Allopathy
Prescription Required
DCGI (Drugs Controller General of India)
Schedule H
Calcitriol belonging to pharmacology class of Vitamin D analogs.
Calcitriol can be used in the treatment of Hypoparathyroidism, Renal osteodystrophy, Secondary hyperparathyroidism in chronic kidney disease, Postmenopausal osteoporosis, Hypocalcemia, Secondary hyperparathyroidism in chronic kidney disease, Plaque psoriasis
Calcitriol is rapidly absorbed from the gastrointestinal tract. Time to peak plasma concentration: Oral: Within 2-6 hours; 8-12 hours (on hemodialysis) and enters breast milk (small amounts). Plasma protein binding: 99.9%, mainly to a specific vitamin D binding protein (DBP) and to a lesser extent to albumin and lipoproteins and get Metabolized in the liver and kidney via hydroxylation and oxidation by CYP24A1 isoenzyme primarily into calcitroic acid and a lactone metabolite and get excreted Mainly via faeces (27%); urine (7% as unchanged drug in 24 hours). Elimination half-life: 5-8 hours; 16-22 hours (on hemodialysis).
The common side effects of Calcitriol includes: Hypercalcemia which may lead to generalized vascular calcification, other soft tissue calcification, nephrocalcinosis, and exacerbated nephrolithiasis; hypercalciuria, hyperphosphatemia, over suppression of PTH, adynamic bone disease (IV), ectopic calcification
Calcitriol is available in the form of Capsules, oral solution and injectable solution.
The molecule is available in India, Japan, Germany, China.
Calcitriol is the active form of vitamin D3 (cholecalciferol). The natural or endogenous supply of vitamin D 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 a 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-αhydroxylase to produce 1,25-(OH)2D3 (calcitriol), the active form of vitamin D3.
Calcitriol, the active form of vitamin D3 (cholecalciferol), binds to and activates the vitamin D receptors in the intestine, kidneys, parathyroid gland and bone, thus stimulating intestinal Ca transport and absorption. It also stimulates bone resorption and increases renal tubular reabsorption of Ca, thereby decreasing PTH levels and improving Ca-phosphate homeostasis. In the treatment of psoriasis, it blocks the proliferation of keratinocytes and T-cells thereby stimulating keratinocytes differentiation and normalizing the production of various inflammation factors, respectively. Synonym: 1α,25-dihydroxyvitamin D3, 1,25-dihydroxycholecalciferol, 1,25-dihydroxyvitamin D3, 1α, 25-dihydroxycholcalciferol.
Calcitriol is approved for use in the following clinical indications
Hypoparathyroidism
Adult: In patients with postsurgical hypoparathyroidism, idiopathic hypoparathyroidism, or pseudohypoparathyroidism: Initially, 0.25 mcg daily given in the morning, may be increased at 2- to 4-week intervals if necessary. Dosage adjustment, dosing interruption, or discontinuation may be required according to individual serum Ca levels (refer to detailed product guideline).
Elderly: Initiate at the lower end of the dosage range.
Oral
Renal osteodystrophy
Adult: In patients undergoing haemodialysis: Initially, 0.25 mcg daily, or 0.25 mcg every other day (in those with normal or only slightly reduced Ca levels), may be increased by 0.25 mcg at 2- to 4-week intervals if necessary. Usual dosing range: 0.5-1 mcg daily. Dosage adjustment, dosing interruption, or discontinuation may be required according to individual serum Ca levels (refer to detailed product guideline).
Oral
Secondary hyperparathyroidism in chronic kidney disease
Adult: In patients with moderate to severe chronic kidney disease (CKD) not yet on dialysis: Initially, 0.25 mcg daily, may be increased to 0.5 mcg daily if necessary.
Elderly: Initiate at the lower end of the dosage range.
Oral
Postmenopausal osteoporosis
Adult: 0.25 mcg bid.
Intravenous
Hypocalcaemia
Adult: In patients undergoing chronic renal dialysis: Usual dose: Initially, 1-2 mcg 3 times weekly, approx every other day, depending on the severity of condition. Dosing range: 0.5-4 mcg 3 times weekly. Dose may be increased by 0.5-1 mcg at 2- to 4-week intervals if necessary. Dosage adjustment, dosing interruption, or discontinuation may be required according to individual PTH, serum Ca, and phosphorus levels (refer to detailed product guideline).
Elderly: Initiate at the lower end of the dosage range.
Intravenous
Secondary hyperparathyroidism in chronic kidney disease
Adult: In patients undergoing chronic renal dialysis: Usual dose: Initially, 1-2 mcg 3 times weekly, approx every other day, depending on the severity of condition. Dosing range: 0.5-4 mcg 3 times weekly. Dose may be increased by 0.5-1 mcg at 2- to 4-week intervals if necessary. Dosage adjustment, dosing interruption, or discontinuation may be required according to individual PTH, serum Ca, and phosphorus levels (refer to detailed product guideline).
Elderly: Initiate at the lower end of the dosage range.
Topical/Cutaneous
Plaque psoriasis
Adult: In patients with mild to moderately severe cases with up to 35% of BSA involvement: As 3 mcg/g ointment: Apply onto the affected area bid. Max: 30 g daily.
Renal impairment: Contraindicated.
Hepatic impairment: Contraindicated.
Hypoparathyroidism
Adult: In patients with postsurgical hypoparathyroidism, idiopathic hypoparathyroidism, or pseudohypoparathyroidism: Initially, 0.25 mcg daily given in the morning, may be increased at 2- to 4-week intervals if necessary. Dosage adjustment, dosing interruption, or discontinuation may be required according to individual serum Ca levels (refer to detailed product guideline).
Elderly: Initiate at the lower end of the dosage range.
Oral
Renal osteodystrophy
Adult: In patients undergoing haemodialysis: Initially, 0.25 mcg daily, or 0.25 mcg every other day (in those with normal or only slightly reduced Ca levels), may be increased by 0.25 mcg at 2- to 4-week intervals if necessary. Usual dosing range: 0.5-1 mcg daily. Dosage adjustment, dosing interruption, or discontinuation may be required according to individual serum Ca levels (refer to detailed product guideline).
Oral
Secondary hyperparathyroidism in chronic kidney disease
Adult: In patients with moderate to severe chronic kidney disease (CKD) not yet on dialysis: Initially, 0.25 mcg daily, may be increased to 0.5 mcg daily if necessary.
Elderly: Initiate at the lower end of the dosage range.
Oral
Postmenopausal osteoporosis
Adult: 0.25 mcg bid.
Intravenous
Hypocalcaemia
Adult: In patients undergoing chronic renal dialysis: Usual dose: Initially, 1-2 mcg 3 times weekly, approx every other day, depending on the severity of condition. Dosing range: 0.5-4 mcg 3 times weekly. Dose may be increased by 0.5-1 mcg at 2- to 4-week intervals if necessary. Dosage adjustment, dosing interruption, or discontinuation may be required according to individual PTH, serum Ca, and phosphorus levels (refer to detailed product guideline).
Elderly: Initiate at the lower end of the dosage range.
Intravenous
Secondary hyperparathyroidism in chronic kidney disease
Adult: In patients undergoing chronic renal dialysis: Usual dose: Initially, 1-2 mcg 3 times weekly, approx every other day, depending on the severity of condition. Dosing range: 0.5-4 mcg 3 times weekly. Dose may be increased by 0.5-1 mcg at 2- to 4-week intervals if necessary. Dosage adjustment, dosing interruption, or discontinuation may be required according to individual PTH, serum Ca, and phosphorus levels (refer to detailed product guideline).
Elderly: Initiate at the lower end of the dosage range.
Topical/Cutaneous
Plaque psoriasis
Adult: In patients with mild to moderately severe cases with up to 35% of BSA involvement: As 3 mcg/g ointment: Apply onto the affected area bid. Max: 30 g daily.
Renal impairment: Contraindicated.
Hepatic impairment: Contraindicated.
Capsules, Oral Solution and Injectable Solution
0.25 mcg, 0.5 mcg, 1 mcg, 1 mcg/ml
Capsules, Oral Solution and Injectable Solution.
Calcitriol may be contraindicated in the following conditions:-
Hypersensitivity. Pre-existing hypercalcaemia, skeletal malignancies or bone metastases, other metabolic bone diseases (e.g. Paget's disease, hyperparathyroidism), unexplained elevations of alkaline phosphatase, previous implant or external beam radiation therapy to the skeleton, hereditary disorders predisposing to osteosarcoma. Young adults with open epiphyses. Severe renal impairment. Pregnancy.
Since calcitriol is the most potent metabolite of vitamin D available, prescription-based doses of vitamin D and its derivatives should be withheld or used with caution during treatment to avoid the risk of hypercalcemia. A non-aluminum phosphate-binding compound should be used to control serum phosphorus levels in patients undergoing dialysis.
Overdosage of any form of vitamin D is dangerous. Progressive hypercalcemia due to overdosage of vitamin D 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 x P) product should not be allowed to exceed 70 mg2 /dL2 . Radiographic evaluation of suspect anatomical regions may be useful in the early detection of this condition.
Precautions
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 should be given cautiously to patients on digitalis, because hypercalcemia in such patients may precipitate cardiac arrhythmias. 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. 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 3 times the upper limit of normal), in patients treated with Calcitriol, the Calcitriol dose should be reduced or therapy discontinued. Discontinuation of Calcitriol therapy may result in rebound effect, therefore, appropriate titration downward to a maintenance dose is recommended.
Alcohol Warning
There is no sufficient scientific evidence traceable regarding use and safety of Calcitriol in concurrent use with alcohol.
Breast Feeding Warning
It is not known if Calcitriol is present in breast milk.
Pregnancy Warning
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 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 orally showed no evidence of teratogenic potential. There are no adequate and well-controlled studies in pregnant women. Calcitriol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
The adverse reactions related to Calcitriol can be categorized as
Common Adverse effects:
Hypercalcemia which may lead to generalized vascular calcification, other soft tissue calcification, nephrocalcinosis, and exacerbated nephrolithiasis; hypercalciuria, hyperphosphatemia, over suppression of PTH, adynamic bone disease (IV), ectopic calcification.
Less Common Adverse effects:
Severe irritation and contact allergy (topical). Eye disorders: Photophobia, calcific conjunctivitis.
Rare Adverse effects:
Rash, pruritus, erythema, skin discomfort or irritation, dry skin, aggravated psoriasis.
The clinically relevant drug interactions of Calcitriol is briefly summarized here
- Concomitant use of magnesium-containing preparations should be used with caution or avoided since such use may lead to the development of hypermagnesemia.
- Corticosteroids with glucocorticoid activity may counteract the bone and mineral metabolism effects of vitamin D analogues.
- Cytochrome P450 enzyme-inducing anticonvulsants such as carbamazepine, phenobarbital and phenytoin may reduce the effects of vitamin D because they increase vitamin D catabolism.
- Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of Calcitriol (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 a Segment I study in rats using oral calcitriol at doses of up to 0.3 mcg/kg.
The most common side effects of Calcitriol includes: Hypercalcemia which may lead to generalized vascular calcification, other soft tissue calcification, nephrocalcinosis, and exacerbated nephrolithiasis; hypercalciuria, hyperphosphataemia, over suppression of PTH, adynamic bone disease (IV), ectopic calcification.
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 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 orally showed no evidence of teratogenic potential. There are no adequate and well-controlled studies in pregnant women. Calcitriol 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 7 to 18 of gestation resulted in 19% maternal mortality, a decrease in mean fetal body weight and a reduced number of newborns surviving to 24 hours. A study of the effects on 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 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 an oral dose of 0.3 mcg/kg/day administered on days 7 to 15 of gestation. The offspring of a woman administered oral calcitriol at 17 to 36 mcg/day during pregnancy manifested mild hypercalcemia in the first 2 days of life which returned to normal at day 3.
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, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use The safety and effectiveness of Calcitriol were examined in a 12-week randomized, double-blind, placebocontrolled study of 35 pediatric 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 D therapy prior to the study. The initial dose of Calcitriol was 0.5 mcg, 1.0 mcg, or 1.5 mcg, 3 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 was adjusted in 0.25 mcg increments based on the levels of serum iPTH, calcium, and Ca x P. The mean baseline levels of iPTH were 769 pg/mL for the 16 Calcitriol-treated patients and 897 pg/mL for the 19 placebo-treated subjects. The mean weekly dose of Calcitriol ranged from 1.0 mcg to 1.4 mcg. In the primary efficacy analysis, 7 of 16 (44%) subjects in the Calcitriol group had 2 consecutive 30% decreases from baseline iPTH compared with 3 of 19 (16%) patients in the placebo group (95% CI for the difference between groups -6%, 62%). One Calcitriol-treated patient experienced transient hypercalcemia (> 11.0 mg/dL), while 6 of 16 (38%) Calcitriol-treated patients vs. 2 of 19 (11%) placebotreated patients experienced Ca x P > 75.
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 dosage range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
- Administration of Calcitriol to patients in excess of their requirements can cause hypercalcemia, hypercalciuria and hyperphosphatemia.
- High intake of calcium and phosphate concomitant with Calcitriol may lead to similar abnormalities
Treatment of Hypercalcemia and Overdosage in Patients on Hemodialysis
General treatment of hypercalcemia (greater than 1 mg/dL above the upper limit of 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 usually resolves in two to seven days. When serum calcium levels have returned to within normal limits, Calcitriol therapy may be reinstituted at a 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 a calcium-free dialysate.
Treatment of Accidental Overdosage of Calcitriol Injection
The treatment of acute accidental overdosage of Calcitriol 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 a 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 a calcium-free dialysate has also been reported.
Pharmacodynamics:
Calcitriol is synthetically manufactured calcitriol and is available as a sterile, isotonic, clear, colorless to yellow, aqueous solution for intravenous injection. Calcitriol is available in 1 mL ampuls. Each 1 mL contains calcitriol, 1 mcg; Polysorbate 20, 4 mg; sodium ascorbate 2.5 mg added. May contain hydrochloric acid and/or sodium hydroxide for pH adjustment. pH is 6.5 (5.9 to 7.0). Contains no more than 1 mcg/mL of aluminum.
Pharmacokinetics:
Absorption Rapidly and extensively absorbed. Absolute bioavailability: Approx 95%. Time to peak plasma concentration: Approx 30 minutes.
Distribution: Volume of distribution: Approx 0.12 L/kg.
Metabolism: Intact PTH and the N-terminal 34-amino acid sequence of PTH are suspected to undergo nonspecific proteolysis in the liver.
Excretion: Via urine (as metabolites). Elimination half-life: Approx 1 hour.
- https://www.uptodate.com/contents/ Calcitriol -drug-information?search= Calcitriol &source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F154338
- https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf
- https://www.medicaid.nv.gov/Downloads/provider/ Calcitriol _2015-1215.pdf
- https://www.mims.com/india/drug/info/ Calcitriol ?type=full&mtype=generic#mechanism-of-action
