Hectorol Injection

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

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 a sterile, clear, colorless aqueous solution for intravenous injection.

Hectorol single-use injection is supplied in a stoppered 2 mL amber glass vial containing either 4 mcg/2 mL or 2 mcg/mL. Each vial includes an aluminum seal and yellow (4 mcg/2 mL) or green (2 mcg/mL) flip-off cap. Each milliliter (mL) of solution contains doxercalciferol, 2 mcg; ethanol, 100%, 0.05 mL; Polysorbate 20, 10 mg; sodium chloride, 1.5 mg; butylated hydroxytoluene, 0.02 mg; sodium phosphate dibasic, heptahydrate, 14.4 mg; sodium phosphate monobasic, monohydrate, 1.8 mg; and disodium edetate, 1.1 mg.

Hectorol is also supplied as a multi-dose injection contained within a stoppered 2 mL amber glass vial containing 4 mcg/2 mL. Each vial includes an aluminum seal and an orange plastic flip-off cap. Each milliliter (mL) of solution contains doxercalciferol, 2 mcg; ethanol, 100%, 0.075 mL; Polysorbate 20, 10 mg; sodium chloride, 1.5 mg; butylated hydroxytoluene, 0.02 mg; sodium phosphate dibasic, heptahydrate, 14.4 mg; sodium phosphate monobasic, monohydrate, 1.8 mg; and disodium edetate, 1.1 mg.

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 structural formula presented in Figure 1.

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

Vitamin D levels in humans depend on two sources: (1) exposure to the ultraviolet rays of the sun for conversion of 7-dehydrocholesterol 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 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 uremic patients, 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 in patients with renal failure.

Pharmacokinetics and Metabolism

After intravenous administration, doxercalciferol is 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.

Peak blood levels of 1α,25-(OH)2D2 are reached at 8 +/- 5.9 hours (mean +/- SD) after a single intravenous dose of 5 mcg of doxercalciferol. The mean elimination half-life of 1α,25-(OH)2D2 after an oral dose 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) and in healthy volunteers appears to be similar following an oral dose. 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

The safety and effectiveness of Hectorol Injection were evaluated in two open-label, single-arm, multi-centered clinical studies (Study C and Study D) in a total of 70 patients with chronic kidney disease on hemodialysis (Stage 5 CKD). Patients in Study C were an average age of 54 years (range: 23–73), were 50% male, and were 61% African-American, 25% Caucasian, and 14% Hispanic, and had been on hemodialysis for an average of 65 months. Patients in Study D were an average age of 51 years (range: 28–76), were 48% male, and 100% African-American and had been on hemodialysis for an average of 61 months. This group of 70 of the 138 patients who had been treated with Hectorol Capsules in prior clinical studies (Study A and Study B) received Hectorol Injection in an open-label fashion for 12 weeks following an 8-week washout (control) period. Dosing of Hectorol Injection was initiated at the rate of 4 mcg administered at the end of each dialysis session (3 times weekly) for a total of 12 mcg per week. The dosage of Hectorol was adjusted in an attempt to achieve iPTH levels within a targeted range of 150 to 300 pg/mL. The dosage was increased by 2 mcg per dialysis session after 8 weeks of treatment if the iPTH levels remained above 300 pg/mL and were greater than 50% of baseline levels. The maximum dosage was limited to 18 mcg per week. If at any time during the trial iPTH fell below 150 pg/mL, Hectorol Injection was immediately suspended and restarted at a lower dosage the following week.

Fifty-two of the 70 patients who were treated with Hectorol Injection achieved iPTH levels ≤ 300 pg/mL. Forty-one of these patients exhibited plasma iPTH levels ≤ 300 pg/mL on at least 3 occasions. Thirty-six patients had plasma iPTH levels < 150 pg/mL on at least one occasion during study participation.

Mean weekly doses in Study C ranged from 8.9 mcg to 12.5 mcg. In Study D, the mean weekly doses ranged from 9.1 mcg to 11.6 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 period and are displayed in the table below. Plasma iPTH levels were measured weekly during the 12-week study.

In both studies, iPTH levels increased progressively and significantly in 62.9% of patients during the 8-week washout (control) period during which no vitamin D derivatives were administered. In contrast, Hectorol Injection treatment resulted in a clinically significant reduction (at least 30%) from baseline in mean iPTH levels during the 12-week open-label treatment period in more than 92% of the 70 treated patients.

Table 2 shows the numbers of patients who achieved iPTH levels below 300 pg/mL on one, two, or three or more non-consecutive occasions during the 12-week treatment period. Thirty-seven of 70 patients (53%) had plasma iPTH levels within the targeted range (150–300 pg/mL) during Weeks 10–12.

Hectorol Injection has been evaluated for safety in 70 patients with chronic renal disease on hemodialysis (who had been previously treated with oral Hectorol) from two 12-week, open-label, single-arm, multi-centered studies. (Dosage titrated to achieve target plasma iPTH levels, see CLINICAL PHARMACOLOGY/Clinical Studies.)

Because there was no placebo group included in the studies of Hectorol Injection, Table 4 provides the adverse event incidence rates from placebo-controlled studies of oral Hectorol.

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.

Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or to establish a causal relationship to drug exposure.

Hypersensitivity reactions, including fatal outcome, have been reported in patients on hemodialysis following administration of Hectorol Injection. Hypersensitivity reactions include anaphylaxis with symptoms of angioedema (involving face, lips, tongue and airways), hypotension, unresponsiveness, chest discomfort, shortness of breath, cardiopulmonary arrest, pruritus and skin burning sensation (see WARNINGS). These reactions may occur separately or together.

Single-Use Vial

Hectorol (doxercalciferol injection) is supplied in single-use amber glass vials containing 4 mcg doxercalciferol in 2 mL of solution or 2 mcg in 1 mL of solution. The closure consists of a fluorocarbon-coated chlorobutyl stopper, with an aluminum seal and either a yellow (4 mcg/2 mL) or green (2 mcg/mL) plastic flip-off cap. Discard unused portion of single-use vial.

Multi-Dose Vial

Hectorol is also supplied in multi-dose amber glass vials containing 4 mcg doxercalciferol in 2 mL of solution. The closure consists of a fluorocarbon-coated chlorobutyl stopper, with an aluminum seal and an orange plastic flip-off cap.

STORAGE

Store at 25°C (77°F): excursions permitted to 15–30°C (59–86°F)
[see USP controlled room temperature]

Protect from light.

Store unopened multi-dose vials at 25°C (77°F): excursions permitted to 15–30°C (59–86°F)
[see USP controlled room temperature]

Store opened multi-dose vials at 2–8°C (36–46°F)

Protect from light.

Manufactured by: Genzyme Biosurgery
For: Genzyme Corporation
500 Kendall Street
Cambridge, MA 02142

HECTOROL and GENZYME are registered trademarks of Genzyme Corporation.

(06/2016)

NDC 58468-0126-1

Rx only

50 Single-use vials

HECTOROL®
(doxercalciferol injection)
2 mcg/mL

Store at 25°C (77°F):
Excursions permitted to 15-30°C (59-86°F)
[See USP controlled room temperature]
Protect from light
For intravenous use only
Usual dosage: See package insert

NDC 58468-0127-1

Rx only

50 Multi-Dose Vials
Discard vial 3 days after opening

HECTOROL®
(doxercalciferol injection)
4 mcg/2 mL
(2 mcg/mL)

Contains Preservative

Unopened: Store at 25°C (77°F):
Excursions permitted to 15-30°C (59-86°F)
[See USP controlled room temperature]
Store opened vials at 2-8°C (36-46°F)
Protect from light
For intravenous use only
Usual dosage: See package insert