Calduit-D

Calcium (Oyster Shells):

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Calduit-D (Calcium (Oyster Shells)) reviews

1 INDICATIONS AND USAGE

Calduit-D (Calcium (Oyster Shells)) 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 Calduit-D (Calcium (Oyster Shells)) 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 Calduit-D (Calcium (Oyster Shells)) acetate capsule.

- Capsule: 667 mg Calduit-D (Calcium (Oyster Shells)) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

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

An overdose of Calduit-D (Calcium (Oyster Shells)) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum Calduit-D (Calcium (Oyster Shells)) levels twice weekly. Should hypercalcemia develop, reduce the Calduit-D (Calcium (Oyster Shells)) 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 Calduit-D (Calcium (Oyster Shells)) 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 Calduit-D (Calcium (Oyster Shells)) 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 Calduit-D (Calcium (Oyster Shells)) 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 Calduit-D (Calcium (Oyster Shells)) 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 Calduit-D (Calcium (Oyster Shells)) 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, Calduit-D (Calcium (Oyster Shells)) acetate has been generally well tolerated.

Calduit-D (Calcium (Oyster Shells)) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of Calduit-D (Calcium (Oyster Shells)) 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.

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 Calduit-D (Calcium (Oyster Shells)) concentration could reduce the incidence and severity of Calduit-D (Calcium (Oyster Shells)) 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 Calduit-D (Calcium (Oyster Shells)) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

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

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

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

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

8.2 Labor and Delivery

The effects of Calduit-D (Calcium (Oyster Shells)) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

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

11 DESCRIPTION

Calduit-D (Calcium (Oyster Shells)) acetate acts as a phosphate binder. Its chemical name is Calduit-D (Calcium (Oyster Shells)) 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 Calduit-D (Calcium (Oyster Shells)) acetate USP (anhydrous; Ca(CH₃COO)₂; MW=158.17 grams) equal to 169 mg (8.45 mEq) Calduit-D (Calcium (Oyster Shells)), 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.

Calduit-D (Calcium (Oyster Shells)) 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 Calduit-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

Calduit-D (Calcium (Oyster Shells)) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Calduit-D (Calcium (Oyster Shells)) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Calduit-D (Calcium (Oyster Shells)) 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 Calduit-D (Calcium (Oyster Shells)) acetate.

14 CLINICAL STUDIES

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

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 Calduit-D (Calcium (Oyster Shells)) 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 Calduit-D (Calcium (Oyster Shells)) 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 Calduit-D (Calcium (Oyster Shells)) acetate is shown in the Table 3.

Overall, 2 weeks of treatment with Calduit-D (Calcium (Oyster Shells)) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Calduit-D (Calcium (Oyster Shells)) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Calduit-D (Calcium (Oyster Shells)) 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 Calduit-D (Calcium (Oyster Shells)) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Calduit-D (Calcium (Oyster Shells)) 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 Calduit-D (Calcium (Oyster Shells)) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016