Doxercalciferol, the active ingredient in Hectorol®, is a synthetic vitamin D₂ analog that undergoes metabolic activation in vivo to form 1α,25-dihydroxyvitamin D₂ (1α,25-(OH)₂D₂), a naturally occurring, biologically active form of vitamin D₂. Hectorol is available as soft gelatin capsules containing 0.5 mcg or 2.5 mcg doxercalciferol. Each capsule also contains fractionated triglyceride of coconut oil, ethanol, and butylated hydroxyanisole (BHA). The capsule shells contain gelatin, glycerin and titanium dioxide. In addition, the 0.5 mcg capsule shell contains yellow iron oxide and FD&C Red No. 40, and the 2.5 mcg capsule shell contains yellow iron oxide.

Doxercalciferol is a colorless crystalline compound with a calculated molecular weight of 412.66 and a molecular formula of C₂₈H₄₄O₂. 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 and has the following structural formula:

Other names frequently used for doxercalciferol are 1α-hydroxyvitamin D2, 1α-OH-D2, and 1α-hydroxyergocalciferol.

Last updated on RxList: 7/29/2008

Dialysis Patients

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

Pre-Dialysis Patients

Hectorol is indicated for the treatment of secondary hyperparathyroidism in patients with Stage 3 or Stage 4 chronic kidney disease.

Adult Administration

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

Target Range of Intact Plasma PTH by Stage of CKD

CKD Stage	GFR (mL/min/1.73m²)	Target “intact” PTH (pg/mL)
3	30-59	35-70
4	15-29	70-110
5	< 15 (or dialysis)	150-300

From Table 15 of National Kidney Foundation, K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. Am J Kidney Dis 42:S1-S202, 2003 (suppl 3)

Dialysis

The recommended initial dose of Hectorol is 10 mcg administered three times weekly at dialysis (approximately every other day). The initial dose should be adjusted, as needed, in order to lower blood iPTH into the range of 150 to 300 pg/mL. The dose may be increased at 8-week intervals by 2.5 mcg if iPTH is not lowered by 50% and fails to reach the target range. The maximum recommended dose of Hectorol is 20 mcg administered three times a week at dialysis for a total of 60 mcg per week. Drug administration should be suspended if iPTH falls below 100 pg/mL and restarted one week later at a dose that is at least 2.5 mcg lower than the last administered dose. During titration, iPTH, serum calcium, and serum phosphorus levels should be obtained weekly. If hypercalcemia, hyperphosphatemia, or a serum calcium times serum phosphorus product greater than 55 mg2/dL2 is noted, the dose of Hectorol should be decreased or suspended and/or the dose of phosphate binders should be appropriately adjusted. If suspended, the drug should be restarted at a dose that is at least 2.5 mcg lower.

Dosing must be individualized and based on iPTH levels with monitoring of serum calcium and serum phosphorus levels. The following is a suggested approach in dose titration:

Initial Dosing
iPTH Level	Hectorol® Dose
> 400 pg/mL	10 mcg three times per week at dialysis
Dose Titration
iPTH Level	Hectorol® Dose
Above 300 pg/mL	Increase by 2.5 mcg at eight-week intervals as necessary
150 - 300 pg/mL	Maintain
< 100 pg/mL	Suspend for one week, then resume at a dose that is at least 2.5 mcg lower

Pre-dialysis

The recommended initial dose of Hectorol is 1 mcg administered once daily. The initial dose should be adjusted, as needed, in order to lower blood iPTH to within target ranges (see table below). The dose may be increased at 2-week intervals by 0.5 mcg to achieve the target range of iPTH. The maximum recommended dose of Hectorol is 3.5 mcg administered once per day.

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 Hectorol therapy or following dose adjustments in Hectorol therapy, then monthly for 3 months, and every 3 months thereafter. If hypercalcemia, hyperphosphatemia, or a serum calcium times phosphorus product greater than 55 mg2/dL2 is noted, the dose of Hectorol should be decreased or suspended and/or the dose of phosphate binders should be appropriately adjusted. If suspended, the drug should be restarted at a dose that is at least 0.5 mcg lower.

Dosing must be individualized and based on iPTH levels with monitoring of serum calcium and serum phosphorus levels. The following is a suggested approach in dose titration:

Initial Dosing
iPTH Level	Hectorol®Dose
> 70 pg/mL (Stage 3)	1 mcg once per day
> 110 pg/mL (Stage 4)
Dose Titration
iPTH Level	Hectorol® Dose
Above 70 pg/mL (Stage 3)	Increase by 0.5 mcg at two-week intervals as necessary
110 pg/mL (Stage 4)
35 - 70 pg/mL (Stage 3)	Maintain
70 - 110 pg/mL (Stage 4)
< 35 pg/mL (Stage 3)	Suspend for one week, then resume at a
< 70 pg/mL (Stage 4)	dose that is at least 0.5 mcg lower

NDC 58468-0120-1

0.5 mcg doxercalciferol in soft gelatin, salmon, oval capsules, imprinted g; foil induction sealed bottles of 50.

NDC 58468-0121-1

2.5 mcg doxercalciferol in soft gelatin, butter yellow, oval capsules, imprinted g; foil induction sealed bottles of 50.

Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].

Manufactured by: Catalent Pharma Solutions for Genzyme Corporation, 500 Kendall Street, Cambridge, MA 02142. FDA revision date: 07/10/08

Last updated on RxList: 7/29/2008

Dialysis

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

Adverse Events Reported by ≥ 2% of Hectorol® Treated Patients and More Frequently Than Placebo During the Double-blind Phase of Two Clinical Studies

Adverse Event	Hectorol® (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
Musculo-Skeletal 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

A patient who reported the same medical term more than once was counted only once for that medical term.

Predialysis

Hectorol has 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 Hectorol for 24 weeks (dosage titrated to achieve target iPTH levels, see CLINICALPHARMACOLOGY/Clinical Studies) and in three (10.7%) of 28 patients treated with placebo for 24 weeks. Adverse events occurring in the Hectorol group at a frequency of 5% or greater and more frequently than in the placebo group are as follows: Body as a Whole . Infection, Chest Pain; Digestive System . Constipation, Dyspepsia; Hematologic and Lymphatic . Anemia; Metabolic and Nutritional . Dehydration; Nervous System . Depression, Hypertonia, Insomnia, Paresthesia; Respiratory System . Cough increased, Dyspnea, Rhinitis.

Potential adverse effects of Hectorol 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.

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

Last updated on RxList: 7/29/2008

Overdosage of any form of vitamin D, including Hectorol, is dangerous (see OVERDOSAGE). 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 mg²/dL² 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)₂D₂, a potent metabolite of vitamin D2, pharmacologic doses of vitamin D and its derivatives should be withheld during Hectorol 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 Hectorol in reducing blood PTH levels. If hypercalcemia occurs after initiating Hectorol therapy, the dose of Hectorol and/or calcium-containing phosphate binders should be decreased. If hyperphosphatemia occurs after initiating Hectorol, the dose of Hectorol should be decreased and/or the dose of phosphate binders increased. (See dosing recommendations for Hectorol under DOSAGE AND ADMINISTRATION section.)

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

General

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

The principal adverse effects of treatment with Hectorol are hypercalcemia, hyperphosphatemia, hypercalciuria, and oversuppression of iPTH. Prolonged hypercalcemia can lead to calcification of soft tissues, including the heart and arteries, and hyperphosphatemia can exacerbate hyperparathyroidism. Hypercalciuria can accelerate the onset of renal failure through nephrocalcinosis. Oversuppression of iPTH may lead to adynamic bone syndrome. All of these potential adverse effects should be managed by regular patient monitoring and appropriate dosage adjustments. During treatment with Hectorol, patients usually require dose titration, as well as adjustment in co-therapy (i.e., dietary phosphate binders) in order to effect and sustain PTH suppression while maintaining serum calcium and phosphorus within prescribed ranges.

Dialysis

In four adequate and well-controlled studies, the incidence of hypercalcemia and hyperphosphatemia increased during therapy with Hectorol. The observed increases during Hectorol 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, Hectorol 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 Hectorol 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 Hectorol 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.

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 Hectorol 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 Hectorol therapy or following dose-adjustments in Hectorol therapy, then monthly for 3 months, and every 3 months thereafter.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to evaluate the carcinogenic potential of doxercalciferol have not been conducted. No evidence of genetic toxicity was observed in an in vitro bacterial mutagenicity assay (Ames test) or a mouse lymphoma gene mutation assay. Doxercalciferol caused structural chromatid and chromosome aberrations in an in vitro human lymphocyte clastogenicity assay with metabolic activation. However, doxercalciferol was negative in an in vivo 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/m² body surface area).

Use in Pregnancy

Pregnancy Category B

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/m² 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 Hectorol in pediatric patients have not been established.

Geriatric Use

Of the 138 patients treated with Hectorol 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 Hectorol 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.

Last updated on RxList: 7/29/2008

Administration of Hectorol 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 Hectorol may lead to similar abnormalities. High levels of calcium in the dialysate bath may contribute to hypercalcemia.

Treatment of Hypercalcemia and Overdosage

General treatment of hypercalcemia (greater than 1 mg/dL above the upper limit of the normal range in dialysis patients; > 10.7 mg/ dL in pre-dialysis patients) consists of immediate suspension of Hectorol therapy, institution of a low calcium diet, and withdrawal of calcium supplements. Serum calcium levels should be determined at least weekly until normocalcemia ensues. Hypercalcemia usually resolves in 2 to 7 days. When serum calcium levels have returned to within normal limits, Hectorol therapy may be reinstituted at a dose that is lower (at least 2.5 mcg in dialysis patients and 0.5 mcg in pre-dialysis patients) than prior therapy. In dialysis patients, serum calcium levels should be obtained weekly after all dosage changes and during subsequent dosage titration. Persistent or markedly elevated serum calcium levels may be corrected by dialysis against a reduced calcium or calcium-free dialysate.

Treatment of Accidental Overdosage of Doxercalciferol

The treatment of acute accidental overdosage of Hectorol should consist of general supportive measures. If drug ingestion is discovered within a relatively short time (10 minutes), induction of emesis or gastric lavage may be of benefit in preventing further absorption. If drug ingestion is discovered later than 10 minutes post-ingestion, the administration of mineral oil may promote its fecal elimination. Serial serum electrolyte determinations (especially calcium), rate of urinary calcium excretion, and assessment of electrocardiographic abnormalities due to hypercalcemia should be obtained. Such monitoring is critical in patients receiving digitalis. Discontinuation of supplemental calcium and institution of a low calcium diet are also indicated in accidental overdosage. If persistent and markedly elevated serum calcium levels occur, there are a variety of therapeutic alternatives that may be considered. These include the use of drugs such as phosphates and corticosteroids as well as measures to induce diuresis. Also, one may consider dialysis against a calcium-free dialysate.

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

Last updated on RxList: 7/29/2008

Vitamin D levels in humans depend on two sources: (1) exposure to the ultraviolet rays of the sun for conversion of 7dehydrocholesterol in the skin to vitamin D₃ (cholecalciferol) and (2) dietary intake of either vitamin D₂ (ergocalciferol) or vitamin D₃. Vitamin D₂ and vitamin D₃ must be metabolically activated in the liver and the kidney before becoming fully active on target tissues. The initial step in the activation process is the introduction of a hydroxyl group in the side chain at C-25 by the hepatic enzyme, CYP 27 (a vitamin D-25-hydroxylase). The products of this reaction are 25-(OH)D₂ and 25-(OH)D₃, respectively. Further hydroxylation of these metabolites occurs in the mitochondria of kidney tissue, catalyzed by renal 25-hydroxyvitamin D-1-α-hydroxylase to produce 1α,25-(OH)₂D₂, the primary biologically active form of vitamin D₂, and 1α,25-(OH)₂D₃ (calcitriol), the biologically active form of vitamin D₃.

Mechanism of Action

Calcitriol (1α,25-(OH)₂D₃) and 1α,25-(OH)₂D₂ 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.

Pharmacokinetics and Metabolism

Doxercalciferol is absorbed from the gastrointestinal tract and activated by CYP 27 in the liver to form 1α,25-(OH)₂D₂ (major metabolite) and 1α,24-dihydroxyvitamin D₂ (minor metabolite). Activation of doxercalciferol does not require the involvement of the kidneys.

In healthy volunteers, peak blood levels of 1α,25-(OH)₂D₂, the major metabolite of doxercalciferol, are attained at 11-12 hours after repeated oral doses of 5 to 15 mcg of Hectorol and the mean elimination half-life of 1α,25-(OH)₂D₂ is approximately 32 to 37 hours with a range of up to 96 hours. The mean elimination half-life in patients with end-stage renal disease (ESRD) on dialysis appears to be similar. Hemodialysis causes a temporary increase in 1α,25-(OH)₂D₂ mean concentrations, presumably due to volume contraction. 1α,25-(OH)2D2 is not removed from blood during hemodialysis.

Clinical Studies

Dialysis

The safety and effectiveness of Hectorol were evaluated in two double-blind, placebo-controlled, multicentered clinical studies (Study A and Study B) in a total of 138 patients with chronic kidney disease on hemodialysis (Stage 5 CKD). Patients in Study A were an average age of 52 years (range: 22-75), were 55% male, and were 58% African-American, 31% Caucasian, and 11% Hispanic, and had been on hemodialysis for an average of 53 months. Patients in Study B were an average of 52 years (range: 27-75), were 45% male, and 99% African-American, and 1% Caucasian, and had been on hemodialysis for an average of 56 months. After randomization to two groups, eligible patients underwent an 8-week washout period during which no vitamin D derivatives were administered to either group. Subsequently, all patients received Hectorol in an open-label fashion for 16 weeks followed by a double-blind period of 8 weeks during which patients received either Hectorol or placebo. The initial dose of Hectorol during the open-label phase was 10 micrograms after each dialysis session (3 times weekly) for a total of 30 mcg per week. The dosage of Hectorol was adjusted as necessary by the investigator in an attempt to achieve intact parathyroid hormone (iPTH) levels within a targeted range of 150 to 300 pg/mL. The maximum dosage was limited to 20 mcg after each dialysis session (60 mcg/week). If at any time during the trial iPTH fell below 150 pg/mL, Hectorol was immediately suspended and restarted at a lower dosage the following week.

Results

One hundred and six of the 138 patients who were treated with Hectorol during the 16-week open-label phase achieved iPTH levels ≤ 300 pg/mL. Ninety-four of these patients exhibited plasma iPTH levels ≤ 300 pg/mL on at least 3 occasions. Eighty-seven patients had plasma iPTH levels < 150 pg/mL on at least one occasion during the open-label phase of study participation.

Mean weekly doses during the 16-week open-label period in Study A ranged from 14.8 mcg to 28.7 mcg. In Study B, the mean weekly doses during the 16-week open-label period ranged from 19.2 mcg to 28 mcg.

Decreases in plasma iPTH from baseline values were calculated using as baseline the average of the last 3 values obtained during the 8-week washout phase and are displayed in the table below.

		iPTH (pg/mL) means± s.d.(n*) p Valuev. Baseline p Value v. Placebo
		Hectorol®	Placebo
Study A	Baseline	797.2 ± 443.8 (30) n.a. 0.97	847.1 ± 765.5 (32)
	Week 16 (open-label)	384.3 ± 397.8 (24) < .001 0.72	526.5 ± 872.2 (29) < .001
	Week 24 (double-blind)	404.4 ± 262.9 (21) < .001 0.008	672.6 ± 356.9 (24) 0.7
Study B	Baseline	973.9 ± 567.0 (41) n.a. 0.81	990.4 ± 488.3(35)
	Week 16 (open-label)	476.1 ± 444.5 (37) < .001 0.91	485.9 ± 443.4 (32) < .001
	Week 24 (double-blind)	459.8 ± 443.0 (35) < .001 < .001	871.9 ± 623.6 (30) < .065
*all subjects; last value carried to discontinuation

In both studies, iPTH levels increased progressively and significantly in 65.9% of the patients during the 8-week washout (control) period during which no vitamin D derivatives were administered. In contrast, Hectorol treatment resulted in a statistically significant reduction from baseline in mean iPTH levels during the 16-week open-label treatment period in more than 93.5% of the 138 treated patients. During the double-blind period (weeks 17 to 24), the reduction in mean iPTH levels was maintained in the Hectorol treatment group compared to a return to near baseline in the placebo group.

In the clinical trials, the values for iPTH varied widely from patient to patient and from week to week for individual patients. The following table shows the numbers of patients within each group who achieved and maintained iPTH levels below 300 pg/mL during the open-label and double-blind phases. Seventy-four of 138 patients (53.6%) had plasma iPTH levels within the target range (150-300 pg/mL) during Weeks 14-16.

		Number of times iPTH ≤ 300pg/mL
		1		2		3
		Hectorol®	Placebo	Hectorol®	Placebo	Hectorol®	Placebo
Study A	Weeks 1-16 (open-label)	2/30	2/32	0/30	0/32	22/30	23/32
	Weeks 17-24 (double-blind)	0/24	9/29	3/24	1/29	17/24	5/29
Study B	Weeks 1-16 (open-label)	2/41	4/35	1/41	0/35	29/41	21/35
	Weeks 17-24 (double-blind)	2/37	6/32	1/37	4/32	26/37	4/32

During the 8-week double-blind phase, more patients achieved and maintained the target range of values for iPTH with Hectorol than with placebo.

Pre-dialysis

The safety and effectiveness of Hectorol were evaluated in two clinical studies in 55 patients with Stage 3 or Stage 4 chronic kidney disease. Eighty-two percent of the patients were male, the average age was 64.6 years, 51% were Caucasian, 40% African-American, and the average serum iPTH level at baseline was 194.6 pg/mL. While levels of 25-(OH) vitamin D were not evaluated at baseline, retrospective assessments of stored serum revealed that the mean ± SD serum 25-(OH)vitamin D was 18.5 ± 8.1 ng/mL (range: < 5 to 54 ng/mL) in the study population.

After randomization to two groups, eligible patients underwent an 8-week washout period during which no vitamin D derivatives were administered to either group. Subsequently, one group received Hectorol and the other placebo during a double-blind period of 24 weeks. The initial dose of Hectorol was 1 mcg per day. The dosage of Hectorol was adjusted as necessary by the investigator in order to reduce intact parathyroid hormone (iPTH) levels to a target of ≥ 30% below post-washout baseline. The maximum dosage was limited to 3.5 mcg per day. If at any time during the trial iPTH fell below 15 pg/mL, Hectorol was immediately suspended and restarted at a lower dosage the following week.

Results

Decreases in the mean plasma iPTH from baseline values were calculated using as baseline the average of the last 2 values obtained during the 8-week washout phase. In analyses of pooled data from the two studies, iPTH levels decreased from baseline by an average of 101.4 pg/mL in the Hectorol group and by 4.4 pg/mL in the placebo group (p < 0.001). Greater reductions of iPTH with Hectorol compared to placebo were observed in each study. Twenty (74%) of 27 subjects in the Hectorol group achieved mean plasma iPTH suppression of ≥ 30% from baseline for the last four weeks of treatment, whereas two (7%) of the 28 subjects treated with placebo achieved this level of iPTH suppression. In the Hectorol-treated patients, the reductions in plasma iPTH were associated with a reduction in serum bone-specific alkaline phosphatase.

Last updated on RxList: 7/29/2008

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 ADVERSE REACTIONS section).

Patients' total combined elemental calcium intake (dietary and phosphate binder) should not exceed 2 g daily.

Last updated on RxList: 7/29/2008

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

DOXERCALCIFEROL - ORAL

(dox-er-kal-SIF-e-role)

COMMON BRAND NAME(S): Hectorol

USES: This medication is used to treat people with serious kidney disease who have high levels of a certain natural substance (parathyroid hormone-PTH), which your body normally makes. High PTH levels affect the balance of other minerals in your body (calcium and phosphorus) and may result in weak bones. Doxercalciferol is a man-made form of vitamin D. It works by decreasing PTH levels and increasing calcium/phosphorus levels in the body.

HOW TO USE: Take this medication by mouth with or without food, usually 3 times a week on dialysis days (e.g., Monday, Wednesday, Friday) or as directed by your doctor.

Dosage is based on your medical condition and response to treatment. Your doctor may adjust your dose or temporarily stop this drug based on laboratory test results (PTH levels). Do not increase your dose, take it more frequently, or stop taking this medication without your doctor's approval.

It is very important to follow the diet recommended by your doctor to get the most benefit from this medication and to prevent serious side effects. Do not take other supplements/vitamins (e.g., calcium, vitamin D) unless otherwise directed by your doctor. (See also Drug Interactions section.)

Use this medication regularly to get the most benefit from it. To help you remember, take it at the same time each day that you have a prescribed dose.

SIDE EFFECTS: Headache, upset stomach, constipation, nausea, vomiting, or tiredness may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: bone/joint/muscle pain, loss of appetite, increased thirst, increased urination, fast/slow/irregular heartbeat, mental/mood changes (e.g., drowsiness, disturbed/irrational thoughts or beliefs), metallic taste in mouth, weakness, unexplained weight gain or loss.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking doxercalciferol, tell your doctor or pharmacist if you are allergic to it; or to vitamin D products; or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: heart problems (e.g., irregular heartbeat), liver disease, high calcium blood levels (hypercalcemia), high phosphate blood levels (hyperphosphatemia), seizure.

Tell your doctor if you are pregnant before using this medication.

It is not known whether this medication passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: digoxin, phosphate binders, drugs affecting liver enzymes that remove doxercalciferol from your body (e.g., glutethimide, rifampin, azole antifungals including ketoconazole, macrolide antibiotics including erythromycin, anti-seizure drugs including phenobarbital/phenytoin).

Certain medications (e.g., bile acid sequestrants such as cholestyramine/colestipol, mineral oil, orlistat) can decrease the effect of doxercalciferol if taken at the same time. Avoid taking these medications within 2 hours before or after this medication.

Check the labels on all your prescription and nonprescription/herbal products (e.g., antacids, laxatives, vitamins/nutritional supplements) because they may contain calcium, magnesium, phosphate, or vitamin D. Ask your pharmacist about using those products safely.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: metallic taste in the mouth, irregular heartbeat, severe mental/mood changes.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., PTH levels, calcium/magnesium/phosphorus levels) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, take it as soon as you remember. Consult your doctor to establish a new dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 68-77 degrees F (20-25 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.