Opti-Cal Chewable + D

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Opti-Cal Chewable + D uses

Opti-Cal Chewable + D consists of Calcium (Calcium Citrate), Calcium (Calcium Fumarate), Calcium (Calcium Glutarate), Calcium (Calcium Malate), Calcium (Calcium Succinate), Vitamin D3.

Calcium (Calcium Citrate):


1 INDICATIONS AND USAGE

Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Citrate)) acetate capsule.

- Capsule: 667 mg Opti-Cal Chewable + D (Calcium (Calcium Citrate)) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

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

An overdose of Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Citrate)) levels twice weekly. Should hypercalcemia develop, reduce the Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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.

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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 Opti-Cal Chewable + D (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, Opti-Cal Chewable + D (Calcium (Calcium Citrate)) acetate has been generally well tolerated.

Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Citrate)) acetate

N=167

N (%)


3 month, open label study of Opti-Cal Chewable + D (Calcium (Calcium Citrate)) acetate

N=98

N (%)


Double blind, placebo-controlled, cross-over study of liquid Opti-Cal Chewable + D (Calcium (Calcium Citrate)) acetate

N=69


Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Citrate)) concentration could reduce the incidence and severity of Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Citrate)) acetate: dizziness, edema, and weakness.

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7 DRUG INTERACTIONS

The drug interaction of Opti-Cal Chewable + D ) acetate is characterized by the potential of Opti-Cal Chewable + D (Calcium (Calcium Citrate)) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Citrate)) acetate and most concomitant drugs. When administering an oral medication with Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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:

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

8.2 Labor and Delivery

The effects of Opti-Cal Chewable + D (Calcium (Calcium Citrate)) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Opti-Cal Chewable + D ) Acetate Capsules contains Opti-Cal Chewable + D (Calcium (Calcium Citrate)) acetate and is excreted in human milk. Human milk feeding by a mother receiving Opti-Cal Chewable + D (Calcium (Calcium Citrate)) acetate is not expected to harm an infant, provided maternal serum Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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.

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10 OVERDOSAGE

Administration of Opti-Cal Chewable + D (Calcium (Calcium Citrate)) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Opti-Cal Chewable + D (Calcium (Calcium Citrate)) acetate acts as a phosphate binder. Its chemical name is Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Citrate)) acetate USP (anhydrous; Ca(CH3COO)2; MW=158.17 grams) equal to 169 mg (8.45 mEq) Opti-Cal Chewable + D (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.

Opti-Cal Chewable + D (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 Opti-Cal Chewable + D ) resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Opti-Cal Chewable + D (Calcium (Calcium Citrate)) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Opti-Cal Chewable + D (Calcium (Calcium Citrate)) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Opti-Cal Chewable + D (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.

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13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with Opti-Cal Chewable + D (Calcium (Calcium Citrate)) acetate.

14 CLINICAL STUDIES

Effectiveness of Opti-Cal Chewable + D (Calcium (Calcium Citrate)) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Citrate)) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Opti-Cal Chewable + D (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


Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Citrate)) acetate is shown in the Table 3.


* ANOVA of Opti-Cal Chewable + D (Calcium (Calcium Citrate)) acetate vs. placebo after 2 weeks of treatment.

Values expressed as mean ± SEM.


Parameter


Pre-Study


Post-Treatment


p-value*


Opti-Cal Chewable + D (Calcium (Calcium Citrate)) Acetate


Placebo


Phosphorus (mg/dL)


7.3 ± 0.18


5.9 ± 0.24


7.8 ± 0.22


<0.01


Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Citrate)) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Opti-Cal Chewable + D (Calcium (Calcium Citrate)) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Citrate)) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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

Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Fumarate)) acetate capsule.

- Capsule: 667 mg Opti-Cal Chewable + D (Calcium (Calcium Fumarate)) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

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

An overdose of Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Fumarate)) levels twice weekly. Should hypercalcemia develop, reduce the Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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, Opti-Cal Chewable + D (Calcium (Calcium Fumarate)) acetate has been generally well tolerated.

Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Fumarate)) acetate

N=167

N (%)


3 month, open label study of Opti-Cal Chewable + D (Calcium (Calcium Fumarate)) acetate

N=98

N (%)


Double blind, placebo-controlled, cross-over study of liquid Opti-Cal Chewable + D (Calcium (Calcium Fumarate)) acetate

N=69


Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Fumarate)) concentration could reduce the incidence and severity of Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Fumarate)) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of Opti-Cal Chewable + D ) acetate is characterized by the potential of Opti-Cal Chewable + D (Calcium (Calcium Fumarate)) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Fumarate)) acetate and most concomitant drugs. When administering an oral medication with Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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:

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

8.2 Labor and Delivery

The effects of Opti-Cal Chewable + D (Calcium (Calcium Fumarate)) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

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

11 DESCRIPTION

Opti-Cal Chewable + D (Calcium (Calcium Fumarate)) acetate acts as a phosphate binder. Its chemical name is Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Fumarate)) acetate USP (anhydrous; Ca(CH3COO)2; MW=158.17 grams) equal to 169 mg (8.45 mEq) Opti-Cal Chewable + D (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.

Opti-Cal Chewable + D (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 Opti-Cal Chewable + D ) resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Opti-Cal Chewable + D (Calcium (Calcium Fumarate)) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Opti-Cal Chewable + D (Calcium (Calcium Fumarate)) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Fumarate)) acetate.

14 CLINICAL STUDIES

Effectiveness of Opti-Cal Chewable + D (Calcium (Calcium Fumarate)) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Fumarate)) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Opti-Cal Chewable + D (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


Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Fumarate)) acetate is shown in the Table 3.


* ANOVA of Opti-Cal Chewable + D (Calcium (Calcium Fumarate)) acetate vs. placebo after 2 weeks of treatment.

Values expressed as mean ± SEM.


Parameter


Pre-Study


Post-Treatment


p-value*


Opti-Cal Chewable + D (Calcium (Calcium Fumarate)) Acetate


Placebo


Phosphorus (mg/dL)


7.3 ± 0.18


5.9 ± 0.24


7.8 ± 0.22


<0.01


Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Fumarate)) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Opti-Cal Chewable + D (Calcium (Calcium Fumarate)) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Fumarate)) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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

Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Glutarate)) acetate capsule.

- Capsule: 667 mg Opti-Cal Chewable + D (Calcium (Calcium Glutarate)) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

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

An overdose of Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Glutarate)) levels twice weekly. Should hypercalcemia develop, reduce the Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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, Opti-Cal Chewable + D (Calcium (Calcium Glutarate)) acetate has been generally well tolerated.

Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Glutarate)) acetate

N=167

N (%)


3 month, open label study of Opti-Cal Chewable + D (Calcium (Calcium Glutarate)) acetate

N=98

N (%)


Double blind, placebo-controlled, cross-over study of liquid Opti-Cal Chewable + D (Calcium (Calcium Glutarate)) acetate

N=69


Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Glutarate)) concentration could reduce the incidence and severity of Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Glutarate)) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of Opti-Cal Chewable + D ) acetate is characterized by the potential of Opti-Cal Chewable + D (Calcium (Calcium Glutarate)) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Glutarate)) acetate and most concomitant drugs. When administering an oral medication with Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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:

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

8.2 Labor and Delivery

The effects of Opti-Cal Chewable + D (Calcium (Calcium Glutarate)) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

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

11 DESCRIPTION

Opti-Cal Chewable + D (Calcium (Calcium Glutarate)) acetate acts as a phosphate binder. Its chemical name is Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Glutarate)) acetate USP (anhydrous; Ca(CH3COO)2; MW=158.17 grams) equal to 169 mg (8.45 mEq) Opti-Cal Chewable + D (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.

Opti-Cal Chewable + D (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 Opti-Cal Chewable + D ) resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Opti-Cal Chewable + D (Calcium (Calcium Glutarate)) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Opti-Cal Chewable + D (Calcium (Calcium Glutarate)) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Glutarate)) acetate.

14 CLINICAL STUDIES

Effectiveness of Opti-Cal Chewable + D (Calcium (Calcium Glutarate)) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Glutarate)) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Opti-Cal Chewable + D (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


Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Glutarate)) acetate is shown in the Table 3.


* ANOVA of Opti-Cal Chewable + D (Calcium (Calcium Glutarate)) acetate vs. placebo after 2 weeks of treatment.

Values expressed as mean ± SEM.


Parameter


Pre-Study


Post-Treatment


p-value*


Opti-Cal Chewable + D (Calcium (Calcium Glutarate)) Acetate


Placebo


Phosphorus (mg/dL)


7.3 ± 0.18


5.9 ± 0.24


7.8 ± 0.22


<0.01


Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Glutarate)) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Opti-Cal Chewable + D (Calcium (Calcium Glutarate)) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Glutarate)) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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

Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Malate)) acetate capsule.

- Capsule: 667 mg Opti-Cal Chewable + D (Calcium (Calcium Malate)) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

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

An overdose of Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Malate)) levels twice weekly. Should hypercalcemia develop, reduce the Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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, Opti-Cal Chewable + D (Calcium (Calcium Malate)) acetate has been generally well tolerated.

Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Malate)) acetate

N=167

N (%)


3 month, open label study of Opti-Cal Chewable + D (Calcium (Calcium Malate)) acetate

N=98

N (%)


Double blind, placebo-controlled, cross-over study of liquid Opti-Cal Chewable + D (Calcium (Calcium Malate)) acetate

N=69


Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Malate)) concentration could reduce the incidence and severity of Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Malate)) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of Opti-Cal Chewable + D ) acetate is characterized by the potential of Opti-Cal Chewable + D (Calcium (Calcium Malate)) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Malate)) acetate and most concomitant drugs. When administering an oral medication with Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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:

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

8.2 Labor and Delivery

The effects of Opti-Cal Chewable + D (Calcium (Calcium Malate)) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

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

11 DESCRIPTION

Opti-Cal Chewable + D (Calcium (Calcium Malate)) acetate acts as a phosphate binder. Its chemical name is Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Malate)) acetate USP (anhydrous; Ca(CH3COO)2; MW=158.17 grams) equal to 169 mg (8.45 mEq) Opti-Cal Chewable + D (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.

Opti-Cal Chewable + D (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 Opti-Cal Chewable + D ) resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Opti-Cal Chewable + D (Calcium (Calcium Malate)) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Opti-Cal Chewable + D (Calcium (Calcium Malate)) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Malate)) acetate.

14 CLINICAL STUDIES

Effectiveness of Opti-Cal Chewable + D (Calcium (Calcium Malate)) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Malate)) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Opti-Cal Chewable + D (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


Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Malate)) acetate is shown in the Table 3.


* ANOVA of Opti-Cal Chewable + D (Calcium (Calcium Malate)) acetate vs. placebo after 2 weeks of treatment.

Values expressed as mean ± SEM.


Parameter


Pre-Study


Post-Treatment


p-value*


Opti-Cal Chewable + D (Calcium (Calcium Malate)) Acetate


Placebo


Phosphorus (mg/dL)


7.3 ± 0.18


5.9 ± 0.24


7.8 ± 0.22


<0.01


Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Malate)) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Opti-Cal Chewable + D (Calcium (Calcium Malate)) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Malate)) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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

Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Succinate)) acetate capsule.

- Capsule: 667 mg Opti-Cal Chewable + D (Calcium (Calcium Succinate)) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

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

An overdose of Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Succinate)) levels twice weekly. Should hypercalcemia develop, reduce the Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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, Opti-Cal Chewable + D (Calcium (Calcium Succinate)) acetate has been generally well tolerated.

Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Succinate)) acetate

N=167

N (%)


3 month, open label study of Opti-Cal Chewable + D (Calcium (Calcium Succinate)) acetate

N=98

N (%)


Double blind, placebo-controlled, cross-over study of liquid Opti-Cal Chewable + D (Calcium (Calcium Succinate)) acetate

N=69


Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Succinate)) concentration could reduce the incidence and severity of Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Succinate)) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of Opti-Cal Chewable + D ) acetate is characterized by the potential of Opti-Cal Chewable + D (Calcium (Calcium Succinate)) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Succinate)) acetate and most concomitant drugs. When administering an oral medication with Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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:

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

8.2 Labor and Delivery

The effects of Opti-Cal Chewable + D (Calcium (Calcium Succinate)) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

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

11 DESCRIPTION

Opti-Cal Chewable + D (Calcium (Calcium Succinate)) acetate acts as a phosphate binder. Its chemical name is Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Succinate)) acetate USP (anhydrous; Ca(CH3COO)2; MW=158.17 grams) equal to 169 mg (8.45 mEq) Opti-Cal Chewable + D (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.

Opti-Cal Chewable + D (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 Opti-Cal Chewable + D ) resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Opti-Cal Chewable + D (Calcium (Calcium Succinate)) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Opti-Cal Chewable + D (Calcium (Calcium Succinate)) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Succinate)) acetate.

14 CLINICAL STUDIES

Effectiveness of Opti-Cal Chewable + D (Calcium (Calcium Succinate)) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Succinate)) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Opti-Cal Chewable + D (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


Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Succinate)) acetate is shown in the Table 3.


* ANOVA of Opti-Cal Chewable + D (Calcium (Calcium Succinate)) acetate vs. placebo after 2 weeks of treatment.

Values expressed as mean ± SEM.


Parameter


Pre-Study


Post-Treatment


p-value*


Opti-Cal Chewable + D (Calcium (Calcium Succinate)) Acetate


Placebo


Phosphorus (mg/dL)


7.3 ± 0.18


5.9 ± 0.24


7.8 ± 0.22


<0.01


Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Succinate)) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Opti-Cal Chewable + D (Calcium (Calcium Succinate)) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Succinate)) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Opti-Cal Chewable + D (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 Opti-Cal Chewable + D (Calcium (Calcium Succinate)) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Opti-Cal Chewable + D 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.


Opti-Cal Chewable + D 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.


Opti-Cal Chewable + D 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.


Opti-Cal Chewable + D 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.


Opti-Cal Chewable + D 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 Opti-Cal Chewable + D?

Depending on the reaction of the Opti-Cal Chewable + D after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Opti-Cal Chewable + D 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 Opti-Cal Chewable + D 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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Review

sdrugs.com conducted a study on Opti-Cal Chewable + D, 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 Opti-Cal Chewable + D 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. Rachana Salvi, MD Pharmacology

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