INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. Calcitriol Injection is indicated in the management of hypocalcemia in patients undergoing chronic renal dialysis. It has been shown to significantly reduce elevated parathyroid hormone levels. Reduction of PTH has been shown to result in an improvement in renal osteodystrophy.

INFORMATION FOR PATIENTS SECTION.

2.Information for the Patient. The patient and his or her parents should be informed about adherence to instructions about diet and calcium supplementation and avoidance of the use of unapproved non-prescription drugs, including magnesium-containing antacids. Patients should also be carefully informed about the symptoms of hypercalcemia (see ADVERSE REACTIONS).

ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. Adverse effects of Calcitriol Injection are, in general, similar to those encountered with excessive vitamin intake. The early and late signs and symptoms of vitamin intoxication associated with hypercalcemia include: 1. Early Weakness, headache, somnolence, nausea, vomiting, dry mouth, constipation, muscle pain, bone pain and metallic taste. 2. Late Polyuria, polydipsia, anorexia, weight loss, nocturia, conjunctivitis (calcific), pancreatitis, photophobia, rhinorrhea, pruritus, hyperthermia, decreased libido, elevated BUN, albuminuria, hypercholesterolemia, elevated SGOT and SGPT, ectopic calcification, hypertension, cardiac arrhythmias and, rarely, overt psychosis. Occasional mild pain on injection has been observed.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

5. Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of Calcitriol Injection. Calcitriol was not mutagenic in vitro in the Ames Test nor was oral calcitriol genotoxic in vivo in the Mouse Micronucleus Test. No significant effects on fertility and/or general reproductive performances were observed in Segment study in rats using oral calcitriol at doses of up to 0.3 mcg/kg.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Calcitriol is the active form of Vitamin D3 (cholecalciferol). The natural or endogenous supply of vitamin in man mainly depends on ultraviolet light for conversion of 7-dehydrocholesterol to vitamin D3 in the skin. Vitamin D3 must be metabolically activated in the liver and the kidney before it is fully active on its target tissues. The initial transformation is catalyzed by vitamin D3-25-hydroxylase enzyme present in the liver, and the product of this reaction is 25-(OH)D3 (calcifediol). The latter undergoes hydroxylation in the mitochondria of kidney tissue, and this reaction is activated by the renal 25-hydroxyvitamin D3-1-(alpha)-hydroxylase to produce 1,25-(OH)2D3 (calcitriol), the active form of vitamin D3. The known sites of action of calcitriol are intestine, bone, kidney and parathyroid gland. Calcitriol is the most active known form of vitamin D3 in stimulating intestinal calcium transport. In acutely uremic rats, calcitriol has been shown to stimulate intestinal calcium absorption. In bone, calcitriol, in conjunction with parathyroid hormone, stimulates resorption of calcium; and in the kidney, calcitriol increases the tubular reabsorption of calcium. In vitro and in vivo studies have shown that calcitriol directly suppresses secretion and synthesis of PTH. vitamin D-resistant state may exist in uremic patients because of the failure of the kidney to adequately convert precursors to the active compound, calcitriol. Calcitriol when administered by bolus injection is rapidly available in the blood stream. Vitamin metabolites are known to be transported in blood, bound to specific plasma proteins. The pharmacologic activity of an administered dose of calcitriol is about to days. Two metabolic pathways for calcitriol have been identified, conversion to 1,24,25-(OH)3D3 and to calcitroic acid.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. Calcitriol Injection should not be given to patients with hypercalcemia or evidence of vitamin toxicity.

DESCRIPTION SECTION.

DESCRIPTION. Calcitriol Injection is synthetically manufactured calcitriol and is available as sterile, isotonic, clear, colorless to yellow, aqueous solution for intravenous injection. Calcitriol Injection is available in mL ampules. Each mL contains calcitriol mcg; polysorbate 20, mg; edetate disodium dehydrate 1.1 mg; sodium phosphate dibasic 7.6 mg; sodium phosphate monobasic 1.8 mg; sodium chloride 1.5 mg; sodium ascorbate 10 mg. pH 6.6 (5.9 7.0). Calcitriol is crystalline compound which occurs naturally in humans. It is soluble in organic solvents but relatively insoluble in water. Calcitriol is chemically designated (5Z,7E)-9, 10-secocholesta-5,7,10(19)-triene-1-(alpha),3 (beta),25-triol and has the following structural formula:Molecular Formula: C27H44O3 The other names frequently used for calcitriol are 1(alpha),25-dihydroxycholecalciferol, 1(alpha),25-dihydroxyvitamin D3, 1,25-DHCC, 1,25(OH)2D3 and 1,25-diOHC. Structural Formula.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. The optimal dose of Calcitriol Injection must be carefully determined for each patient. The effectiveness of Calcitriol Injection therapy is predicated on the assumption that each patient is receiving an adequate and appropriate daily intake of calcium. The RDA for calcium in adults is 800 mg. To ensure that each patient receives an adequate daily intake of calcium, the physician should either prescribe calcium supplement or instruct the patient in proper dietary measures. The recommended initial dose of Calcitriol Injection, depending on the severity of the hypocalcemia and/or secondary hyperparathyroidism, is mcg (0.02 mcg/kg) to mcg administered three times weekly, approximately every other day. Doses as small as 0.5 mcg and as large as mcg three times weekly have been used as an initial dose. If satisfactory response is not observed, the dose may be increased by 0.5 to mcg at two to four week intervals. During this titration period, serum calcium and phosphorus levels should be obtained at least twice weekly. If hypercalcemia or serum calcium times phosphate product greater than 70 is noted, the drug should be immediately discontinued until these parameters are appropriate. Then, the Calcitriol Injection dose should be reinitiated at lower dose. Doses may need to be reduced as the PTH levels decrease in response to the therapy. Thus, incremental dosing must be individualized and commensurate with PTH, serum calcium and phosphorus levels. The following is suggested approach in dose titration: PTH LevelsCalcitriol Injection Dose The same or increasing increase Decreasing by <30% increase Decreasing by >30%, <60% maintain Decreasing by >60% decrease One and one-half to three times the upper limit of normal maintainParenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard unused portion.

DRUG INTERACTIONS SECTION.

4. Drug Interactions. Magnesium-containing antacid and Calcitriol Injection should not be used concomitantly, because such use may lead to the development of hypermagnesemia.

GENERAL PRECAUTIONS SECTION.

1. General. Excessive dosage of Calcitriol Injection induces hypercalcemia and in some instances hypercalciuria; therefore, early in treatment during dosage adjustment, serum calcium and phosphorus should be determined at least twice weekly. Should hypercalcemia develop, the drug should be discontinued immediately. Calcitriol Injection should be given cautiously to patients on digitalis, because hypercalcemia in such patients may precipitate cardiac arrhythmias.

GERIATRIC USE SECTION.

9. Geriatric Use. Clinical studies of Calcitriol Injection 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 dosage range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

HOW SUPPLIED SECTION.

HOW SUPPLIED. Calcitriol Injection is supplied as follows:Container Concentration Fill Ampule mcg/mL mL. Storage and Handling. Store at 20 to 25oC (68 to 77oF) [See USP Controlled Room Temperature].Protect from light.

LABORATORY TESTS SECTION.

3. Essential Laboratory Tests. Serum calcium, phosphorus, magnesium and alkaline phosphatase and 24-hour urinary calcium and phosphorus should be determined periodically. During the initial phase of the medication, serum calcium and phosphorus should be determined more frequently (twice weekly). Adynamic bone disease may develop if PTH levels are suppressed to abnormal levels. If biopsy is not being done for other (diagnostic) reasons, PTH levels may be used to indicate the rate of bone turnover. If PTH levels fall below recommended target range (1.5 to times the upper limit of normal), in patients treated with Calcitriol Injection, the Calcitriol Injection dose should be reduced or therapy discontinued. Discontinuation of Calcitriol Injection therapy may result in rebound effect, therefore, appropriate titration downward to maintenance dose is recommended.

NONTERATOGENIC EFFECTS SECTION.

Nonteratogenic Effects. In the rabbit, oral dosages of 0.3 mcg/kg/day administered on days to 18 of gestation resulted in 19% maternal mortality, decrease in mean fetal body weight and reduced number of newborns surviving to 24 hours. study of the effects of orally administered calcitriol on peri- 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, hypercalcemia and hypophosphatemia in dams given calcitriol at dose of 0.08 or 0.3 mcg/kg/day and increased serum urea nitrogen in dams given calcitriol at dose of 0.3 mcg/kg/day. In another study in rats, maternal weight gain was slightly reduced at an oral dose of 0.3 mcg/kg/day administered on days to 15 of gestation.The offspring of woman administered oral calcitriol at 17 to 36 mcg/day during pregnancy manifested mild hypercalcemia in the first days of life which returned to normal at day 3.

NURSING MOTHERS SECTION.

7.Nursing Mothers. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from calcitriol, decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

OVERDOSAGE SECTION.

OVERDOSAGE. Administration of Calcitriol Injection to patients in excess of their requirements can cause hypercalcemia, hypercalciuria and hyperphosphatemia. High intake of calcium and phosphate concomitant with Calcitriol Injection may lead to similar abnormalities. 1. Treatment of Hypercalcemia and Overdosage in Patients on Hemodialysis. General treatment of hypercalcemia (greater than mg/dL above the upper limit of normal range) consists of immediate discontinuation of Calcitriol Injection therapy, institution of low calcium diet and withdrawal of calcium supplements. Serum calcium levels should be determined daily until normocalcemia ensues. Hypercalcemia usually resolves in two to seven days. When serum calcium levels have returned to within normal limits, Calcitriol Injection therapy may be reinstituted at dose 0.5 mcg less than prior therapy. Serum calcium levels should be obtained at least twice weekly after all dosage changes. Persistent or markedly elevated serum calcium levels may be corrected by dialysis against calcium-free dialysate. 2. Treatment of Accidental Overdosage of Calcitriol Injection. The treatment of acute accidental overdosage of Calcitriol Injection should consist of general supportive measures. 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 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 variety of therapeutic alternatives which may be considered, depending on the patients 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 calcium-free dialysate has also been reported.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL. NDC 0143-9728-05Calcitriol Injection mcg/mL1 mL Single Dose VialsFor IV Injection Only. Calcitriol mcg/mL Label.

PEDIATRIC USE SECTION.

8. Pediatric Use. The safety and effectiveness of Calcitriol Injection were examined in 12-week randomized, double-blind, placebo-controlled study of 35 patients, aged 13-18 years, with end-stage renal disease on hemodialysis. Sixty-six percent of the patients were male, 57% were African-American, and nearly all had received some form of vitamin therapy prior to the study. The initial dose of Calcitriol Injection was 0.5 mcg, 1.0 mcg, or 1.5 mcg, times per week, based on baseline iPTH level of less than 500 pg/mL, 500-1000 pg/mL, or greater than 1000 pg/mL, respectively. The dose of Calcitriol Injection was adjusted in 0.25 mcg increments based on the levels of serum iPTH, calcium and Ca P. The mean baseline levels of iPTH were 769 pg/mL for the 16 Calcitriol Injection-treated patients and 897 pg/mL for the 19 placebo-treated subjects. The mean weekly dose of Calcitriol Injection ranged from 1.0 mcg to 1.4 mcg. In the primary efficacy analysis, of 16 (44%) subjects in the Calcitriol Injection group had consecutive 30% decreases from baseline iPTH compared with of 19 (16%) patients in the placebo group (95% CI for the difference between groups -6%, 62%). One Calcitriol Injection-treated patient experienced transient hypercalcemia (>11 mg/dL), while of 16 (38%) Calcitriol Injection-treated patients vs. of 19 (11%) placebo-treated patients experienced Ca P >75.

PRECAUTIONS SECTION.

PRECAUTIONS. 1. General. Excessive dosage of Calcitriol Injection induces hypercalcemia and in some instances hypercalciuria; therefore, early in treatment during dosage adjustment, serum calcium and phosphorus should be determined at least twice weekly. Should hypercalcemia develop, the drug should be discontinued immediately. Calcitriol Injection should be given cautiously to patients on digitalis, because hypercalcemia in such patients may precipitate cardiac arrhythmias. 2.Information for the Patient. The patient and his or her parents should be informed about adherence to instructions about diet and calcium supplementation and avoidance of the use of unapproved non-prescription drugs, including magnesium-containing antacids. Patients should also be carefully informed about the symptoms of hypercalcemia (see ADVERSE REACTIONS). 3. Essential Laboratory Tests. Serum calcium, phosphorus, magnesium and alkaline phosphatase and 24-hour urinary calcium and phosphorus should be determined periodically. During the initial phase of the medication, serum calcium and phosphorus should be determined more frequently (twice weekly). Adynamic bone disease may develop if PTH levels are suppressed to abnormal levels. If biopsy is not being done for other (diagnostic) reasons, PTH levels may be used to indicate the rate of bone turnover. If PTH levels fall below recommended target range (1.5 to times the upper limit of normal), in patients treated with Calcitriol Injection, the Calcitriol Injection dose should be reduced or therapy discontinued. Discontinuation of Calcitriol Injection therapy may result in rebound effect, therefore, appropriate titration downward to maintenance dose is recommended. 4. Drug Interactions. Magnesium-containing antacid and Calcitriol Injection should not be used concomitantly, because such use may lead to the development of hypermagnesemia. 5. Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of Calcitriol Injection. Calcitriol was not mutagenic in vitro in the Ames Test nor was oral calcitriol genotoxic in vivo in the Mouse Micronucleus Test. No significant effects on fertility and/or general reproductive performances were observed in Segment study in rats using oral calcitriol at doses of up to 0.3 mcg/kg.. 6. Pregnancy. Teratogenic Effects: Pregnancy Category C. Calcitriol has been found to be teratogenic in rabbits when given orally at doses of 0.08 and 0.3 mcg/kg. All 15 fetuses in 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 orally showed no evidence of teratogenic potential. There are no adequate and well-controlled studies in pregnant women. Calcitriol Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.. Nonteratogenic Effects. In the rabbit, oral dosages of 0.3 mcg/kg/day administered on days to 18 of gestation resulted in 19% maternal mortality, decrease in mean fetal body weight and reduced number of newborns surviving to 24 hours. study of the effects of orally administered calcitriol on peri- 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, hypercalcemia and hypophosphatemia in dams given calcitriol at dose of 0.08 or 0.3 mcg/kg/day and increased serum urea nitrogen in dams given calcitriol at dose of 0.3 mcg/kg/day. In another study in rats, maternal weight gain was slightly reduced at an oral dose of 0.3 mcg/kg/day administered on days to 15 of gestation.The offspring of woman administered oral calcitriol at 17 to 36 mcg/day during pregnancy manifested mild hypercalcemia in the first days of life which returned to normal at day 3. 7.Nursing Mothers. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from calcitriol, decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8. Pediatric Use. The safety and effectiveness of Calcitriol Injection were examined in 12-week randomized, double-blind, placebo-controlled study of 35 patients, aged 13-18 years, with end-stage renal disease on hemodialysis. Sixty-six percent of the patients were male, 57% were African-American, and nearly all had received some form of vitamin therapy prior to the study. The initial dose of Calcitriol Injection was 0.5 mcg, 1.0 mcg, or 1.5 mcg, times per week, based on baseline iPTH level of less than 500 pg/mL, 500-1000 pg/mL, or greater than 1000 pg/mL, respectively. The dose of Calcitriol Injection was adjusted in 0.25 mcg increments based on the levels of serum iPTH, calcium and Ca P. The mean baseline levels of iPTH were 769 pg/mL for the 16 Calcitriol Injection-treated patients and 897 pg/mL for the 19 placebo-treated subjects. The mean weekly dose of Calcitriol Injection ranged from 1.0 mcg to 1.4 mcg. In the primary efficacy analysis, of 16 (44%) subjects in the Calcitriol Injection group had consecutive 30% decreases from baseline iPTH compared with of 19 (16%) patients in the placebo group (95% CI for the difference between groups -6%, 62%). One Calcitriol Injection-treated patient experienced transient hypercalcemia (>11 mg/dL), while of 16 (38%) Calcitriol Injection-treated patients vs. of 19 (11%) placebo-treated patients experienced Ca P >75. 9. Geriatric Use. Clinical studies of Calcitriol Injection 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 dosage range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

PREGNANCY SECTION.

6. Pregnancy. Teratogenic Effects: Pregnancy Category C. Calcitriol has been found to be teratogenic in rabbits when given orally at doses of 0.08 and 0.3 mcg/kg. All 15 fetuses in 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 orally showed no evidence of teratogenic potential. There are no adequate and well-controlled studies in pregnant women. Calcitriol Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.. Nonteratogenic Effects. In the rabbit, oral dosages of 0.3 mcg/kg/day administered on days to 18 of gestation resulted in 19% maternal mortality, decrease in mean fetal body weight and reduced number of newborns surviving to 24 hours. study of the effects of orally administered calcitriol on peri- 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, hypercalcemia and hypophosphatemia in dams given calcitriol at dose of 0.08 or 0.3 mcg/kg/day and increased serum urea nitrogen in dams given calcitriol at dose of 0.3 mcg/kg/day. In another study in rats, maternal weight gain was slightly reduced at an oral dose of 0.3 mcg/kg/day administered on days to 15 of gestation.The offspring of woman administered oral calcitriol at 17 to 36 mcg/day during pregnancy manifested mild hypercalcemia in the first days of life which returned to normal at day 3.

SPL UNCLASSIFIED SECTION.

1. Treatment of Hypercalcemia and Overdosage in Patients on Hemodialysis. General treatment of hypercalcemia (greater than mg/dL above the upper limit of normal range) consists of immediate discontinuation of Calcitriol Injection therapy, institution of low calcium diet and withdrawal of calcium supplements. Serum calcium levels should be determined daily until normocalcemia ensues. Hypercalcemia usually resolves in two to seven days. When serum calcium levels have returned to within normal limits, Calcitriol Injection therapy may be reinstituted at dose 0.5 mcg less than prior therapy. Serum calcium levels should be obtained at least twice weekly after all dosage changes. Persistent or markedly elevated serum calcium levels may be corrected by dialysis against calcium-free dialysate.

STORAGE AND HANDLING SECTION.

Storage and Handling. Store at 20 to 25oC (68 to 77oF) [See USP Controlled Room Temperature].Protect from light.

TERATOGENIC EFFECTS SECTION.

Teratogenic Effects: Pregnancy Category C. Calcitriol has been found to be teratogenic in rabbits when given orally at doses of 0.08 and 0.3 mcg/kg. All 15 fetuses in 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 orally showed no evidence of teratogenic potential. There are no adequate and well-controlled studies in pregnant women. Calcitriol Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

WARNINGS SECTION.

WARNINGS. Since calcitriol is the most potent metabolite of vitamin available, vitamin and its derivatives should be withheld during treatment. non-aluminum phosphate-binding compound should be used to control serum phosphorus levels in patients undergoing dialysis. Overdosage of any form of vitamin is dangerous (see also OVERDOSAGE). Progressive hypercalcemia due to overdosage of vitamin and its metabolites may be so severe as to require emergency attention. Chronic hypercalcemia can lead to generalized vascular calcification, nephrocalcinosis and other soft-tissue calcification. The serum calcium times phosphate (Ca P) product should not be allowed to exceed 70. Radiographic evaluation of suspect anatomical regions may be useful in the early detection of this condition.