 weeks of the study.

ANOVA of difference in values at pre-study and study completion.

‡ Values expressed as mean ± SE.


Parameter


Pre-Study


Week 4*


Week 8


Week 12


p-value†


Phosphorus (mg/dL)‡


7.4 ± 0.17


5.9 ± 0.16


5.6 ± 0.17


5.2 ± 0.17


≤0.01


Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) (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; Vitamin D3 (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 Calcium; Vitamin D3 (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 Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate is shown in the Table 3.


* ANOVA of Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate vs. placebo after 2 weeks of treatment.

Values expressed as mean ± SEM.


Parameter


Pre-Study


Post-Treatment


p-value*


Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) Acetate


Placebo


Phosphorus (mg/dL)


7.3 ± 0.18


5.9 ± 0.24


7.8 ± 0.22


<0.01


Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) (mg/dL)


8.9 ± 0.11


9.5 ± 0.13


8.8 ± 0.12


<0.01


Overall, 2 weeks of treatment with Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Calcium; Vitamin D3 (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 Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Calcium; Vitamin D3 (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 Calcium; Vitamin D3 (Calcium (Calcium Carbonate)) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Calcium (Calcium Citrate):


1 INDICATIONS AND USAGE

Calcium; Vitamin D3 (Calcium (Calcium Citrate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Citrate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Citrate)) acetate capsule.

- Capsule: 667 mg Calcium; Vitamin D3 (Calcium (Calcium Citrate)) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Calcium; Vitamin D3 ) acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Calcium; Vitamin D3 (Calcium (Calcium Citrate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Citrate)), including Calcium; Vitamin D3 (Calcium (Calcium Citrate)) acetate. Avoid the use of Calcium; Vitamin D3 (Calcium (Calcium Citrate)) supplements, including Calcium; Vitamin D3 (Calcium (Calcium Citrate)) based nonprescription antacids, concurrently with Calcium; Vitamin D3 (Calcium (Calcium Citrate)) acetate.

An overdose of Calcium; Vitamin D3 (Calcium (Calcium Citrate)) 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; Vitamin D3 (Calcium (Calcium Citrate)) levels twice weekly. Should hypercalcemia develop, reduce the Calcium; Vitamin D3 (Calcium (Calcium Citrate)) 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; Vitamin D3 (Calcium (Calcium Citrate)) 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; Vitamin D3 (Calcium (Calcium Citrate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Citrate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Citrate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Citrate)) 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, Calcium; Vitamin D3 (Calcium (Calcium Citrate)) acetate has been generally well tolerated.

Calcium; Vitamin D3 (Calcium (Calcium Citrate)) 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; Vitamin D3 (Calcium (Calcium Citrate)) 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.


Preferred Term


Total adverse reactions reported for Calcium; Vitamin D3 (Calcium (Calcium Citrate)) acetate

N=167

N (%)


3 month, open label study of Calcium; Vitamin D3 (Calcium (Calcium Citrate)) acetate

N=98

N (%)


Double blind, placebo-controlled, cross-over study of liquid Calcium; Vitamin D3 (Calcium (Calcium Citrate)) acetate

N=69


Calcium; Vitamin D3 (Calcium (Calcium Citrate)) acetate

N (%)


Placebo

N (%)


Nausea


6 (3.6)


6 (6.1)


0 (0)


0 (0)


Vomiting


4 (2.4)


4 (4.1)


0 (0)


0 (0)


Hypercalcemia


21 (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; Vitamin D3 (Calcium (Calcium Citrate)) concentration could reduce the incidence and severity of Calcium; Vitamin D3 (Calcium (Calcium Citrate)) 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; Vitamin D3 (Calcium (Calcium Citrate)) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of Calcium; Vitamin D3 ) acetate is characterized by the potential of Calcium; Vitamin D3 (Calcium (Calcium Citrate)) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Calcium; Vitamin D3 (Calcium (Calcium Citrate)) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between Calcium; Vitamin D3 (Calcium (Calcium Citrate)) acetate and most concomitant drugs. When administering an oral medication with Calcium; Vitamin D3 (Calcium (Calcium Citrate)) 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; Vitamin D3 (Calcium (Calcium Citrate)) 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; Vitamin D3 (Calcium (Calcium Citrate)) 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; Vitamin D3 (Calcium (Calcium Citrate)) 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; Vitamin D3 (Calcium (Calcium Citrate)) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

Calcium; Vitamin D3 ) acetate capsules contains Calcium; Vitamin D3 (Calcium (Calcium Citrate)) acetate. Animal reproduction studies have not been conducted with Calcium; Vitamin D3 (Calcium (Calcium Citrate)) acetate, and there are no adequate and well controlled studies of Calcium; Vitamin D3 (Calcium (Calcium Citrate)) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Calcium; Vitamin D3 (Calcium (Calcium Citrate)) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Calcium; Vitamin D3 (Calcium (Calcium Citrate)) 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; Vitamin D3 (Calcium (Calcium Citrate)) acetate treatment, as recommended, is not expected to harm a fetus if maternal Calcium; Vitamin D3 (Calcium (Calcium Citrate)) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Calcium; Vitamin D3 (Calcium (Calcium Citrate)) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Calcium; Vitamin D3 ) Acetate Capsules contains Calcium; Vitamin D3 (Calcium (Calcium Citrate)) acetate and is excreted in human milk. Human milk feeding by a mother receiving Calcium; Vitamin D3 (Calcium (Calcium Citrate)) acetate is not expected to harm an infant, provided maternal serum Calcium; Vitamin D3 (Calcium (Calcium Citrate)) 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; Vitamin D3 (Calcium (Calcium Citrate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Citrate)) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Calcium; Vitamin D3 (Calcium (Calcium Citrate)) acetate acts as a phosphate binder. Its chemical name is Calcium; Vitamin D3 (Calcium (Calcium Citrate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Citrate)) acetate USP (anhydrous; Ca(CH3COO)2; MW=158.17 grams) equal to 169 mg (8.45 mEq) Calcium; Vitamin D3 (Calcium (Calcium Citrate)), 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; Vitamin D3 (Calcium (Calcium Citrate)) 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 Calcium; Vitamin D3 ) 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; Vitamin D3 (Calcium (Calcium Citrate)) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Calcium; Vitamin D3 (Calcium (Calcium Citrate)) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Calcium; Vitamin D3 (Calcium (Calcium Citrate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Citrate)) acetate.

14 CLINICAL STUDIES

Effectiveness of Calcium; Vitamin D3 (Calcium (Calcium Citrate)) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Calcium; Vitamin D3 (Calcium (Calcium Citrate)) 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; Vitamin D3 (Calcium (Calcium Citrate)) 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; Vitamin D3 (Calcium (Calcium Citrate)) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Calcium; Vitamin D3 (Calcium (Calcium Citrate)) levels are also presented.


* Ninety-one patients completed at least 6 weeks of the study.

ANOVA of difference in values at pre-study and study completion.

‡ Values expressed as mean ± SE.


Parameter


Pre-Study


Week 4*


Week 8


Week 12


p-value†


Phosphorus (mg/dL)‡


7.4 ± 0.17


5.9 ± 0.16


5.6 ± 0.17


5.2 ± 0.17


≤0.01


Calcium; Vitamin D3 (Calcium (Calcium Citrate)) (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; Vitamin D3 (Calcium (Calcium Citrate)) 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; Vitamin D3 (Calcium (Calcium Citrate)) 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; Vitamin D3 (Calcium (Calcium Citrate)) acetate is shown in the Table 3.


* ANOVA of Calcium; Vitamin D3 (Calcium (Calcium Citrate)) acetate vs. placebo after 2 weeks of treatment.

Values expressed as mean ± SEM.


Parameter


Pre-Study


Post-Treatment


p-value*


Calcium; Vitamin D3 (Calcium (Calcium Citrate)) Acetate


Placebo


Phosphorus (mg/dL)


7.3 ± 0.18


5.9 ± 0.24


7.8 ± 0.22


<0.01


Calcium; Vitamin D3 (Calcium (Calcium Citrate)) (mg/dL)


8.9 ± 0.11


9.5 ± 0.13


8.8 ± 0.12


<0.01


Overall, 2 weeks of treatment with Calcium; Vitamin D3 (Calcium (Calcium Citrate)) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Calcium; Vitamin D3 (Calcium (Calcium Citrate)) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Calcium; Vitamin D3 (Calcium (Calcium Citrate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Citrate)) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Calcium; Vitamin D3 (Calcium (Calcium Citrate)) 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; Vitamin D3 (Calcium (Calcium Citrate)) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Calcium (Calcium Fumarate):


1 INDICATIONS AND USAGE

Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate capsule.

- Capsule: 667 mg Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Calcium; Vitamin D3 ) acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Fumarate)), including Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate. Avoid the use of Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) supplements, including Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) based nonprescription antacids, concurrently with Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate.

An overdose of Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) 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; Vitamin D3 (Calcium (Calcium Fumarate)) levels twice weekly. Should hypercalcemia develop, reduce the Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) 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; Vitamin D3 (Calcium (Calcium Fumarate)) 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; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) 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, Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate has been generally well tolerated.

Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) 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; Vitamin D3 (Calcium (Calcium Fumarate)) 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.


Preferred Term


Total adverse reactions reported for Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate

N=167

N (%)


3 month, open label study of Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate

N=98

N (%)


Double blind, placebo-controlled, cross-over study of liquid Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate

N=69


Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate

N (%)


Placebo

N (%)


Nausea


6 (3.6)


6 (6.1)


0 (0)


0 (0)


Vomiting


4 (2.4)


4 (4.1)


0 (0)


0 (0)


Hypercalcemia


21 (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; Vitamin D3 (Calcium (Calcium Fumarate)) concentration could reduce the incidence and severity of Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) 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; Vitamin D3 (Calcium (Calcium Fumarate)) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of Calcium; Vitamin D3 ) acetate is characterized by the potential of Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate and most concomitant drugs. When administering an oral medication with Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) 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; Vitamin D3 (Calcium (Calcium Fumarate)) 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; Vitamin D3 (Calcium (Calcium Fumarate)) 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; Vitamin D3 (Calcium (Calcium Fumarate)) 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; Vitamin D3 (Calcium (Calcium Fumarate)) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

Calcium; Vitamin D3 ) acetate capsules contains Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate. Animal reproduction studies have not been conducted with Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate, and there are no adequate and well controlled studies of Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) 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; Vitamin D3 (Calcium (Calcium Fumarate)) acetate treatment, as recommended, is not expected to harm a fetus if maternal Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Calcium; Vitamin D3 ) Acetate Capsules contains Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate and is excreted in human milk. Human milk feeding by a mother receiving Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate is not expected to harm an infant, provided maternal serum Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) 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; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate acts as a phosphate binder. Its chemical name is Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate USP (anhydrous; Ca(CH3COO)2; MW=158.17 grams) equal to 169 mg (8.45 mEq) Calcium; Vitamin D3 (Calcium (Calcium Fumarate)), 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; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Vitamin D3 ) 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; Vitamin D3 (Calcium (Calcium Fumarate)) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate.

14 CLINICAL STUDIES

Effectiveness of Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) 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; Vitamin D3 (Calcium (Calcium Fumarate)) 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; Vitamin D3 (Calcium (Calcium Fumarate)) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) levels are also presented.


* Ninety-one patients completed at least 6 weeks of the study.

ANOVA of difference in values at pre-study and study completion.

‡ Values expressed as mean ± SE.


Parameter


Pre-Study


Week 4*


Week 8


Week 12


p-value†


Phosphorus (mg/dL)‡


7.4 ± 0.17


5.9 ± 0.16


5.6 ± 0.17


5.2 ± 0.17


≤0.01


Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) (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; Vitamin D3 (Calcium (Calcium Fumarate)) 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; Vitamin D3 (Calcium (Calcium Fumarate)) 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; Vitamin D3 (Calcium (Calcium Fumarate)) acetate is shown in the Table 3.


* ANOVA of Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate vs. placebo after 2 weeks of treatment.

Values expressed as mean ± SEM.


Parameter


Pre-Study


Post-Treatment


p-value*


Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) Acetate


Placebo


Phosphorus (mg/dL)


7.3 ± 0.18


5.9 ± 0.24


7.8 ± 0.22


<0.01


Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) (mg/dL)


8.9 ± 0.11


9.5 ± 0.13


8.8 ± 0.12


<0.01


Overall, 2 weeks of treatment with Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Calcium; Vitamin D3 (Calcium (Calcium Fumarate)) 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; Vitamin D3 (Calcium (Calcium Fumarate)) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Calcium (Calcium Glutarate):


1 INDICATIONS AND USAGE

Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate capsule.

- Capsule: 667 mg Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Calcium; Vitamin D3 ) acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Glutarate)), including Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate. Avoid the use of Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) supplements, including Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) based nonprescription antacids, concurrently with Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate.

An overdose of Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) 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; Vitamin D3 (Calcium (Calcium Glutarate)) levels twice weekly. Should hypercalcemia develop, reduce the Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) 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; Vitamin D3 (Calcium (Calcium Glutarate)) 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; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) 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, Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate has been generally well tolerated.

Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) 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; Vitamin D3 (Calcium (Calcium Glutarate)) 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.


Preferred Term


Total adverse reactions reported for Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate

N=167

N (%)


3 month, open label study of Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate

N=98

N (%)


Double blind, placebo-controlled, cross-over study of liquid Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate

N=69


Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate

N (%)


Placebo

N (%)


Nausea


6 (3.6)


6 (6.1)


0 (0)


0 (0)


Vomiting


4 (2.4)


4 (4.1)


0 (0)


0 (0)


Hypercalcemia


21 (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; Vitamin D3 (Calcium (Calcium Glutarate)) concentration could reduce the incidence and severity of Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) 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; Vitamin D3 (Calcium (Calcium Glutarate)) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of Calcium; Vitamin D3 ) acetate is characterized by the potential of Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate and most concomitant drugs. When administering an oral medication with Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) 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; Vitamin D3 (Calcium (Calcium Glutarate)) 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; Vitamin D3 (Calcium (Calcium Glutarate)) 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; Vitamin D3 (Calcium (Calcium Glutarate)) 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; Vitamin D3 (Calcium (Calcium Glutarate)) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

Calcium; Vitamin D3 ) acetate capsules contains Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate. Animal reproduction studies have not been conducted with Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate, and there are no adequate and well controlled studies of Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) 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; Vitamin D3 (Calcium (Calcium Glutarate)) acetate treatment, as recommended, is not expected to harm a fetus if maternal Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Calcium; Vitamin D3 ) Acetate Capsules contains Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate and is excreted in human milk. Human milk feeding by a mother receiving Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate is not expected to harm an infant, provided maternal serum Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) 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; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate acts as a phosphate binder. Its chemical name is Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate USP (anhydrous; Ca(CH3COO)2; MW=158.17 grams) equal to 169 mg (8.45 mEq) Calcium; Vitamin D3 (Calcium (Calcium Glutarate)), 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; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Vitamin D3 ) 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; Vitamin D3 (Calcium (Calcium Glutarate)) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate.

14 CLINICAL STUDIES

Effectiveness of Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) 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; Vitamin D3 (Calcium (Calcium Glutarate)) 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; Vitamin D3 (Calcium (Calcium Glutarate)) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) levels are also presented.


* Ninety-one patients completed at least 6 weeks of the study.

ANOVA of difference in values at pre-study and study completion.

‡ Values expressed as mean ± SE.


Parameter


Pre-Study


Week 4*


Week 8


Week 12


p-value†


Phosphorus (mg/dL)‡


7.4 ± 0.17


5.9 ± 0.16


5.6 ± 0.17


5.2 ± 0.17


≤0.01


Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) (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; Vitamin D3 (Calcium (Calcium Glutarate)) 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; Vitamin D3 (Calcium (Calcium Glutarate)) 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; Vitamin D3 (Calcium (Calcium Glutarate)) acetate is shown in the Table 3.


* ANOVA of Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate vs. placebo after 2 weeks of treatment.

Values expressed as mean ± SEM.


Parameter


Pre-Study


Post-Treatment


p-value*


Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) Acetate


Placebo


Phosphorus (mg/dL)


7.3 ± 0.18


5.9 ± 0.24


7.8 ± 0.22


<0.01


Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) (mg/dL)


8.9 ± 0.11


9.5 ± 0.13


8.8 ± 0.12


<0.01


Overall, 2 weeks of treatment with Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Calcium; Vitamin D3 (Calcium (Calcium Glutarate)) 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; Vitamin D3 (Calcium (Calcium Glutarate)) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Calcium (Calcium Malate):


1 INDICATIONS AND USAGE

Calcium; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Malate)) acetate capsule.

- Capsule: 667 mg Calcium; Vitamin D3 (Calcium (Calcium Malate)) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Calcium; Vitamin D3 ) acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Calcium; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Malate)), including Calcium; Vitamin D3 (Calcium (Calcium Malate)) acetate. Avoid the use of Calcium; Vitamin D3 (Calcium (Calcium Malate)) supplements, including Calcium; Vitamin D3 (Calcium (Calcium Malate)) based nonprescription antacids, concurrently with Calcium; Vitamin D3 (Calcium (Calcium Malate)) acetate.

An overdose of Calcium; Vitamin D3 (Calcium (Calcium Malate)) 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; Vitamin D3 (Calcium (Calcium Malate)) levels twice weekly. Should hypercalcemia develop, reduce the Calcium; Vitamin D3 (Calcium (Calcium Malate)) 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; Vitamin D3 (Calcium (Calcium Malate)) 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; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Malate)) 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, Calcium; Vitamin D3 (Calcium (Calcium Malate)) acetate has been generally well tolerated.

Calcium; Vitamin D3 (Calcium (Calcium Malate)) 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; Vitamin D3 (Calcium (Calcium Malate)) 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.


Preferred Term


Total adverse reactions reported for Calcium; Vitamin D3 (Calcium (Calcium Malate)) acetate

N=167

N (%)


3 month, open label study of Calcium; Vitamin D3 (Calcium (Calcium Malate)) acetate

N=98

N (%)


Double blind, placebo-controlled, cross-over study of liquid Calcium; Vitamin D3 (Calcium (Calcium Malate)) acetate

N=69


Calcium; Vitamin D3 (Calcium (Calcium Malate)) acetate

N (%)


Placebo

N (%)


Nausea


6 (3.6)


6 (6.1)


0 (0)


0 (0)


Vomiting


4 (2.4)


4 (4.1)


0 (0)


0 (0)


Hypercalcemia


21 (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; Vitamin D3 (Calcium (Calcium Malate)) concentration could reduce the incidence and severity of Calcium; Vitamin D3 (Calcium (Calcium Malate)) 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; Vitamin D3 (Calcium (Calcium Malate)) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of Calcium; Vitamin D3 ) acetate is characterized by the potential of Calcium; Vitamin D3 (Calcium (Calcium Malate)) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Calcium; Vitamin D3 (Calcium (Calcium Malate)) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between Calcium; Vitamin D3 (Calcium (Calcium Malate)) acetate and most concomitant drugs. When administering an oral medication with Calcium; Vitamin D3 (Calcium (Calcium Malate)) 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; Vitamin D3 (Calcium (Calcium Malate)) 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; Vitamin D3 (Calcium (Calcium Malate)) 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; Vitamin D3 (Calcium (Calcium Malate)) 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; Vitamin D3 (Calcium (Calcium Malate)) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

Calcium; Vitamin D3 ) acetate capsules contains Calcium; Vitamin D3 (Calcium (Calcium Malate)) acetate. Animal reproduction studies have not been conducted with Calcium; Vitamin D3 (Calcium (Calcium Malate)) acetate, and there are no adequate and well controlled studies of Calcium; Vitamin D3 (Calcium (Calcium Malate)) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Calcium; Vitamin D3 (Calcium (Calcium Malate)) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Calcium; Vitamin D3 (Calcium (Calcium Malate)) 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; Vitamin D3 (Calcium (Calcium Malate)) acetate treatment, as recommended, is not expected to harm a fetus if maternal Calcium; Vitamin D3 (Calcium (Calcium Malate)) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Calcium; Vitamin D3 (Calcium (Calcium Malate)) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Calcium; Vitamin D3 ) Acetate Capsules contains Calcium; Vitamin D3 (Calcium (Calcium Malate)) acetate and is excreted in human milk. Human milk feeding by a mother receiving Calcium; Vitamin D3 (Calcium (Calcium Malate)) acetate is not expected to harm an infant, provided maternal serum Calcium; Vitamin D3 (Calcium (Calcium Malate)) 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; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Malate)) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Calcium; Vitamin D3 (Calcium (Calcium Malate)) acetate acts as a phosphate binder. Its chemical name is Calcium; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Malate)) acetate USP (anhydrous; Ca(CH3COO)2; MW=158.17 grams) equal to 169 mg (8.45 mEq) Calcium; Vitamin D3 (Calcium (Calcium Malate)), 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; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Vitamin D3 ) 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; Vitamin D3 (Calcium (Calcium Malate)) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Calcium; Vitamin D3 (Calcium (Calcium Malate)) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Calcium; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Malate)) acetate.

14 CLINICAL STUDIES

Effectiveness of Calcium; Vitamin D3 (Calcium (Calcium Malate)) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Calcium; Vitamin D3 (Calcium (Calcium Malate)) 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; Vitamin D3 (Calcium (Calcium Malate)) 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; Vitamin D3 (Calcium (Calcium Malate)) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Calcium; Vitamin D3 (Calcium (Calcium Malate)) levels are also presented.


* Ninety-one patients completed at least 6 weeks of the study.

ANOVA of difference in values at pre-study and study completion.

‡ Values expressed as mean ± SE.


Parameter


Pre-Study


Week 4*


Week 8


Week 12


p-value†


Phosphorus (mg/dL)‡


7.4 ± 0.17


5.9 ± 0.16


5.6 ± 0.17


5.2 ± 0.17


≤0.01


Calcium; Vitamin D3 (Calcium (Calcium Malate)) (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; Vitamin D3 (Calcium (Calcium Malate)) 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; Vitamin D3 (Calcium (Calcium Malate)) 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; Vitamin D3 (Calcium (Calcium Malate)) acetate is shown in the Table 3.


* ANOVA of Calcium; Vitamin D3 (Calcium (Calcium Malate)) acetate vs. placebo after 2 weeks of treatment.

Values expressed as mean ± SEM.


Parameter


Pre-Study


Post-Treatment


p-value*


Calcium; Vitamin D3 (Calcium (Calcium Malate)) Acetate


Placebo


Phosphorus (mg/dL)


7.3 ± 0.18


5.9 ± 0.24


7.8 ± 0.22


<0.01


Calcium; Vitamin D3 (Calcium (Calcium Malate)) (mg/dL)


8.9 ± 0.11


9.5 ± 0.13


8.8 ± 0.12


<0.01


Overall, 2 weeks of treatment with Calcium; Vitamin D3 (Calcium (Calcium Malate)) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Calcium; Vitamin D3 (Calcium (Calcium Malate)) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Calcium; Vitamin D3 (Calcium (Calcium Malate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Malate)) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Calcium; Vitamin D3 (Calcium (Calcium Malate)) 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; Vitamin D3 (Calcium (Calcium Malate)) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Calcium (Calcium Succinate):


1 INDICATIONS AND USAGE

Calcium; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Succinate)) acetate capsule.

- Capsule: 667 mg Calcium; Vitamin D3 (Calcium (Calcium Succinate)) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Calcium; Vitamin D3 ) acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Calcium; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Succinate)), including Calcium; Vitamin D3 (Calcium (Calcium Succinate)) acetate. Avoid the use of Calcium; Vitamin D3 (Calcium (Calcium Succinate)) supplements, including Calcium; Vitamin D3 (Calcium (Calcium Succinate)) based nonprescription antacids, concurrently with Calcium; Vitamin D3 (Calcium (Calcium Succinate)) acetate.

An overdose of Calcium; Vitamin D3 (Calcium (Calcium Succinate)) 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; Vitamin D3 (Calcium (Calcium Succinate)) levels twice weekly. Should hypercalcemia develop, reduce the Calcium; Vitamin D3 (Calcium (Calcium Succinate)) 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; Vitamin D3 (Calcium (Calcium Succinate)) 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; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Succinate)) 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, Calcium; Vitamin D3 (Calcium (Calcium Succinate)) acetate has been generally well tolerated.

Calcium; Vitamin D3 (Calcium (Calcium Succinate)) 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; Vitamin D3 (Calcium (Calcium Succinate)) 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.


Preferred Term


Total adverse reactions reported for Calcium; Vitamin D3 (Calcium (Calcium Succinate)) acetate

N=167

N (%)


3 month, open label study of Calcium; Vitamin D3 (Calcium (Calcium Succinate)) acetate

N=98

N (%)


Double blind, placebo-controlled, cross-over study of liquid Calcium; Vitamin D3 (Calcium (Calcium Succinate)) acetate

N=69


Calcium; Vitamin D3 (Calcium (Calcium Succinate)) acetate

N (%)


Placebo

N (%)


Nausea


6 (3.6)


6 (6.1)


0 (0)


0 (0)


Vomiting


4 (2.4)


4 (4.1)


0 (0)


0 (0)


Hypercalcemia


21 (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; Vitamin D3 (Calcium (Calcium Succinate)) concentration could reduce the incidence and severity of Calcium; Vitamin D3 (Calcium (Calcium Succinate)) 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; Vitamin D3 (Calcium (Calcium Succinate)) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of Calcium; Vitamin D3 ) acetate is characterized by the potential of Calcium; Vitamin D3 (Calcium (Calcium Succinate)) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Calcium; Vitamin D3 (Calcium (Calcium Succinate)) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between Calcium; Vitamin D3 (Calcium (Calcium Succinate)) acetate and most concomitant drugs. When administering an oral medication with Calcium; Vitamin D3 (Calcium (Calcium Succinate)) 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; Vitamin D3 (Calcium (Calcium Succinate)) 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; Vitamin D3 (Calcium (Calcium Succinate)) 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; Vitamin D3 (Calcium (Calcium Succinate)) 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; Vitamin D3 (Calcium (Calcium Succinate)) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

Calcium; Vitamin D3 ) acetate capsules contains Calcium; Vitamin D3 (Calcium (Calcium Succinate)) acetate. Animal reproduction studies have not been conducted with Calcium; Vitamin D3 (Calcium (Calcium Succinate)) acetate, and there are no adequate and well controlled studies of Calcium; Vitamin D3 (Calcium (Calcium Succinate)) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Calcium; Vitamin D3 (Calcium (Calcium Succinate)) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Calcium; Vitamin D3 (Calcium (Calcium Succinate)) 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; Vitamin D3 (Calcium (Calcium Succinate)) acetate treatment, as recommended, is not expected to harm a fetus if maternal Calcium; Vitamin D3 (Calcium (Calcium Succinate)) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Calcium; Vitamin D3 (Calcium (Calcium Succinate)) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Calcium; Vitamin D3 ) Acetate Capsules contains Calcium; Vitamin D3 (Calcium (Calcium Succinate)) acetate and is excreted in human milk. Human milk feeding by a mother receiving Calcium; Vitamin D3 (Calcium (Calcium Succinate)) acetate is not expected to harm an infant, provided maternal serum Calcium; Vitamin D3 (Calcium (Calcium Succinate)) 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; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Succinate)) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Calcium; Vitamin D3 (Calcium (Calcium Succinate)) acetate acts as a phosphate binder. Its chemical name is Calcium; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Succinate)) acetate USP (anhydrous; Ca(CH3COO)2; MW=158.17 grams) equal to 169 mg (8.45 mEq) Calcium; Vitamin D3 (Calcium (Calcium Succinate)), 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; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Vitamin D3 ) 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; Vitamin D3 (Calcium (Calcium Succinate)) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Calcium; Vitamin D3 (Calcium (Calcium Succinate)) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Calcium; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Succinate)) acetate.

14 CLINICAL STUDIES

Effectiveness of Calcium; Vitamin D3 (Calcium (Calcium Succinate)) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Calcium; Vitamin D3 (Calcium (Calcium Succinate)) 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; Vitamin D3 (Calcium (Calcium Succinate)) 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; Vitamin D3 (Calcium (Calcium Succinate)) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Calcium; Vitamin D3 (Calcium (Calcium Succinate)) levels are also presented.


* Ninety-one patients completed at least 6 weeks of the study.

ANOVA of difference in values at pre-study and study completion.

‡ Values expressed as mean ± SE.


Parameter


Pre-Study


Week 4*


Week 8


Week 12


p-value†


Phosphorus (mg/dL)‡


7.4 ± 0.17


5.9 ± 0.16


5.6 ± 0.17


5.2 ± 0.17


≤0.01


Calcium; Vitamin D3 (Calcium (Calcium Succinate)) (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; Vitamin D3 (Calcium (Calcium Succinate)) 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; Vitamin D3 (Calcium (Calcium Succinate)) 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; Vitamin D3 (Calcium (Calcium Succinate)) acetate is shown in the Table 3.


* ANOVA of Calcium; Vitamin D3 (Calcium (Calcium Succinate)) acetate vs. placebo after 2 weeks of treatment.

Values expressed as mean ± SEM.


Parameter


Pre-Study


Post-Treatment


p-value*


Calcium; Vitamin D3 (Calcium (Calcium Succinate)) Acetate


Placebo


Phosphorus (mg/dL)


7.3 ± 0.18


5.9 ± 0.24


7.8 ± 0.22


<0.01


Calcium; Vitamin D3 (Calcium (Calcium Succinate)) (mg/dL)


8.9 ± 0.11


9.5 ± 0.13


8.8 ± 0.12


<0.01


Overall, 2 weeks of treatment with Calcium; Vitamin D3 (Calcium (Calcium Succinate)) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Calcium; Vitamin D3 (Calcium (Calcium Succinate)) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Calcium; Vitamin D3 (Calcium (Calcium Succinate)) 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 Calcium; Vitamin D3 (Calcium (Calcium Succinate)) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Calcium; Vitamin D3 (Calcium (Calcium Succinate)) 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; Vitamin D3 (Calcium (Calcium Succinate)) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Calcium; Vitamin D3 pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Calcium; Vitamin D3 available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Calcium; Vitamin D3 destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Calcium; Vitamin D3 Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Calcium; Vitamin D3 pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."CHOLECALCIFEROL: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."CALCIUM: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "Calcium". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Calcium; Vitamin D3?

Depending on the reaction of the Calcium; Vitamin D3 after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Calcium; Vitamin D3 not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Calcium; Vitamin D3 addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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sdrugs.com conducted a study on Calcium; Vitamin D3, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Calcium; Vitamin D3 consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Arunabha Ray, MD Pharmacology

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