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Calcitriol

Pronunciation

Pronunciation

(kal si TRYE ole)

Index Terms

  • 1,25 Dihydroxycholecalciferol

Pharmacologic Category

  • Vitamin D Analog

Pharmacology

Calcitriol, the active form of vitamin D (1,25 hydroxyvitamin D3), binds to and activates the vitamin D receptor in kidney, parathyroid gland, intestine, and bone, stimulating intestinal calcium transport and absorption. It reduces PTH levels and improves calcium and phosphate homeostasis by stimulating bone resorption of calcium and increasing renal tubular reabsorption of calcium. Decreased renal conversion of vitamin D to its primary active metabolite (1,25 hydroxyvitamin D) in chronic renal failure leads to reduced activation of vitamin D receptor, which subsequently removes inhibitory suppression of parathyroid hormone (PTH) release; increased serum PTH (secondary hyperparathyroidism) reduces calcium excretion and enhances bone resorption.

The mechanism by which calcitriol is beneficial in the treatment of psoriasis has not been established.

Absorption

Oral: Rapid

Metabolism

Primarily to calcitroic acid and a lactone metabolite

Excretion

Feces (27%); urine (7%, unchanged in 24 hours)

Clearance: Children 1.8 to 16 years undergoing peritoneal dialysis: 15.3 mL/hour/kg

Onset of Action

Oral: 2 hours; maximum effect: 10 hours

Time to Peak

Oral: 3 to 6 hours; Hemodialysis: 8 to 12 hours

Duration of Action

Oral, IV: 3 to 5 days

Half-Life Elimination

Children 1.8 to 16 years undergoing peritoneal dialysis: 27.4 hours; Healthy adults: 5 to 8 hours; Hemodialysis: 16 to 22 hours

Protein Binding

99.9%

Special Populations: Renal Function Impairment

The half-life is increased by at least 2-fold.

Special Populations: Children

The half-life is prolonged.

Use: Labeled Indications

Management of hypocalcemia in patients on chronic renal dialysis (oral, injection); management of secondary hyperparathyroidism in patients with chronic kidney disease (CKD) not yet on dialysis (predialysis patients) (oral); management of hypocalcemia in patients with hypoparathyroidism and pseudohypoparathyroidism (oral); management of mild-to-moderate plaque psoriasis (topical)

Canadian labeling: Additional uses (not in U.S. labeling): Vitamin D-resistant rickets (oral)

Use: Unlabeled

Vitamin D-dependent rickets type I/pseudovitamin D deficiency rickets (PDDR)

Contraindications

U.S. labeling:

Oral, injection: Hypersensitivity to calcitriol or any component of the formulation; hypercalcemia, vitamin D toxicity

Topical: There are no contraindications listed in the manufacturer's labeling.

Canadian labeling:

Oral, injection: Hypersensitivity to calcitriol, vitamin D or its analogues or derivatives, or any component of the formulation or container; hypercalcemia, vitamin D toxicity

Topical: Ophthalmic or internal use; hypercalcemia or a history of abnormal calcium metabolism; concurrent systemic treatment of calcium homeostasis; severe renal impairment or end-stage renal disease (ESRD)

Dosage

Hypocalcemia in patients on chronic renal dialysis: Adults:

Oral: Initial: 0.25 mcg daily; may increase dose by 0.25 mcg daily at 4- to 8-week intervals (US labeling) or 2- to 4-week intervals (Canadian labeling, up to 0.5-1 mcg daily; patients with normal or mildly decreased serum calcium levels may respond to 0.25 mcg every other day

IV:

U.S. labeling: Initial: 1-2 mcg 3 times weekly approximately every other day. Adjust dose by 0.5-1 mcg at 2- to 4-week intervals; dosing range: 0.5-4 mcg 3 times weekly. Gradual dose reduction and discontinuation of therapy may be necessary as PTH levels decrease below target of (1.5-3 x ULN) in response to therapy.

Canadian labeling: Initial: 0.5 mcg 3 times weekly, approximately every other day. Adjust dose by 0.25-0.5 mcg at 2- to 4-week intervals; dosing range: 0.5-3 mcg 3 times weekly

Hypocalcemia in hypoparathyroidism/pseudohypoparathyroidism:

U.S. labeling: Oral:

Children 1-5 years: Usual dosage range: 0.25-0.75 mcg once daily (may adjust dose at 2- to 4-week intervals)

Children ≥6 years, Adolescents, and Adults: Initial: 0.25 mcg daily (may adjust dose at 2- to 4-week intervals); range: 0.5-2 mcg once daily

Canadian labeling: Oral: Adults: Initial: 0.25 mcg daily; may increase dose by 0.25 mcg daily at 2- to 4-week intervals. Discontinue use immediately for hypercalcemia; may resume therapy after calcium levels normalize.

Psoriasis: Adults: Topical: Apply twice daily to affected areas (maximum: 200 g weekly); Canadian labeling recommends maximum of 30 g daily

Secondary hyperparathyroidism associated with moderate-to-severe CKD in patients not yet on dialysis: U.S. labeling: Oral:

Children <3 years: Initial dose: 0.01-0.015 mcg/kg/day

Children ≥3 years, Adolescents, and Adults: Initial: 0.25 mcg daily; may increase to 0.5 mcg daily

Note: KDIGO guidelines do not recommend routine vitamin D therapy (with vitamin D supplements or a vitamin D analog [eg, calcitriol]) for progressive or persistently elevated PTH concentrations in CKD patients (stages 3-5) not on dialysis in the absence of suspected/documented Vitamin D deficiency. Caution is advised to avoid hypercalcemia or elevated phosphate levels (KDIGO, 2009; KDIGO, 2012; Uhlig, 2010).

Vitamin D-dependent rickets type 1/pseudovitamin D deficiency rickets (PDDR) (off-label use): Adults: Oral: Initial: 0.5 mcg twice daily; subsequent dosing adjusted to maintain normal serum calcium and PTH levels; median dose after 2 years: 0.25 mcg daily (range: 0.1-0.5 mcg daily) (Edouard, 2011)

Vitamin D-resistant rickets: Canadian labeling: Adults: Oral: Initial: 0.25 mcg daily; may increase dose by 0.25 mcg daily at 2- to 4-week intervals if response is inadequate; discontinue use immediately for hypercalcemia and do not resume until calcium levels normalize.

Elderly: Start at the lower end of the dosage range. Refer to adult dosing.

Dosage adjustment in renal impairment: No dosage adjustment necessary.

Dosage adjustment in hepatic impairment: There are no dosage adjustments provided in the manufacturer’s labeling.

Administration

IV: May be administered as a bolus dose IV through the catheter at the end of hemodialysis.

Oral: May be administered without regard to food. Administer with meals to reduce GI problems.

Topical: Apply externally; not for ophthalmic, oral, or intravaginal use. Do not apply to eyes, lips, or facial skins. Rub in gently so that no medication remains visible. Limit application to only the areas of skin affected by psoriasis.

Dietary Considerations

May be taken without regard to food. Give with meals to reduce GI problems. Adequate calcium intake should be maintained during therapy; dietary phosphorous may need to be restricted.

Compatibility

Stable in D5W, NS, SWFI.

Storage

Oral capsule, injection, solution: Store at room temperature of 15°C to 30°C (59°F to 86°F). Protect from light.

Topical: Store at room temperature of 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F); do not refrigerate; do not freeze.

Drug Interactions

Aluminum Hydroxide: Vitamin D Analogs may increase the serum concentration of Aluminum Hydroxide. Specifically, the absorption of aluminum may be increased, leading to increased serum aluminum concentrations. Avoid combination

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Bile Acid Sequestrants: May decrease the serum concentration of Vitamin D Analogs. More specifically, bile acid sequestrants may impair absorption of Vitamin D Analogs. Management: Avoid concomitant administration of vitamin D analogs and bile acid sequestrants (e.g., cholestyramine). Separate administration of these agents by several hours to minimize the potential risk of interaction. Monitor plasma calcium concentrations. Consider therapy modification

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Calcium Salts: May enhance the adverse/toxic effect of Vitamin D Analogs. Monitor therapy

Cardiac Glycosides: Vitamin D Analogs may enhance the arrhythmogenic effect of Cardiac Glycosides. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Corticosteroids (Systemic): May diminish the therapeutic effect of Calcitriol. Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Danazol: May enhance the hypercalcemic effect of Vitamin D Analogs. Monitor therapy

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Magnesium Salts: Calcitriol may increase the serum concentration of Magnesium Salts. Consider therapy modification

Mifepristone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Mineral Oil: May decrease the serum concentration of Vitamin D Analogs. More specifically, mineral oil may interfere with the absorption of Vitamin D Analogs. Management: Avoid concomitant, oral administration of mineral oil and vitamin D analogs. Consider separating the administration of these agents by several hours to minimize the risk of interaction. Monitor plasma calcium concentrations. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Multivitamins/Fluoride (with ADE): May enhance the adverse/toxic effect of Vitamin D Analogs. Avoid combination

Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the adverse/toxic effect of Vitamin D Analogs. Avoid combination

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Orlistat: May decrease the serum concentration of Vitamin D Analogs. More specifically, orlistat may impair absorption of Vitamin D Analogs. Management: Monitor clinical response (including serum calcium) to oral vitamin D analogs closely if used with orlistat. If this combination must be used, consider giving the vitamin D analog at least 2 hrs before or after orlistat. Consider therapy modification

Osimertinib: May increase the serum concentration of CYP3A4 Substrates. Osimertinib may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Sevelamer: May decrease the serum concentration of Calcitriol. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

St Johns Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Sucralfate: Vitamin D Analogs may increase the serum concentration of Sucralfate. Specifically, the absorption of aluminum from sucralfate may be increased, leading to an increase in the serum aluminum concentration. Avoid combination

Thiazide and Thiazide-Like Diuretics: May enhance the hypercalcemic effect of Vitamin D Analogs. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Vitamin D Analogs: May enhance the adverse/toxic effect of other Vitamin D Analogs. Avoid combination

Adverse Reactions

Oral, IV: Frequency not defined.

Cardiovascular: Cardiac arrhythmia, hypertension

Central nervous system: Apathy, drowsiness, headache, hyperthermia, metallic taste, psychosis, sensory disturbance

Dermatologic: Erythema, erythema multiforme, pruritus, skin rash, urticaria

Endocrine & metabolic: Albuminuria, calcinosis, decreased libido, dehydration, growth suppression, hypercalcemia, hypercholesterolemia, polydipsia, weight loss

Gastrointestinal: Abdominal pain, anorexia, constipation, nausea, pancreatitis, stomach pain, vomiting, xerostomia

Genitourinary: Hypercalciuria, nocturia, urinary tract infection

Hepatic: Increased serum ALT, increased serum AST

Hypersensitivity: Hypersensitivity reaction

Local: Pain at injection site (mild)

Neuromuscular & skeletal: Dystrophy, myalgia, ostealgia, weakness

Ophthalmic: Conjunctivitis, photophobia

Renal: Calcium nephrolithiasis, increased blood urea nitrogen, increased serum creatinine, polyuria

Respiratory: Rhinorrhea

Postmarketing and/or case reports: Anaphylaxis

Topical:

>10%: Endocrine: Hypercalcemia (24%)

1% to 10%:

Dermatologic: Psoriasis (4%), skin discomfort (3%), pruritus (1% to 3%)

Genitourinary: Urine abnormality (4%), hypercalciuria (3%)

<1%, postmarketing, and/or case reports: Nephrolithiasis

Warnings/Precautions

Concerns related to adverse effects:

• Excessive vitamin D: Excessive vitamin D administration may lead to over suppression of PTH, progressive or acute hypercalcemia, hypercalciuria, hyperphosphatemia and adynamic bone disease. Withhold pharmacologic doses of vitamin D and its derivatives during therapy to avoid the potential for hypercalcemia to develop. In addition, several months may be required for ergocalciferol levels to return to baseline in patients switching from ergocalciferol therapy to calcitriol.

• Hypercalcemia: Monitor calcium levels closely with initiation of therapy and with dose adjustments; discontinue use promptly in patients who develop hypercalcemia. Avoid abrupt dietary modifications (eg, increased intake of dairy products) which may lead to hypercalcemia; adjust calcium intake if indicated and maintain adequate hydration. Chronic hypercalcemia can result in generalized vascular and soft tissue calcification. Immobilized patients may be at a higher risk for hypercalcemia.

Disease-related concerns:

• Hepatic impairment: Canadian labeling (topical formulation) does not recommend use in patients with hepatic impairment.

• Malabsorption syndrome: Use oral calcitriol with caution in patients with malabsorption syndromes; efficacy may be limited and/or response may be unpredictable.

• Renal impairment: Use of calcitriol for the treatment of secondary hyperparathyroidism associated with CKD is not recommended in patients with rapidly worsening kidney function or in noncompliant patients. Increased serum phosphate levels in patients with renal failure may lead to ectopic calcification; the use of an aluminum-containing phosphate binder is recommended along with a low phosphate diet in these patients. Canadian labeling (topical formulation) does not recommend use in patients with mild-to-moderate renal impairment.

Concurrent drug therapy issues:

• Calcium: Adequate dietary (supplemental) calcium is necessary for clinical response to vitamin D.

• Cardiac glycosides: Use with caution in patients taking cardiac glycosides; digitalis toxicity is potentiated by hypercalcemia.

• Magnesium-containing products: Concomitant use with magnesium-containing products such as antacids may lead to hypermagnesemia in patients receiving chronic renal dialysis.

Dosage form specific issues:

• Aluminum: The parenteral product may contain aluminum; toxic aluminum concentrations may be seen with high doses, prolonged use, or renal dysfunction. Premature neonates are at higher risk due to immature renal function and aluminum intake from other parenteral sources. Parenteral aluminum exposure of >4 to 5 mcg/kg/day is associated with CNS and bone toxicity; tissue loading may occur at lower doses (Federal Register, 2002). See manufacturer’s labeling.

• Coconut oil: Products may contain coconut oil (capsule).

• Palm seed oil: Products may contain palm seed oil (oral solution).

• Tartrazine: Some products may contain tartrazine.

• Topical: May cause hypercalcemia; if alterations in calcium occur, discontinue treatment until levels return to normal. For external use only; not for ophthalmic, oral, or intravaginal use. Do not apply to facial skin, eyes, or lips. Absorption may be increased with occlusive dressings. Avoid or limit excessive exposure to natural or artificial sunlight, or phototherapy. The safety and effectiveness has not been evaluated in patients with erythrodermic, exfoliative, or pustular psoriasis.

Other warnings/precautions:

• Calcium-phosphate product: Discontinue use immediately in adult patients with a calcium-phosphate product (serum calcium times phosphorus) >70 mg2/dL2; may resume therapy at decreased doses when levels are appropriate.

Monitoring Parameters

Manufacturer’s labeling:

Oral therapy:

Dialysis patients: Serum calcium, phosphorus, magnesium, and alkaline phosphate monitored periodically

Hypoparathyroid patients: Serum calcium, phosphorus, 24 hour urinary calcium monitored periodically

Predialysis patients: Serum calcium, phosphorus, alkaline phosphatase, creatinine, and intact PTH, initially; then serum calcium, phosphorus, alkaline phosphatase, and creatinine monthly x 6 months, then periodically. Intact PTH should be monitored every 3-4 months.

During titration periods (all patients), monitor serum calcium levels at least twice weekly.

IV therapy: Serum calcium and phosphorus twice weekly (following initiation and during dosage adjustments) and periodically during therapy; periodic magnesium, alkaline phosphatase, 24 hour urinary calcium and phosphorous

KDIGO guidelines (2009):

Serum calcium, phosphorus, and PTH: CKD stages 3-5D: Frequency of monitoring should be based on the presence and magnitude of abnormalities, as well as the rate of CKD progression. Reasonable intervals are:

CKD stage 3: Serum calcium and phosphorus, every 6 to 12 months; PTH: monitor based on baseline level and CKD progression

CKD stage 4: Serum calcium and phosphorus every 3 to 6 months; PTH every 6 to 12 months

CKD stage 5 (includes 5D): Serum calcium and phosphorus every 1 to 3 months; PTH every 3 to 6 months

Alkaline phosphatase: CKD stages 4-5D: Monitor every 12 months or more frequently in the presence of increased PTH levels

Pregnancy Risk Factor

C

Pregnancy Considerations

Teratogenic effects have been observed in some animal reproduction studies. Mild hypercalcemia has been reported in a newborn following maternal use of calcitriol during pregnancy. Adverse effects on fetal development were not observed with use of calcitriol during pregnancy in women (N=9) with pseudovitamin D-dependent rickets. Doses were adjusted every 4 weeks to keep calcium concentrations within normal limits (Edouard, 2011). If calcitriol is used for the management of hypoparathyroidism in pregnancy, dose adjustments may be needed as pregnancy progresses and again following delivery. Vitamin D and calcium levels should be monitored closely and kept in the lower normal range.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Have patient report immediately to prescriber signs of hypercalcemia, severe skin irritation, signs of fluid and electrolyte imbalance, polyuria, dysgeusia, dyspepsia, or excessive weight loss (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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