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  • CLASSES

    Topical Antipsoriasis Agents
    Vitamin D Supplements

    DEA CLASS

    Rx

    DESCRIPTION

    Active form of vitamin D3 (cholecalciferol)
    Used for secondary hyperparathyroidism, metabolic bone disease in chronic renal failure patients not receiving dialysis, hypoparathyroidism, familial hypophosphatemia, and vitamin D-dependent rickets
    More than twice the vitamin D activity of calcifediol

    COMMON BRAND NAMES

    Calcijex, Rocaltrol, Vectical

    HOW SUPPLIED

    Calcijex/Calcitriol Intramuscular Inj Sol: 1mcg, 1ml
    Calcijex/Calcitriol Intravenous Inj Sol: 1mcg, 1ml
    Calcitriol/Rocaltrol Oral Cap: 0.25mcg, 0.5mcg
    Calcitriol/Rocaltrol Oral Sol: 1mcg, 1mL
    Calcitriol/Vectical Topical Ointment: 1g, 3mcg

    DOSAGE & INDICATIONS

    For the treatment of hypocalcemia and secondary hyperparathyroidism and resultant metabolic bone disease (renal osteodystrophy) in patients with chronic kidney disease.
    For the treatment of hypocalcemia and secondary hyperparathyroidism and resultant metabolic bone disease (renal osteodystrophy) in predialysis patients with moderate to severe chronic kidney disease.
    NOTE: Assess serum calcium, phosphorus, alkaline phosphatase, and creatinine concentrations at baseline, monthly for 6 months, then periodically. Monitor serum iPTH at baseline and then every 3 to 4 months. During dosage titration, monitor serum calcium concentrations at least twice weekly.
    Oral dosage
    Adults

    0.25 mcg PO once daily, initially. May increase dosage to 0.5 mcg/day if necessary.[30153]

    Children and Adolescents 3 to 17 years

    0.25 mcg PO once daily, initially. May increase dosage to 0.5 mcg/day if necessary.[30153]

    Infants and Children 1 month to 2 years

    0.01 to 0.015 mcg/kg/dose PO once daily, initially. May increase dosage if necessary. Max: 0.5 mcg/day.

    For the treatment of hypocalcemia and secondary hyperparathyroidism and resultant metabolic bone disease (renal osteodystrophy) in dialysis patients.
    NOTE: Assess serum calcium, phosphorus, magnesium, alkaline phosphatase, iPTH, and 24-hour urinary calcium and phosphorus concentrations periodically. During dosage titration, monitor serum calcium and phosphorus concentrations twice weekly.
    Oral dosage
    Adults

    0.25 mcg PO once daily, initially. May increase dosage by 0.25 mcg/day every 4 to 8 weeks if necessary. Patients with normal or only slightly reduced serum calcium concentrations may respond to doses of 0.25 mcg every other day. Most patients undergoing dialysis respond to 0.5 to 1 mcg/day.

    Intravenous dosage
    Adults

    1 mcg (0.02 mcg/kg) to 2 mcg IV 3 times weekly, approximately every other day. Initial doses of 0.5 to 4 mcg IV 3 times weekly have been used. May increase dosage by 0.5 to 1 mcg every 2 to 4 weeks if necessary based on iPTH concentrations. Increase dosage if iPTH concentration is same, increasing, or decreasing less than 30% from baseline and decrease dosage if iPTH concentration is decreasing more than 60% from baseline; maintain calcitriol dose if iPTH concentration is decreasing 30% to 60% from baseline or 1.5- to 3-times the upper limit of normal. Hold therapy for hypercalcemia or serum calcium-phosphorus product (Ca x PO4) more than 70; resume at lower dose once parameters normalize.[60115]

    Adolescents

    0.5 to 1.5 mcg IV 3 times weekly, approximately every other day. In a double-blind, placebo-controlled clinical study of adolescents (n = 35) with end-stage renal disease on hemodialysis, patients received 0.5 mcg IV for a baseline iPTH concentration less than 500 pg/mL, 1 mcg IV for a baseline iPTH concentration of 500 to 1,000 pg/mL, and 1.5 mcg IV for a baseline iPTH concentration of more than 1,000 pg/mL. May increase dosage by 0.25 mcg every 2 weeks if necessary based on serum iPTH, calcium, and calcium-phosphorus product (Ca x PO4). Increase dose by 0.25 mcg for calcium 11 mg/dL or less, Ca x PO4 75 mg2/dL2 or less, and iPTH not decreased by at least 30% from baseline; decrease dose by 0.25 mcg for calcium 11 mg/dL or less, Ca x PO4 75 mg2/dL2 or less, and iPTH less than 200 pg/mL or iPTH decreased more than 60% from baseline or calcium 11 mg/dL or less and Ca x PO4 more than 75 mg2/dL2; for calcium more than 11 mg/dL, hold therapy and resume dose at 50% once calcium is 10.5 mg/dL or less. Maintain dose for calcium 11 mg/dL or less, Ca x PO4 75 mg2/dL2 or less, iPTH 200 pg/mL or more, and iPTH decreased from 30% to 60% from baseline.

    For the treatment of patients with postsurgical hypoparathyroidism, idiopathic hypoparathyroidism and pseudohypoparathyroidism manifesting as hypocalcemia.
    Oral dosage
    Adults

    0.25 mcg PO once daily, initially. May increase dosage every 2 to 4 weeks if necessary. Usual dose: 0.5 to 2 mcg/day.

    Children and Adolescents 6 to 17 years

    0.25 mcg PO once daily, initially. May increase dosage every 2 to 4 weeks if necessary. Usual dose: 0.5 to 2 mcg/day.[30153]

    Children 1 to 5 years

    0.25 mcg PO once daily, initially. May increase dosage every 2 to 4 weeks if necessary. Usual dose: 0.25 to 0.75 mcg/day.

    Neonates† and Infants†

    0.25 mcg PO once daily.

    For the treatment of mild to moderate plaque psoriasis.
    NOTE: According to the American Academy of Dermatology (AAD), combining calcitriol with a topical corticosteroid is more effective than either treatment alone. In addition, fewer adverse events were reported with combination therapy in most clinical studies.
    Topical dosage (Vectical ointment)
    Adults

    Apply topically to the affected areas twice daily. Do not exceed 200 g ointment per week.

    Children and Adolescents 7 to 17 years

    Apply topically to the affected areas twice daily. Do not exceed 200 g ointment per week.

    Children 2 to 6 years

    Apply topically to the affected areas twice daily. Do not exceed 100 g ointment per week.

    For the management of hypocalcemia associated with vitamin D deficiency†.
    NOTE: For hypocalcemia associated with chronic kidney disease, see hyperparathyroidism indication.
    Oral dosage
    Infants, Children, and Adolescents

    0.05 mcg/kg/day PO (Max: 0.5 mcg/day) until calcium levels normalize; give in addition to calcium supplements.

    For the treatment of vitamin D-dependent rickets†.
    Oral dosage
    Adults

    1 mcg PO once daily.

    Children and Adolescents

    1 mcg PO once daily.

    For the treatment of familial hypophosphatemia†.
    Oral dosage
    Adults

    2 mcg PO once daily.

    Children and Adolescents

    0.015 to 0.02 mcg/kg PO once daily initially. Maintenance dosage is 0.03 to 0.06 mcg/kg PO once daily. Max: 2 mcg/day PO.

    For the treatment of postmenopausal osteoporosis†.
    Oral dosage
    Postmenopausal females

    0.25 mcg PO twice daily. Modify dose according to serum calcium concentration.

    For osteoporosis prophylaxis† in recipients of chronic corticosteroid therapy.
    Oral dosage
    Adults

    Calcitriol 0.5 to 1 mcg/day PO was beneficial in preventing bone loss in patients receiving corticosteroid therapy for 2 years, although benefit was seen only in lumbar spine. In this study, the mean daily dose of prednisone was 13.5 mg/day.

    For the treatment of osteopetrosis†.
    Oral dosage
    Children

    High-dose calcitriol 1 to 2 mcg/kg/day PO, given in 4 to 6 divided doses has been shown to stimulate osteoclast activity and bone resorption in some but not all patients. Treatment with calcitriol only seems to be effective for as long as therapy is continued; indicators of bone resorption fall rapidly when calcitriol therapy is stopped.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    200 g ointment/week topically. Specific maximum dosage information for systemic use is not available; individualize dosage based on clinical parameters.

    Geriatric

    200 g ointment/week topically. Specific maximum dosage information for systemic use is not available; individualize dosage based on clinical parameters.

    Adolescents

    200 g ointment/week topically. Specific maximum dosage information for systemic use is not available; individualize dosage based on clinical parameters.

    Children

    7 to 12 years: 200 g ointment/week topically. Specific maximum dosage information for systemic use is not available; individualize dosage based on clinical parameters.
    2 to 6 years: 100 g ointment/week topically. Specific maximum dosage information for systemic use is not available; individualize dosage based on clinical parameters.

    Infants

    Safety and efficacy of the topical ointment have not been established. Specific maximum dosage information for systemic use is not available; individualize dosage based on clinical parameters.

    Neonates

    Safety and efficacy have not been established; however, 0.25 mcg/day PO has been used off-label.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

     
    NOTE: Patients must receive an adequate amount of calcium while taking calcitriol. Patients are advised to have a dietary intake of calcium of at least 600 mg/day. The US RDA for calcium in adults is 1000—1500 mg/day.

    Oral Administration

    Calcitriol may be administered without regard to meals.
    Calcitriol capsules and oral solution should be protected from light.
    During titration of calcitriol, serum calcium should be monitored twice weekly. If hypercalcemia develops, discontinue calcitriol until normocalcemia is noted.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
    During titration period, serum calcium and phosphorus levels should be monitored twice weekly.

    Intravenous Administration

    No dilution necessary.
    Administer by rapid IV injection through the catheter at the end of a hemodialysis session.

    Topical Administration

    For external use only. Do not apply to the face, lips, or eyes.
    Wash hands after use.
    Apply a thin film to the affected area and rub into the skin gently and completely.

    STORAGE

    Calcijex:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in carton until time of use
    Rocaltrol:
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Vectical:
    - Do not freeze
    - Do not refrigerate
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Patients must receive an adequate amount of calcium while taking calcitriol. Patients are advised to have a dietary intake of calcium of at least 600 mg/day. The US RDA for calcium in adults is 1000-1500 mg/day.

    Hypercalcemia, hypervitaminosis D, occlusive dressing, renal failure

    Calcitriol is a potent vitamin D analog and should not be given to patients with hypercalcemia or hypervitaminosis D. Increased calcium levels may also occur with topical administration. Do not cover with an occlusive dressing as this may enhance the absorption of calcitriol. Chronic hypercalcemia can lead to soft tissue calcification, nephrocalcinosis, and other toxicities. The serum calcium times phosphate (Ca x P) product should not exceed 70. Radiographic evaluation of suspect areas may be useful in the early detection of soft tissue calcification. Patients with renal failure may be at increased risk for vitamin D-induced hypercalcemia even with usual dosages. During titration of calcitriol dose, serum calcium levels should be monitored twice weekly. If hypercalcemia develops or if the calcium-phosphorus product (Ca x PO4) is greater than 70, discontinue calcitriol until these parameters normalize.

    Accidental exposure, ocular exposure

    Calcitriol topical ointment should not be applied to the face; avoid ocular exposure. Accidental exposure to unaffected areas of skin may lead to skin irritation and should be avoided.

    Hyperphosphatemia

    Calcitriol should be used cautiously in patients with hyperphosphatemia due to the risk of metastatic calcification. Treatment with calcitriol may be initiated after stabilization of phosphorus levels.

    Arteriosclerosis, cardiac disease

    Calcitriol should be administered with caution to patients with cardiac disease, arteriosclerosis, or those receiving digoxin because hypercalcemia and/or cardiac arrhythmias can result.

    Geriatric

    Clinical experience has not identified differences in responses between geriatric and younger patients receiving calcitriol. However, dosage should be initiated conservatively, at the lower end of the adult dosage range, reflecting the greater frequency of decreased hepatic and renal function in the elderly.

    Dehydration

    Patients who are taking calcitriol should avoid dehydration. Adequate fluid intake should be maintained.

    Sarcoidosis

    Patients with sarcoidosis, and possibly other granulomatous diseases, may have increased sensitivity to the effects of vitamin D analogs (e.g., calcitriol).

    Sunlight (UV) exposure

    Excessive exposure to natural or artificial sunlight (UV) exposure with topical application of calcitriol may increase the risk of skin tumor formation and should be avoided. It may also be prudent to limit or avoid the use of phototherapy or other photosensitizing agents.

    Pregnancy

    There are no adequate and well-controlled studies of calcitriol in pregnant women. Systemic absorption may occur after topical application. During calcitriol administration to pregnant women, major birth defects, miscarriages, or adverse maternal or fetal outcomes were not identified during the clinical development of calcitriol ointment or in published case series of oral and intravenous calcitriol. However, in animal studies, topical administration of calcitriol to pregnant rabbits during the period of organogenesis resulted in an increased incidence of fetal deaths, as well as an increased incidence of minor skeletal abnormalities. External and skeletal abnormalities were observed when oral calcitriol at doses of 0.08 and 0.3 mcg/kg (approximately 2 and 6 times the maximum recommended dose based on mg/m2) was administered to rabbits. Teratogenicity studies in rats at doses up to 0.45 mcg/kg (approximately 5 times maximum recommended dose based on mg/m2) showed no evidence of teratogenic potential. Calcitriol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Most pregnant patients with hypoparathyroidism are managed with vitamin D analogs similar to when they are not pregnant. However, pregnancy is associated with variable changes in calcium homeostasis due to pregnancy-induced alterations in the production, metabolism, and excretion of calcium and calcitropic hormones. The pregnant female requiring calcitriol therapy will require close monitoring, as calcitriol requirements may change during pregnancy. Published literature indicates those changes may be highly variable patient to patient. In one female, oral calcitriol administered at 17 to 36 mcg/day during pregnancy resulted in mild hypercalcemia in the neonate during the first 2 days of life which returned to normal on the third day. Hypercalcemia during pregnancy has been associated with suppression of parathyroid hormone in the neonate, resulting in mental retardation and congenital aortic stenosis; close monitoring is needed to maintain calcium homeostasis and avoid this potential side effect of therapy. The risks to benefits of untreated hypoparathyroidism or hypophosphatemia in the mother should be considered before using vitamin D analogs such as calcitriol.

    Breast-feeding

    Systemically administered vitamin D and its metabolites, including calcitriol, are distributed in small amounts into breast milk. Most patients with hypoparathyroidism are managed with vitamin D analogs similar to when they are not nursing, and breast-feeding may be continued. However, lactation is associated with variable changes in calcium homeostasis due to postpartum and lactation-induced alterations in the production, metabolism, and excretion of calcium and calcitropic hormones. The lactating female who requires calcitriol therapy will require close monitoring, as calcitriol requirements may decrease. Published literature indicates requirements may be highly variable patient to patient. It is not known whether topical administration of calcitriol could result in sufficient systemic absorption to produce detectable quantities in breast milk. To avoid direct infant exposure, calcitriol ointment should not be applied directly to the nipple and areola. Close monitoring of the mother is needed to maintain calcium homeostasis and avoid hypercalcemia and other potential side effects of therapy during lactation; it is recommended that the nursing infant also receive monitoring to ensure proper calcium homeostasis.

    ADVERSE REACTIONS

    Severe

    hypervitaminosis D / Delayed / Incidence not known
    acute generalized exanthematous pustulosis (AGEP) / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known

    Moderate

    hypercalcemia / Delayed / 33.0-33.0
    hypercalciuria / Delayed / 3.0-14.0
    psoriasis / Delayed / 4.0-4.0
    hypertension / Early / Incidence not known
    hyperthermia / Delayed / Incidence not known
    ataxia / Delayed / Incidence not known
    constipation / Delayed / Incidence not known
    photophobia / Early / Incidence not known
    growth inhibition / Delayed / Incidence not known
    dehydration / Delayed / Incidence not known
    hyperphosphatemia / Delayed / Incidence not known
    contact dermatitis / Delayed / Incidence not known
    erythema / Early / Incidence not known
    nephrolithiasis / Delayed / Incidence not known

    Mild

    pruritus / Rapid / 3.0-3.0
    diarrhea / Early / Incidence not known
    tinnitus / Delayed / Incidence not known
    myalgia / Early / Incidence not known
    rhinorrhea / Early / Incidence not known
    nausea / Early / Incidence not known
    xerostomia / Early / Incidence not known
    vertigo / Early / Incidence not known
    libido decrease / Delayed / Incidence not known
    polyuria / Early / Incidence not known
    irritability / Delayed / Incidence not known
    polydipsia / Early / Incidence not known
    vomiting / Early / Incidence not known
    fatigue / Early / Incidence not known
    arthralgia / Delayed / Incidence not known
    abdominal pain / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    metallic taste / Early / Incidence not known
    headache / Early / Incidence not known
    weakness / Early / Incidence not known
    injection site reaction / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known
    rash / Early / Incidence not known

    DRUG INTERACTIONS

    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Aluminum Hydroxide; Magnesium Hydroxide: (Major) Avoid vitamin D analog coadministration with magnesium hydroxide in persons on chronic hemodialysis due to the risk for hypermagnesemia.
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Major) Avoid vitamin D analog coadministration with magnesium hydroxide in persons on chronic hemodialysis due to the risk for hypermagnesemia.
    Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Atenolol; Chlorthalidone: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Azilsartan; Chlorthalidone: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Barbiturates: (Moderate) Barbiturates can decrease the activity of vitamin D by increasing its metabolism. In rare cases, this has caused anticonvulsant-induced rickets and osteomalacia. Vitamin D supplementation may be required in patients with inadequate dietary intake of vitamin D who are receiving chronic treatment with barbiturates.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Bendroflumethiazide; Nadolol: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Burosumab: (Contraindicated) Vitamin D analogs are contraindicated in patients receiving burosumab; discontinue vitamin D analogs 1 week prior to initiation of burosumab.
    Calcifediol: (Major) Withhold calcifediol treatment when using other vitamin D analogs, like calcitrol, due to the risk of additive toxicity including hypercalcemia, hypercalciuria, and hyperphosphatemia.
    Calcitonin: (Moderate) Calcitonin is given to hypercalcemic patients to reduce serum calcium concentrations. For the treatment of hypercalcemia, vitamin D preparations should be avoided. Vitamin D analogs can elevate serum calcium concentrations and antagonize the effects of the calcitonin for this condition. For the treatment of osteoporosis adequate intake of vitamin D is necessary in conjunction with calcitonin. An increase in serum calcium concentrations helps to reduce bone resorption and loss of bone mass, and offsets the effect of calcitonin in lowering serum calcium levels.
    Calcium Acetate: (Moderate) Monitor serum calcium concentrations during concomitant use of high doses of calcium and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Calcium Carbonate: (Moderate) Monitor serum calcium concentrations during concomitant use of high doses of calcium and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Moderate) Monitor serum calcium concentrations during concomitant use of high doses of calcium and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Calcium Carbonate; Magnesium Hydroxide: (Moderate) Monitor serum calcium concentrations during concomitant use of high doses of calcium and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Moderate) Monitor serum calcium concentrations during concomitant use of high doses of calcium and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Calcium Carbonate; Risedronate: (Moderate) Monitor serum calcium concentrations during concomitant use of high doses of calcium and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Calcium Carbonate; Simethicone: (Moderate) Monitor serum calcium concentrations during concomitant use of high doses of calcium and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Calcium Chloride: (Moderate) Monitor serum calcium concentrations during concomitant use of high doses of calcium and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Calcium Gluconate: (Moderate) Monitor serum calcium concentrations during concomitant use of high doses of calcium and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Calcium: (Moderate) Monitor serum calcium concentrations during concomitant use of high doses of calcium and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Calcium; Vitamin D: (Moderate) Monitor serum calcium concentrations during concomitant use of high doses of calcium and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Chlorothiazide: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Chlorthalidone: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Chlorthalidone; Clonidine: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Cholestyramine: (Moderate) Separate administration of calcitriol by 1 hour before or 4 hours after a cholestyramine dose to limit effects on oral absorption. Dose adjustment of calcitriol may be necessary during coadministration with cholestyramine. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with cholestyramine. Cholestyramine can decrease the intestinal absorption of fat-soluble vitamins like calcitriol.
    Chromium: (Moderate) Monitor serum calcium concentrations during concomitant use of high doses of calcium and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Colestipol: (Moderate) Separate administration of calcitriol by 1 hour before or 4 hours after a colestipol dose to limit effects on oral absorption. Because it sequesters bile acids, colestipol may interfere with normal fat absorption and thus may reduce absorption of fat-soluble vitamins like calcitriol.
    Digoxin: (Moderate) Monitor serum calcium concentration and for digoxin toxicity during concomitant calcitriol and digoxin use. Calcitriol may cause hypercalcemia, which may precipitate digoxin toxicity and cardiac arrhythmias.
    Dihydrotachysterol: (Major) The use of dihydrotachysterol with calcitriol is not recommended because of the increased potential for additive effects and toxicity. Due to the possibility of systemic absorption after topical administration of calcitriol, caution may be warranted in patients receiving high doses of dihydrotachysterol.
    Doxercalciferol: (Major) The use of doxercalciferol with calcitriol is not recommended because of the increased potential for additive effects and toxicity. Due to the possibility of systemic absorption after topical administration of calcitriol, caution may be warranted in patients receiving high doses of doxercalciferol.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Erdafitinib: (Major) Avoid coadministration of calcitriol with erdafitinib before the initial dose increase period (days 14 to 21) which is based on serum phosphate levels. Calcitriol can increase serum phosphate levels. Erdafitinib causes hyperphosphatemia as a consequence of FGFR inhibition; additionally, the initial dose increase of erdafitinib on days 14 to 21 is based on serum phosphate levels. Changes in serum phosphate levels by calcitriol may interfere with the determination of this initial dose increase and may cause additive hyperphosphatemia.
    Ethotoin: (Moderate) Dosage adjustments of vitamin D analogs may be required during coadministration with phenytoin and fosphenytoin (which is metabolized to phenytoin). Phenytoin can increase the metabolism of endogenous vitamin D, thereby lowering serum concentrations and decreasing its activity. In rare cases, this has caused antiepileptic drug-induced rickets and osteomalacia.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Fosphenytoin: (Moderate) Dosage adjustments of vitamin D analogs may be required during coadministration with phenytoin and fosphenytoin (which is metabolized to phenytoin). Phenytoin can increase the metabolism of endogenous vitamin D, thereby lowering serum concentrations and decreasing its activity. In rare cases, this has caused antiepileptic drug-induced rickets and osteomalacia.
    Hydantoins: (Moderate) Dosage adjustments of vitamin D analogs may be required during coadministration with phenytoin and fosphenytoin (which is metabolized to phenytoin). Phenytoin can increase the metabolism of endogenous vitamin D, thereby lowering serum concentrations and decreasing its activity. In rare cases, this has caused antiepileptic drug-induced rickets and osteomalacia.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Ibritumomab Tiuxetan: (Major) High intake of phosphates concomitantly with vitamin D analogs may lead to hyperphosphatemia. Dose adjustment of vitamin D analogs may be necessary during coadministration with phosphorus salts. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia.
    Irbesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Ketoconazole: (Moderate) Ketoconazole may inhibit both synthetic and catabolic enzymes of calcitriol. Reductions in endogenous serum calcitriol concentrations have been observed following the the administration of ketoconazole 300 to 1,200 mg/day.
    Levoketoconazole: (Moderate) Ketoconazole may inhibit both synthetic and catabolic enzymes of calcitriol. Reductions in endogenous serum calcitriol concentrations have been observed following the the administration of ketoconazole 300 to 1,200 mg/day.
    Lisinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Magnesium Citrate: (Major) Avoid vitamin D analog coadministration with magnesium citrate in persons on chronic hemodialysis due to the risk for hypermagnesemia.
    Magnesium Hydroxide: (Major) Avoid vitamin D analog coadministration with magnesium hydroxide in persons on chronic hemodialysis due to the risk for hypermagnesemia.
    Magnesium Salts: (Major) Avoid vitamin D analog coadministration with magnesium-containing products, such as antacids, in persons on chronic hemodialysis due to the risk for hypermagnesemia.
    Magnesium: (Major) Avoid vitamin D analog coadministration with magnesium-containing products, such as antacids, in persons on chronic hemodialysis due to the risk for hypermagnesemia.
    Methyclothiazide: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Metolazone: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Mineral Oil: (Moderate) Separate administration of oral vitamin D analogs by 1 hour before or 4 to 6 hours after mineral oil to limit effects on absorption and availability of the vitamin D analog. Absorption of fat-soluble vitamins may be decreased with concomitant administration of mineral oil. The bioavailability of orally administered vitamin D analogs may also be decreased.
    Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Orlistat: (Moderate) Orlistat reduced the absorption of fat-soluble vitamins absorption during clinical trials. The bioavailability of orally administered vitamin D analogs may also be decreased. In patients receiving orally-administered vitamin D analogs along with orlistat, close monitoring is recommended. In addition, the manufacturer recommends that fat-soluble vitamin analogs be administered at least 2 hours before or after the administration of orlistat to limit effects on oral absorption.
    Paricalcitol: (Major) The use of paricalcitol with calcitriol is not recommended because of the increased potential for additive effects and toxicity. Due to the possibility of systemic absorption after topical administration of calcitriol, caution may be warranted in patients receiving high doses of paricalcitol.
    Phenytoin: (Moderate) Dosage adjustments of vitamin D analogs may be required during coadministration with phenytoin and fosphenytoin (which is metabolized to phenytoin). Phenytoin can increase the metabolism of endogenous vitamin D, thereby lowering serum concentrations and decreasing its activity. In rare cases, this has caused antiepileptic drug-induced rickets and osteomalacia.
    Phosphorated Carbohydrate Solution: (Major) High intake of phosphates concomitantly with vitamin D analogs may lead to hyperphosphatemia. Dose adjustment of vitamin D analogs may be necessary during coadministration with phosphorus salts. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia.
    Phosphorus: (Major) High intake of phosphates concomitantly with vitamin D analogs may lead to hyperphosphatemia. Dose adjustment of vitamin D analogs may be necessary during coadministration with phosphorus salts. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia.
    Polycarbophil: (Major) The concurrent use of vitamin D analogs, like calcitriol with calcium polycarbophil may contribute to vitamin D-induced hypercalcemia. Each 625 mg of calcium polycarbophil contains a substantial amount of calcium (approximately 125 mg).
    Porfimer: (Major) Avoid the concomitant use of porfimer with calcitriol ointment. The vehicle of the ointment may enhance the ability of ultraviolet radiation to induce skin tumors. Coadministration of photosensitizing agents such as porfimer may increase this risk.
    Potassium Phosphate: (Major) High intake of phosphates concomitantly with vitamin D analogs may lead to hyperphosphatemia. Dose adjustment of vitamin D analogs may be necessary during coadministration with phosphorus salts. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia.
    Potassium Phosphate; Sodium Phosphate: (Major) High intake of phosphates concomitantly with vitamin D analogs may lead to hyperphosphatemia. Dose adjustment of vitamin D analogs may be necessary during coadministration with phosphorus salts. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia.
    Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Pyridoxine, Vitamin B6: (Moderate) Monitor serum calcium concentrations during concomitant use of high doses of calcium and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Quinapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Sodium Sulfate; Magnesium Sulfate; Potassium Chloride: (Major) Avoid vitamin D analog coadministration with magnesium-containing products, such as antacids, in persons on chronic hemodialysis due to the risk for hypermagnesemia.
    Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Telmisartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Thiazide diuretics: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Triamterene; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
    Verteporfin: (Major) Limit or avoid the concomitant use of verteporfin with calcitriol ointment. The vehicle of the ointment may enhance the ability of ultraviolet radiation to induce skin tumors. Coadministration of photosensitizing agents such as verteporfin may increase this risk.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no adequate and well-controlled studies of calcitriol in pregnant women. Systemic absorption may occur after topical application. During calcitriol administration to pregnant women, major birth defects, miscarriages, or adverse maternal or fetal outcomes were not identified during the clinical development of calcitriol ointment or in published case series of oral and intravenous calcitriol. However, in animal studies, topical administration of calcitriol to pregnant rabbits during the period of organogenesis resulted in an increased incidence of fetal deaths, as well as an increased incidence of minor skeletal abnormalities. External and skeletal abnormalities were observed when oral calcitriol at doses of 0.08 and 0.3 mcg/kg (approximately 2 and 6 times the maximum recommended dose based on mg/m2) was administered to rabbits. Teratogenicity studies in rats at doses up to 0.45 mcg/kg (approximately 5 times maximum recommended dose based on mg/m2) showed no evidence of teratogenic potential. Calcitriol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Most pregnant patients with hypoparathyroidism are managed with vitamin D analogs similar to when they are not pregnant. However, pregnancy is associated with variable changes in calcium homeostasis due to pregnancy-induced alterations in the production, metabolism, and excretion of calcium and calcitropic hormones. The pregnant female requiring calcitriol therapy will require close monitoring, as calcitriol requirements may change during pregnancy. Published literature indicates those changes may be highly variable patient to patient. In one female, oral calcitriol administered at 17 to 36 mcg/day during pregnancy resulted in mild hypercalcemia in the neonate during the first 2 days of life which returned to normal on the third day. Hypercalcemia during pregnancy has been associated with suppression of parathyroid hormone in the neonate, resulting in mental retardation and congenital aortic stenosis; close monitoring is needed to maintain calcium homeostasis and avoid this potential side effect of therapy. The risks to benefits of untreated hypoparathyroidism or hypophosphatemia in the mother should be considered before using vitamin D analogs such as calcitriol.

    Systemically administered vitamin D and its metabolites, including calcitriol, are distributed in small amounts into breast milk. Most patients with hypoparathyroidism are managed with vitamin D analogs similar to when they are not nursing, and breast-feeding may be continued. However, lactation is associated with variable changes in calcium homeostasis due to postpartum and lactation-induced alterations in the production, metabolism, and excretion of calcium and calcitropic hormones. The lactating female who requires calcitriol therapy will require close monitoring, as calcitriol requirements may decrease. Published literature indicates requirements may be highly variable patient to patient. It is not known whether topical administration of calcitriol could result in sufficient systemic absorption to produce detectable quantities in breast milk. To avoid direct infant exposure, calcitriol ointment should not be applied directly to the nipple and areola. Close monitoring of the mother is needed to maintain calcium homeostasis and avoid hypercalcemia and other potential side effects of therapy during lactation; it is recommended that the nursing infant also receive monitoring to ensure proper calcium homeostasis.

    MECHANISM OF ACTION

    In the body, active vitamin D (1,25-(OH)2D3), also known as calcitriol, plays an important role in maintaining calcium balance and in the regulation of parathyroid hormone (PTH). Calcitriol promotes renal reabsorption of calcium, increases intestinal absorption of calcium and phosphorus, and increases calcium and phosphorus mobilization from bone to plasma. Calcitriol appears to promote intestinal absorption of calcium through binding to a specific receptor in the mucosal cytoplasm of the intestine. Subsequently, calcium is absorbed through formation of a calcium-binding protein. Some evidence suggests that calcitriol acts at the level of the cell nucleus to increase plasma calcium and phosphorus. Once plasma saturation of these electrolytes occurs, bone mineralization takes place. Calcitriol decreases PTH levels through several mechanisms. Calcitriol suppresses PTH, first, by a negative feedback mechanism due to increased calcium levels and, second, by suppressing the synthesis and release of PTH by inhibiting PTH gene transcription in specific target cells.
     
    Calcitriol is synthesized from calcifediol in the kidneys. The synthesis of calcitriol is stimulated by PTH activating renal alpha-hydroxylase enzymes and low plasma phosphorus levels. Hypocalcemia stimulates the release of PTH. Patients with uremia are unable to synthesize calcitriol in response to hypocalcemia, which perpetuates the hypocalcemia and leads to secondary hyperparathyroidism. This may be a contributory factor to renal osteodystrophy, characteristic of renal failure. The beneficial effect of calcitriol in renal osteodystrophy is due to the correction of hypocalcemia and secondary hyperparathyroidism. It is not certain if calcitriol produces other independent beneficial effects.
     
    The mechanism of topical calcitriol in the treatment of plaque psoriasis is unknown.

    PHARMACOKINETICS

    Calcitriol is administered orally, topically, and by intravenous injection. Calcitriol has a duration of action of 3—5 days. Response to vitamin D can be monitored through serum calcium levels, which should be maintained at 9—10 mg/dL. This vitamin is widely distributed. Vitamin D is excreted into breast milk in small amounts.
     
    Calcitriol is metabolized in the liver to hydroxy metabolites. When circulating concentrations of the metabolites are adequate, further hydroxylation in the kidneys occurs. Metabolism is influenced by parathyroid hormone, serum calcium and phosphate concentrations, and other hormones. The plasma half-life is 3—6 hours. Calcitriol and its metabolites are excreted primarily via the bile, with some renal elimination.

    Oral Route

    Following an oral dose, calcitriol is readily absorbed from the intestine. Absorption can be delayed in patients with hepatic, biliary, or GI disease. Increased calcium absorption occurs in 2—6 hours. Peak hypercalcemic effects are attained in about 10 hours.

    Topical Route

    The mean Cmax and AUC were increased by 36% and 44%, respectively, over baseline after twice daily topical application of calcitriol 3 mcg/g (total dose of 30 g ointment/day) for 21 days to 35% of body surface area in patients with at least 25% body surface area affected by psoriasis. The elevated calcitriol levels were not correlated to changes in serum albumin adjusted calcium, serum phosphorus, urinary calcium, or urinary phosphorus.