Calcitriol: Package Insert and Label Information (Page 2 of 3)

Vitamin D

Since calcitriol is the most potent active metabolite of vitamin D ₃ , pharmacological doses of vitamin D and its derivatives should be withheld during treatment with calcitriol to avoid possible additive effects and hypercalcemia (see WARNINGS).

Calcium Supplements

Uncontrolled intake of additional calcium-containing preparations should be avoided (see PRECAUTIONS: General).

Magnesium

Magnesium-containing preparations (e.g., antacids) may cause hypermagnesemia and should therefore not be taken during therapy with calcitriol by patients on chronic renal dialysis.

Carcinogenesis, Mutagenesis and Impairment of Fertility

Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of calcitriol. Calcitriol is not mutagenic in vitro in the Ames Test, nor is it genotoxic in vivo in the Mouse Micronucleus Test. No significant effects of calcitriol on fertility and/or general reproductive performances were observed in a Segment I study in rats at doses of up to 0.3 mcg/kg (approximately 3 times the maximum recommended dose based on body surface area).

Pregnancy

Teratogenic Effects
Pregnancy Category C. Calcitriol has been found to be teratogenic in rabbits when given at doses of 0.08 and 0.3 mcg/kg (approximately 2 and 6 times the maximum recommended dose based on mg/m ²). All 15 fetuses in 3 litters at these doses showed external and skeletal abnormalities. However, none of the other 23 litters (156 fetuses) showed external and skeletal abnormalities compared with controls.

Teratogenicity studies in rats at doses up to 0.45 mcg/kg (approximately 5 times maximum recommended dose based on mg/m ²) showed no evidence of teratogenic potential. There are no adequate and well-controlled studies in pregnant women. Calcitriol capsules should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects
In the rabbit, dosages of 0.3 mcg/kg/day (approximately 6 times maximum recommended dose based on surface area) administered on days 7 to 18 of gestation resulted in 19% maternal mortality, a decrease in mean fetal body weight and a reduced number of newborn surviving to 24 hours. A study of perinatal and postnatal development in rats resulted in hypercalcemia in the offspring of dams given calcitriol at doses of 0.08 or 0.3 mcg/kg/day (approximately 1 and 3 times the maximum recommended dose based on mg/m ²), hypercalcemia and hypophosphatemia in dams given calcitriol at a dose of 0.08 or 0.3 mcg/kg/day, and increased serum urea nitrogen in dams given calcitriol at a dose of 0.3 mcg/kg/day. In another study in rats, maternal weight gain was slightly reduced at a dose of 0.3 mcg/kg/day (approximately 3 times the maximum recommended dose based on mg/m ²) administered on days 7 to 15 of gestation. The offspring of a woman administered 17 mcg/day to 36 mcg/day of calcitriol (approximately 17 to 36 times the maximum recommended dose), during pregnancy manifested mild hypercalcemia in the first 2 days of life which returned to normal at day 3.

Nursing Mothers

Calcitriol from ingested calcitriol may be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from calcitriol in nursing infants, a mother should not nurse while taking calcitriol.

Pediatric Use

Safety and effectiveness of calcitriol in pediatric patients undergoing dialysis have not been established. The safety and effectiveness of calcitriol in pediatric predialysis patients is based on evidence from adequate and well-controlled studies of calcitriol in adults with predialysis chronic renal failure and additional supportive data from non- placebo controlled studies in pediatric patients. Dosing guidelines have not been established for pediatric patients under 1 year of age with hypoparathyroidism or for pediatric patients less than 6 years of age with pseudohypoparathyroidism (see DOSAGE AND ADMINISTRATION: Hypoparathyroidism).

Oral doses of calcitriol ranging from 10 to 55 ng/kg/day have been shown to improve calcium homeostasis and bone disease in pediatric patients with chronic renal failure for whom hemodialysis is not yet required (predialysis). Long-term calcitriol therapy is well tolerated by pediatric patients. The most common safety issues are mild, transient episodes of hypercalcemia, hyperphosphatemia, and increases in the serum calcium times phosphate (Ca x P) product which are managed effectively by dosage adjustment or temporary discontinuation of the vitamin D derivative.

Geriatric Use

Clinical studies of calcitriol did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the 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.

ADVERSE REACTIONS

Since calcitriol is believed to be the active hormone which exerts vitamin D activity in the body, adverse effects are, in general, similar to those encountered with excessive vitamin D intake, i.e., hypercalcemia syndrome or calcium intoxication (depending on the severity and duration of hypercalcemia) (see WARNINGS). Because of the short biological half-life of calcitriol, pharmacokinetic investigations have shown normalization of elevated serum calcium within a few days of treatment withdrawal, i.e., much faster than in treatment with vitamin D ₃ preparations.

The early and late signs and symptoms of vitamin D intoxication associated with hypercalcemia include:

Early: weakness, headache, somnolence, nausea, vomiting, dry mouth, constipation, muscle pain, bone pain, metallic taste, and anorexia, abdominal pain or stomach ache.

Late: polyuria, polydipsia, anorexia, weight loss, nocturia, conjunctivitis (calcific), pancreatitis, photophobia, rhinorrhea, pruritus, hyperthermia, decreased libido, elevated BUN, albuminuria, hypercholesterolemia, elevated SGOT (AST) and SGPT (ALT), ectopic calcification, nephrocalcinosis, hypertension, cardiac arrhythmias, dystrophy, sensory disturbances, dehydration, apathy, arrested growth, urinary tract infections, and, rarely, overt psychosis.

In clinical studies on hypoparathyroidism and pseudohypoparathyroidism, hypercalcemia was noted on at least one occasion in about 1 in 3 patients and hypercalciuria in about 1 in 7 patients. Elevated serum creatinine levels were observed in about 1 in 6 patients (approximately one half of whom had normal levels at baseline).

In concurrent hypercalcemia and hyperphosphatemia, soft-tissue calcification may occur; this can be seen radiographically (see WARNINGS).

In patients with normal renal function, chronic hypercalcemia may be associated with an increase in serum creatinine (see PRECAUTIONS: General).

Hypersensitivity reactions (pruritus, rash, urticaria, and very rarely severe erythematous skin disorders) may occur in susceptible individuals. One case of erythema multiforme and one case of allergic reaction (swelling of lips and hives all over the body) were confirmed by rechallenge.

Call your doctor for medical advice about side effects. You may report side effects to Strides Pharma Inc. at 1-877-244-9825 or go to www.stridesshasun.com

OVERDOSAGE

Administration of calcitriol to patients in excess of their daily requirements can cause hypercalcemia, hypercalciuria, and hyperphosphatemia. Since calcitriol is a derivative of vitamin D, the signs and symptoms of overdose are the same as for an overdose of vitamin D (see ADVERSE REACTIONS). High intake of calcium and phosphate concomitant with calcitriol may lead to similar abnormalities. The serum calcium times phosphate (Ca x P) product should not be allowed to exceed 70 mg ² /dL ². High levels of calcium in the dialysate bath may contribute to the hypercalcemia (see WARNINGS).

Treatment of Hypercalcemia and Overdosage in Dialysis Patients and Hypoparathyroidism Patients

General treatment of hypercalcemia (greater than 1 mg/dL above the upper limit of the normal range) consists of immediate discontinuation of calcitriol therapy, institution of a low-calcium diet and withdrawal of calcium supplements. Serum calcium levels should be determined daily until normocalcemia ensues. Hypercalcemia frequently resolves in 2 to 7 days. When serum calcium levels have returned to within normal limits, calcitriol capsule therapy may be reinstituted at a dose of 0.25 mcg/day less than prior therapy. Serum calcium levels should be obtained at least twice weekly after all dosage changes and subsequent dosage titration. In dialysis patients, persistent or markedly elevated serum calcium levels may be corrected by dialysis against a calcium-free dialysate.

Treatment of Hypercalcemia and Overdosage in Predialysis Patients

If hypercalcemia ensues (greater than 1 mg/dL above the upper limit of the normal range), adjust dosage to achieve normocalcemia by reducing calcitriol capsule therapy from 0.5 mcg to 0.25 mcg daily. If the patient is receiving a therapy of 0.25 mcg daily, discontinue calcitriol capsule until patient becomes normocalcemic. Calcium supplements should also be reduced or discontinued. Serum calcium levels should be determined 1 week after withdrawal of calcium supplements. If serum calcium levels have returned to normal, calcitriol capsule therapy may be reinstituted at a dosage of 0.25 mcg/day if previous therapy was at a dosage of 0.5 mcg/day. If calcitriol capsule therapy was previously administered at a dosage of 0.25 mcg/day, calcitriol capsule therapy may be reinstituted at a dosage of 0.25 mcg every other day. If hypercalcemia is persistent at the reduced dosage, serum PTH should be measured. If serum PTH is normal, discontinue calcitriol capsule therapy and monitor patient in 3 months’ time.

Treatment of Hyperphosphatemia in Predialysis Patients

If serum phosphorus levels exceed 5.0 mg/dL to 5.5 mg/dL, a calcium-containing phosphate-binding agent (i.e., calcium carbonate or calcium acetate) should be taken with meals. Serum phosphorus levels should be determined as described earlier (see PRECAUTIONS: Laboratory Tests). Aluminum-containing gels should be used with caution as phosphate-binding agents because of the risk of slow aluminum accumulation.

Treatment of Accidental Overdosage of calcitriol capsules

The treatment of acute accidental overdosage of calcitriol should consist of general supportive measures. If drug ingestion is discovered within a relatively short time, induction of emesis or gastric lavage may be of benefit in preventing further absorption. If the drug has passed through the stomach, the administration of mineral oil may promote its fecal elimination. Serial serum electrolyte determinations (especially calcium), rate of urinary calcium excretion, and assessment of electrocardiographic abnormalities due to hypercalcemia should be obtained. Such monitoring is critical in patients receiving digitalis. Discontinuation of supplemental calcium and a low-calcium diet are also indicated in accidental overdosage. Due to the relatively short duration of the pharmacological action of calcitriol, further measures are probably unnecessary. Should, however, persistent and markedly elevated serum calcium levels occur, there are a variety of therapeutic alternatives which may be considered, depending on the patient’s underlying condition. These include the use of drugs such as phosphates and corticosteroids as well as measures to induce an appropriate forced diuresis. The use of peritoneal dialysis against a calcium-free dialysate has also been reported.

DOSAGE AND ADMINISTRATION

The optimal daily dose of calcitriol capsules must be carefully determined for each patient. Calcitriol capsule can be administered orally as a capsule (0.25 mcg or 0.50 mcg). Calcitriol capsule therapy should always be started at the lowest possible dose and should not be increased without careful monitoring of serum calcium.

The effectiveness of calcitriol capsule therapy is predicated on the assumption that each patient is receiving an adequate but not excessive daily intake of calcium. Patients are advised to have a dietary intake of calcium at a minimum of 600 mg daily. The U.S. RDA for calcium in adults is 800 mg to 1200 mg. To ensure that each patient receives an adequate daily intake of calcium, the physician should either prescribe a calcium supplement or instruct the patient in proper dietary measures.

Because of improved calcium absorption from the gastrointestinal tract, some patients on calcitriol capsule may be maintained on a lower calcium intake. Patients who tend to develop hypercalcemia may require only low doses of calcium or no supplementation at all.

During the titration period of treatment with calcitriol, serum calcium levels should be checked at least twice weekly. When the optimal dosage of calcitriol has been determined, serum calcium levels should be checked every month (or as given below for individual indications). Samples for serum calcium estimation should be taken without a tourniquet.

Dialysis Patients

The recommended initial dose of calcitriol capsule is 0.25 mcg/day. If a satisfactory response in the biochemical parameters and clinical manifestations of the disease state is not observed, dosage may be increased by 0.25 mcg/day at 4 to 8 week intervals. During this titration period, serum calcium levels should be obtained at least twice weekly, and if hypercalcemia is noted, the drug should be immediately discontinued until normocalcemia ensues (see PRECAUTIONS: General). Phosphorus, magnesium, and alkaline phosphatase should be determined periodically.

Patients with normal or only slightly reduced serum calcium levels may respond to calcitriol capsules doses of 0.25 mcg every other day. Most patients undergoing hemodialysis respond to doses between 0.5 and 1 mcg/day.

Oral calcitriol capsules may normalize plasma ionized calcium in some uremic patients, yet fail to suppress parathyroid hyperfunction. In these individuals with autonomous parathyroid hyperfunction, oral calcitriol may be useful to maintain normocalcemia, but has not been shown to be adequate treatment for hyperparathyroidism.

Hypoparathyroidism

The recommended initial dosage of calcitriol capsules is 0.25 mcg/day given in the morning. If a satisfactory response in the biochemical parameters and clinical manifestations of the disease is not observed, the dose may be increased at 2- to 4-week intervals. During the dosage titration period, serum calcium levels should be obtained at least twice weekly and, if hypercalcemia is noted, calcitriol capsules should be immediately discontinued until normocalcemia ensues (see PRECAUTIONS: General). Careful consideration should also be given to lowering the dietary calcium intake. Serum calcium, phosphorus, and 24- hour urinary calcium should be determined periodically.

Most adult patients and pediatric patients age 6 years and older have responded to dosages in the range of 0.5 mcg to 2 mcg daily. Pediatric patients in the 1 to 5 year age group with hypoparathyroidism have usually been given 0.25 mcg to 0.75 mcg daily. The number of treated patients with pseudohypoparathyroidism less than 6 years of age is too small to make dosage recommendations.

Malabsorption is occasionally noted in patients with hypoparathyroidism; hence, larger doses of calcitriol capsules may be needed.

Predialysis Patients

The recommended initial dosage of calcitriol capsules is 0.25 mcg/day in adults and pediatric patients 3 years of age and older. This dosage may be increased if necessary to 0.5 mcg/day.

For pediatric patients less than 3 years of age, the recommended initial dosage of calcitriol is 10 to 15 ng/kg/day.

HOW SUPPLIED

Capsules: 0.25 mcg calcitriol in soft gelatin, orange, oval capsules, imprinted with 673; unit dose packages of 100 (10 x 10) NDC 68087-345-01

Calcitriol Capsules should be protected from light.

Store at 20° to 25°C (68° to 77°C F) [See USP Controlled Room Temperature]

FOR YOUR PROTECTION: Do not use if blister if torn or broken.

REFERENCES

1. Jones CL, et al. Comparisons between oral and intraperitoneal 1, 25-dihydroxyvitamin D ₃ therapy in children treated with peritoneal dialysis. Clin Nephrol. 1994; 42:44-49.

PACKAGING INFORMATION

American Health Packaging unit dose blisters (see How Supplied section) contain drug product from Strides Pharma Inc. as follows:
(0.25 mcg / 100 UD) NDC 60687-345-01 packaged from NDC 64380-723

Distributed by:
American Health Packaging
Columbus, Ohio 43217

8434501/1017

Package/Label Display Panel — Carton — 0.25 mcg

NDC 60687- 345 -01

CALCITRIOL
CAPSULES

0.25 mcg

100 Capsules (10 x 10)                Rx Only

Each Capsule Contains:
Calcitriol ……………………………………………………… 0.25 mcg

Usual Dosage: See package insert for full prescribing
information.

Store at 20° to 25°C (68° to 77°F); excursions permitted
between 15° to 30°C (59° to 86°F) [see USP Controlled
Room Temperature]. Protect from light.

Keep this and all drugs out of reach of children.

FOR YOUR PROTECTION: Do not use if blister is torn or
broken.

The drug product contained in this package is from
NDC # 64380-723, Strides Pharma Inc.

Packaged and Distributed by:
American Health Packaging
Columbus, Ohio 43217

734501
0434501/0119