Doxercalciferol

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Overview

What is Doxercalciferol?

Doxercalciferol, the active ingredient in doxercalciferol capsule, is a synthetic vitamin D analog that undergoes metabolic activation to form 1α,25-dihydroxyvitamin D (1α,25-(OH)D), a naturally occurring, biologically active form of vitamin D. Doxercalciferol Capsules is available as soft gelatin capsules containing 0.5 mcg, 1 mcg or 2.5 mcg doxercalciferol. Each capsule also contains triglyceridemedium chain (MCT), ammonium hydroxide, butylated hydroxyanisole (BHA), ethanol, propylene glycol, SDA 35A alcohol, black iron oxide, ployvinyl acetate phthalate and propylene glycol. The capsule shells contain gelatin, glycerin and titanium dioxide. In addition, the 0.5 mcg capsule shells contain D&C Yellow# 10 and FD&C Red# 40, the 1 mcg capsule shells contain FD&C Red # 40, and the 2.5 mcg capsule shells contain D&C Yellow# 10.

Doxercalciferol is a colorless crystalline compound with a calculated molecular weight of 412.66 and a molecular formula of CHO. It is soluble in oils and organic solvents, but is relatively insoluble in water. Chemically, doxercalciferol is (1α,3β,5Z,7E,22E)-9,10-secoergosta-5,7,10(19),22-tetraene-1,3-diol. The structural formula is presented in Figure 1 below:

Other names frequently used for doxercalciferol are 1α-hydroxyvitamin D, 1α-OH-D, and 1α-hydroxyergocalciferol.

What does Doxercalciferol look like?

What are the available doses of Doxercalciferol?

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What should I talk to my health care provider before I take Doxercalciferol?

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How should I use Doxercalciferol?

Doxercalciferol Capsules is indicated for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis.

The optimal dose of doxercalciferol must be carefully determined for each patient. provides the current recommended therapeutic target levels for iPTH in patients with chronic kidney disease:

What interacts with Doxercalciferol?

Doxercalciferol Capsules should not be given to patients with a tendency towards hypercalcemia or current evidence of vitamin D toxicity.

What are the warnings of Doxercalciferol?

When used for endotracheal tube lubrication, care should be taken to avoid introducing the product into the lumen of the tube. Do not use the jelly to lubricate the endotracheal stylettes. If allowed into the inner lumen, the jelly may dry on the inner surface leaving a residue which tends to clump with flexion, narrowing the lumen. There have been rare reports in which this residue has caused the lumen to occlude. See also ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION.

Overdosage of any form of vitamin D, including doxercalciferol, is dangerous (see ). Progressive hypercalcemia due to overdosage of vitamin D and its metabolites may be so severe as to require emergency attention. Acute hypercalcemia may exacerbate tendencies for cardiac arrhythmias and seizures and may potentiate the action of digitalis drugs. Chronic hypercalcemia can lead to generalized vascular calcification and other soft-tissue calcification. The serum calcium times serum phosphorus (Ca X P) product should be maintained at <55 mg/dL in patients with chronic kidney disease. Radiographic evaluation of suspect anatomical regions may be useful in the early detection of this condition.

Since doxercalciferol is a precursor for 1α,25-(OH)D, a potent metabolite of vitamin D, pharmacologic doses of vitamin D and its derivatives should be withheld during doxercalciferol treatment to avoid possible additive effects and hypercalcemia.

Oral calcium-based or other non-aluminum-containing phosphate binders and a low phosphate diet should be used to control serum phosphorus levels in patients with chronic kidney disease. Uncontrolled serum phosphorus exacerbates secondary hyperparathyroidism and can lessen the effectiveness of doxercalciferol in reducing blood PTH levels. If hypercalcemia occurs after initiating doxercalciferol therapy, the dose of doxercalciferol and/or calcium-containing phosphate binders should be decreased. If hyperphosphatemia occurs after initiating doxercalciferol, the dose of doxercalciferol should be decreased and/or the dose of phosphate binders increased. (See dosing recommendations for doxercalciferol under section.)

Magnesium-containing antacids and doxercalciferol should not be used concomitantly in patients on chronic renal dialysis because such use may lead to the development of hypermagnesemia.

What are the precautions of Doxercalciferol?

General

Active vitamin D sterols should not be used as initial treatment of nutritional vitamin D deficiency (as defined by low 25-hydroxyvitamin D). Patients should be checked and treated for nutritional vitamin D deficiency prior to initiating treatment with Doxercalciferol capsule.

Dialysis

In four adequate and well-controlled studies, the incidence of hypercalcemia and hyperphosphatemia increased during therapy with Doxercalciferol Capsules. The observed increases during doxercalciferol treatment, although occurring at a low rate, underscore the importance of regular safety monitoring of serum calcium and phosphorus levels throughout treatment. Patients with higher pre-treatment serum levels of calcium (>10.5 mg/dL) or phosphorus (>6.9 mg/dL) were more likely to experience hypercalcemia or hyperphosphatemia. Therefore, doxercalciferol should not be given to patients with a recent history of hypercalcemia or hyperphosphatemia, or evidence of vitamin D toxicity.

Pre-dialysis

In two clinical studies, the incidences of hypercalcemia and hyperphosphatemia during therapy with Doxercalciferol Capsules were similar to placebo therapy, and no episodes of hypercalciuria were observed. The baseline median 25-(OH) vitamin D levels of patients enrolled in these studies was 17.2 ng/mL. Ninety-three percent of patients had 25-(OH) vitamin D levels less than 30 ng/mL; 26% had 25-(OH) vitamin D levels ≥20 to <30 ng/mL; 58% had levels >10 to <20 ng/mL; 7% had levels >5 to <10 ng/mL; and 2% had levels <5 ng/mL. The incidences of hypercalcemia, hyperphosphatemia, and hypercalciuria in patients treated with doxercalciferol for hyperparathyroidism related to pre-dialysis renal insufficiency has not been fully studied when 25-(OH) vitamin D levels are greater than or equal to 30 ng/mL.

Information for the Patient

The patient, spouse, or guardian should be informed about compliance with dosage instructions, adherence to instructions about diet, calcium supplementation, and avoidance of the use of nonprescription drugs without prior approval from their physician. Patients should also be carefully informed about the symptoms of hypercalcemia (see section).

Laboratory Tests

Serum or plasma iPTH and serum calcium, phosphorus, and alkaline phosphatase should be determined periodically. In the early phase of treatment for dialysis patients, iPTH, serum calcium, and serum phosphorus should be determined prior to initiation of doxercalciferol treatment and weekly thereafter. For pre-dialysis patients, serum levels of calcium and phosphorus and plasma levels of iPTH should be monitored at least every two weeks for 3 months after initiation of doxercalciferol therapy or following dose-adjustments in doxercalciferol therapy, then monthly for 3 months, and every 3 months thereafter.

Drug Interactions

Specific drug interaction studies have not been conducted. Cholestyramine has been reported to reduce intestinal absorption of fat-soluble vitamins; therefore, it may impair intestinal absorption of doxercalciferol. Magnesium-containing antacids and doxercalciferol should not be used concomitantly because such use may lead to the development of hypermagnesemia (see ). The use of mineral oil or other substances that may affect absorption of fat may influence the absorption and availability of doxercalciferol. Although not examined specifically, enzyme inducers (such as glutethimide and phenobarbital) may affect the 25-hydroxylation of doxercalciferol and may necessitate dosage adjustments. Cytochrome P450 inhibitors (such as ketoconazole and erythromycin) may inhibit the 25-hydroxylation of doxercalciferol. Hence, formation of the active doxercalciferol moiety may be hindered.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 104-week carcinogenicity study in rats, there was an increased incidence of benign and malignant adrenal pheochromocytomas in both males and females at oral doses of 0.04, 0.13 and 0.39 mcg/kg/day (≤1 times the human exposure in pre-dialysis patients with a maximum recommended dose of 3.5 mcg/day or 24.5 mcg/week). This increased incidence of pheochromocytomas in rats may be due to altered calcium homeostasis by doxercalciferol. No evidence of genetic toxicity was observed in an bacterial mutagenicity assay (Ames test) or a mouse lymphoma gene mutation assay. Doxercalciferol caused structural chromatid and chromosome aberrations in an human lymphocyte clastogenicity assay with metabolic activation. However, doxercalciferol was negative in an mouse micronucleus clastogenicity assay. Doxercalciferol had no effect on male or female fertility in rats at oral doses up to 2.5 mcg/kg/day (approximately 3 times the maximum recommended human dose of 60 mcg/week based on mcg/m body surface area).

Use in Pregnancy

Reproduction studies in rats and rabbits, at doses up to 20 mcg/kg/day and 0.1 mcg/kg/day (approximately 25 times and less than the maximum recommended human dose of 60 mcg/week based on mcg/m body surface area, respectively) have revealed no teratogenic or fetotoxic effects due to doxercalciferol. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether doxercalciferol is excreted in human milk. Because other vitamin D derivatives are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from doxercalciferol, 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

Safety and efficacy of doxercalciferol in pediatric patients have not been established.

Geriatric Use

Of the 138 patients treated with Doxercalciferol Capsules in two Phase 3 clinical studies, 30 patients were 65 years or over. In these studies, no overall differences in efficacy or safety were observed between patients 65 years or older and younger patients.

Hepatic Insufficiency

Since patients with hepatic insufficiency may not metabolize doxercalciferol appropriately, the drug should be used with caution in patients with impaired hepatic function. More frequent monitoring of iPTH, calcium, and phosphorus levels should be done in such individuals.

What are the side effects of Doxercalciferol?

Dialysis

Doxercalciferol Capsules have been evaluated for safety in clinical studies in 165 patients with chronic kidney disease on hemodialysis. In two placebo-controlled, double-blind, multicenter studies, discontinuation of therapy due to any adverse event occurred in 2.9% of 138 patients treated with Doxercalciferol Capsules for four to six months (dosage titrated to achieve target iPTH levels, see ) and in 3.3% of 61 patients treated with placebo for two months. Adverse events occurring in the Doxercalciferol Capsules group at a frequency of 2% or greater and more frequently than in the placebo group are presented in below:

Array

**Table 3: Adverse Events Reported by ≥2% of Doxercalciferol Capsules Treated Patients and More Frequently Than Placebo During the Double-blind Phase of Two Clinical Studies**
Adverse Event	Doxercalciferol Capsules (n=61)%	Placebo (n=61)%
	Body as a Whole
Abscess	3.3	0.0
Headache	27.9	18.0
Malaise	27.9	19.7
	Cardiovascular System
Bradycardia	6.6	4.9
	Digestive System
Anorexia	4.9	3.3
Constipation	3.3	3.3
Dyspepsia	4.9	1.6
Nausea/Vomiting	21.3	19.7
	Musculoskeletal System
Arthralgia	4.9	0.0
	Metabolic and Nutritional
Edema	34.4	21.3
Weight increase	4.9	0.0
	Nervous System
Dizziness	11.5	9.8
Sleep disorder	3.3	0.0
	Respiratory System
Dyspnea	11.5	6.6
	Skin
Pruritus	8.2	6.6

Pre-dialysis

Doxercalciferol Capsules have been evaluated for safety in clinical studies in 55 patients (27 active and 28 placebo) with chronic kidney disease, Stages 3 or 4. In two placebo-controlled, double-blind, multicenter studies, discontinuation of therapy due to any adverse event occurred in one (3.7%) of 27 patients treated with Doxercalciferol Capsules for 24 weeks (dosage titrated to achieve target iPTH levels, see ) and in three (10.7%) of 28 patients treated with placebo for 24 weeks. Adverse events occurring in the Doxercalciferol Capsules group at a frequency of 5% or greater and more frequently than in the placebo group are as follows: – Infection, Chest Pain; – Constipation, Dyspepsia; – Anemia; – Dehydration; – Depression, Hypertonia, Insomnia, Paresthesia; – Cough increased, Dyspnea, Rhinitis.

Potential adverse effects of doxercalciferol are, in general, similar to those encountered with excessive vitamin D intake. The early and late signs and symptoms of vitamin D intoxication associated with hypercalcemia include:

Early

Weakness, headache, somnolence, nausea, vomiting, dry mouth, constipation, muscle pain, bone pain, metallic taste, and anorexia.

Late

Polyuria, polydipsia, anorexia, weight loss, nocturia, conjunctivitis (calcific), pancreatitis, photophobia, rhinorrhea, pruritus, hyperthermia, decreased libido, elevated blood urea nitrogen (BUN), albuminuria, hypercholesterolemia, elevated serum aspartate transaminase (AST) and alanine transaminase (ALT), ectopic calcification, hypertension, cardiac arrhythmias, sensory disturbances, dehydration, apathy, arrested growth, urinary tract infections, and, rarely, overt psychosis.

Array

To report SUSPECTED ADVERSE REACTIONS, contact Rising Pharmaceuticals, Inc. at 1-866-562-4597 or FDA at 1-800-FDA-1088 or

What should I look out for while using Doxercalciferol?

Doxercalciferol Capsules should not be given to patients with a tendency towards hypercalcemia or current evidence of vitamin D toxicity.

Overdosage of any form of vitamin D, including doxercalciferol, is dangerous (see ). Progressive hypercalcemia due to overdosage of vitamin D and its metabolites may be so severe as to require emergency attention. Acute hypercalcemia may exacerbate tendencies for cardiac arrhythmias and seizures and may potentiate the action of digitalis drugs. Chronic hypercalcemia can lead to generalized vascular calcification and other soft-tissue calcification. The serum calcium times serum phosphorus (Ca X P) product should be maintained at <55 mg/dL in patients with chronic kidney disease. Radiographic evaluation of suspect anatomical regions may be useful in the early detection of this condition.

Since doxercalciferol is a precursor for 1α,25-(OH)D, a potent metabolite of vitamin D, pharmacologic doses of vitamin D and its derivatives should be withheld during doxercalciferol treatment to avoid possible additive effects and hypercalcemia.

Oral calcium-based or other non-aluminum-containing phosphate binders and a low phosphate diet should be used to control serum phosphorus levels in patients with chronic kidney disease. Uncontrolled serum phosphorus exacerbates secondary hyperparathyroidism and can lessen the effectiveness of doxercalciferol in reducing blood PTH levels. If hypercalcemia occurs after initiating doxercalciferol therapy, the dose of doxercalciferol and/or calcium-containing phosphate binders should be decreased. If hyperphosphatemia occurs after initiating doxercalciferol, the dose of doxercalciferol should be decreased and/or the dose of phosphate binders increased. (See dosing recommendations for doxercalciferol under section.)

Magnesium-containing antacids and doxercalciferol should not be used concomitantly in patients on chronic renal dialysis because such use may lead to the development of hypermagnesemia.

What might happen if I take too much Doxercalciferol?

Administration of doxercalciferol to patients in excess doses can cause hypercalcemia, hypercalciuria, hyperphosphatemia, and oversuppression of PTH secretion leading in certain cases to adynamic bone disease. High intake of calcium and phosphate concomitant with doxercalciferol may lead to similar abnormalities. High levels of calcium in the dialysate bath may contribute to hypercalcemia.

How should I store and handle Doxercalciferol?

Store in a refrigerator between 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze or expose to temperatures above 30°C (86°F). Discard if frozen. If refrigeration is unavailable, ZINBRYTA may be stored protected from light up to 30°C (86°F) for a period up to 30 days. Do not place ZINBRYTA back into the refrigerator after allowing it to warm to room temperature. Discard after 30 days without refrigeration. Store in a refrigerator between 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze or expose to temperatures above 30°C (86°F). Discard if frozen. If refrigeration is unavailable, ZINBRYTA may be stored protected from light up to 30°C (86°F) for a period up to 30 days. Do not place ZINBRYTA back into the refrigerator after allowing it to warm to room temperature. Discard after 30 days without refrigeration. Doxercalciferol capsules 0.5 mcg are available in opaque red oval soft gel capsules with "L" imprinted on one side and plain on the other side. Bottle of 50 count Doxercalciferol capsules 1 mcg are available in opaque pink oval soft gel capsules with "M" imprinted on one side and plain on the other side. Bottle of 50 count NDC 64980-229-50Doxercalciferol capsules 2.5 mcg are available in opaque yellow oval soft gel capsules with "H" imprinted on one side and plain on the other side. Bottle of 50 count NDC 64980-230-50Doxercalciferol capsules 0.5 mcg are available in opaque red oval soft gel capsules with "L" imprinted on one side and plain on the other side. Bottle of 50 count Doxercalciferol capsules 1 mcg are available in opaque pink oval soft gel capsules with "M" imprinted on one side and plain on the other side. Bottle of 50 count NDC 64980-229-50Doxercalciferol capsules 2.5 mcg are available in opaque yellow oval soft gel capsules with "H" imprinted on one side and plain on the other side. Bottle of 50 count NDC 64980-230-50Doxercalciferol capsules 0.5 mcg are available in opaque red oval soft gel capsules with "L" imprinted on one side and plain on the other side. Bottle of 50 count Doxercalciferol capsules 1 mcg are available in opaque pink oval soft gel capsules with "M" imprinted on one side and plain on the other side. Bottle of 50 count NDC 64980-229-50Doxercalciferol capsules 2.5 mcg are available in opaque yellow oval soft gel capsules with "H" imprinted on one side and plain on the other side. Bottle of 50 count NDC 64980-230-50

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Clinical Information

Chemical Structure

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Clinical Pharmacology

Calcitriol (1α,25-(OH)D) and 1α,25-(OH)D regulate blood calcium at levels required for essential body functions. Specifically, the biologically active vitamin D metabolites control the intestinal absorption of dietary calcium, the tubular reabsorption of calcium by the kidney and, in conjunction with parathyroid hormone (PTH), the mobilization of calcium from the skeleton. They act directly on bone cells (osteoblasts) to stimulate skeletal growth, and on the parathyroid glands to suppress PTH synthesis and secretion. These functions are mediated by the interaction of these biologically active metabolites with specific receptor proteins in the various target tissues. In patients with chronic kidney disease (CKD), deficient production of biologically active vitamin D metabolites (due to lack of or insufficient 25-hydroxyvitamin D-1-alpha-hydroxylase activity) leads to secondary hyperparathyroidism, which contributes to the development of metabolic bone disease.

Non-Clinical Toxicology

Doxercalciferol Capsules should not be given to patients with a tendency towards hypercalcemia or current evidence of vitamin D toxicity.

Overdosage of any form of vitamin D, including doxercalciferol, is dangerous (see ). Progressive hypercalcemia due to overdosage of vitamin D and its metabolites may be so severe as to require emergency attention. Acute hypercalcemia may exacerbate tendencies for cardiac arrhythmias and seizures and may potentiate the action of digitalis drugs. Chronic hypercalcemia can lead to generalized vascular calcification and other soft-tissue calcification. The serum calcium times serum phosphorus (Ca X P) product should be maintained at <55 mg/dL in patients with chronic kidney disease. Radiographic evaluation of suspect anatomical regions may be useful in the early detection of this condition.

Since doxercalciferol is a precursor for 1α,25-(OH)D, a potent metabolite of vitamin D, pharmacologic doses of vitamin D and its derivatives should be withheld during doxercalciferol treatment to avoid possible additive effects and hypercalcemia.

Oral calcium-based or other non-aluminum-containing phosphate binders and a low phosphate diet should be used to control serum phosphorus levels in patients with chronic kidney disease. Uncontrolled serum phosphorus exacerbates secondary hyperparathyroidism and can lessen the effectiveness of doxercalciferol in reducing blood PTH levels. If hypercalcemia occurs after initiating doxercalciferol therapy, the dose of doxercalciferol and/or calcium-containing phosphate binders should be decreased. If hyperphosphatemia occurs after initiating doxercalciferol, the dose of doxercalciferol should be decreased and/or the dose of phosphate binders increased. (See dosing recommendations for doxercalciferol under section.)

Magnesium-containing antacids and doxercalciferol should not be used concomitantly in patients on chronic renal dialysis because such use may lead to the development of hypermagnesemia.

Specific drug interaction studies have not been conducted. Cholestyramine has been reported to reduce intestinal absorption of fat-soluble vitamins; therefore, it may impair intestinal absorption of doxercalciferol. Magnesium-containing antacids and doxercalciferol should not be used concomitantly because such use may lead to the development of hypermagnesemia (see ). The use of mineral oil or other substances that may affect absorption of fat may influence the absorption and availability of doxercalciferol. Although not examined specifically, enzyme inducers (such as glutethimide and phenobarbital) may affect the 25-hydroxylation of doxercalciferol and may necessitate dosage adjustments. Cytochrome P450 inhibitors (such as ketoconazole and erythromycin) may inhibit the 25-hydroxylation of doxercalciferol. Hence, formation of the active doxercalciferol moiety may be hindered.

Active vitamin D sterols should not be used as initial treatment of nutritional vitamin D deficiency (as defined by low 25-hydroxyvitamin D). Patients should be checked and treated for nutritional vitamin D deficiency prior to initiating treatment with Doxercalciferol capsule.

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Reference

This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72

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