Hectorol

 Prior to Initiation of HECTOROL Capsules or Injection

• Ensure serum calcium is not above the upper limit of normal before initiating treatment with HECTOROL capsules or injection [see Warnings and Precautions (5.1)].

  Dosage Recommendations for HECTOROL Capsules in Patients with Stage 3 or 4 CKD

• Initiate HECTOROL capsules at a dose of 1 mcg orally once daily.
• Target the maintenance dose of HECTOROL to intact parathyroid hormone (PTH) levels within the desired therapeutic range and serum calcium within normal limits.
• Monitor serum calcium, phosphorus, and intact PTH levels at least every two weeks for 3 months after initiation of therapy or dose adjustment, then monthly for 3 months, and every 3 months thereafter.
• Titrate the dose of HECTOROL capsules based on intact PTH. The dose may be increased at 2-week intervals by 0.5 mcg to achieve the desired therapeutic range of intact PTH. The maximum recommended dose of HECTOROL capsules is 3.5 mcg administered once daily. Prior to raising the dose, ensure serum calcium is within normal limits.
• Suspend or decrease the dose if intact PTH is persistently and abnormally low to reduce the risk of adynamic bone disease [see Warnings and Precautions (5.4)] or if serum calcium is consistently above the normal range to reduce the risk of hypercalcemia [see Warnings and Precautions (5.1)]. If suspended, the drug should be restarted after one week at a dose that is at least 0.5 mcg lower.

 Dosage Recommendations for HECTOROL Capsules in Patients with CKD on Dialysis

• Initiate HECTOROL capsules at a dose of 10 mcg orally administered three times weekly at dialysis (no more frequently than every other day).
• Target the maintenance dose of HECTOROL to intact parathyroid hormone (PTH) levels within the desired therapeutic range and serum calcium within normal limits.
• Monitor serum calcium, phosphorus, and intact PTH levels frequently (e.g., weekly) after initiation of therapy or dose adjustment.
• Titrate the dose of HECTOROL capsules based on intact PTH. The dose may be increased at 8-week intervals by 2.5 mcg to achieve the desired therapeutic range of intact PTH. The maximum recommended dose of HECTOROL is 20 mcg administered three times weekly at dialysis for a total dose of 60 mcg weekly. Prior to raising the dose, ensure serum calcium is within normal limits.
• Suspend or decrease the dose if intact PTH is persistently and abnormally low to reduce the risk of adynamic bone disease [see Warnings and Precautions (5.4)] or if serum calcium is consistently above the normal range to reduce the risk of hypercalcemia [see Warnings and Precautions (5.1)]. If suspended, the drug should be restarted one week later at a dose that is at least 2.5 mcg lower.

 Important Administration Instructions for HECTOROL Injection

• Administer HECTOROL injection intravenously as a bolus dose at the end of dialysis.
• Inspect HECTOROL injection visually prior to administration; the solution should appear clear and colorless. Do not use if the solution is not clear or particles are present.
• After initial vial use:
  • discard unused portion of the single-dose vial;
  • store opened multiple-dose vial for up to 3 days at 2°C to 8°C (36°F to 46°F). Discard unused portion of multiple-dose vial after 3 days [see How Supplied/Storage and Handling (16)].

 Dosage Recommendations for HECTOROL Injection in Patients with CKD on Dialysis

• Initiate HECTOROL injection at a dose of 4 mcg given by bolus intravenous administration three times weekly at the end of dialysis (no more frequently than every other day).
• Target the maintenance dose of HECTOROL to intact parathyroid hormone (PTH) levels within the desired therapeutic range and serum calcium within normal limits.
• Monitor serum calcium, phosphorus, and intact PTH levels weekly after initiation of therapy or dose adjustment.
• Titrate the dose of HECTOROL injection based on intact PTH. The dose may be increased at 8-week intervals by 1 mcg to 2 mcg if intact PTH is not lowered by 50% and fails to reach the target range. The maximum dose is 18 mcg weekly. Prior to raising the dose, ensure serum calcium is within normal limits.
• Suspend or decrease the dose if intact PTH is persistently and abnormally low to reduce the risk of adynamic bone disease [see Warnings and Precautions (5.4)] or if serum calcium is consistently above the normal range to reduce the risk of hypercalcemia [see Warnings and Precautions (5.1)]. If suspended, the drug should be restarted one week later at a dose that is at least 1 mcg lower.

 Drug Interactions that May Require Dosage Adjustments of HECTOROL

• Increased monitoring of serum calcium and dose adjustment of HECTOROL may be necessary when given concomitantly with drugs that may increase the risk of hypercalcemia [see Drug Interactions (7)].
• Increased monitoring of both serum calcium and intact PTH as well as dose adjustment of HECTOROL may be necessary when given concomitantly with cytochrome P450 inhibitors or enzyme inducers [see Drug Interactions (7)].

Pregnancy

Lactation

Pediatric Use

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

Geriatric Use

Clinical studies of HECTOROL did not include sufficient numbers of patients 65 years or over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic or cardiac function, and of concomitant disease or other drug therapy.

 Hepatic Impairment

Patients with hepatic impairment may not metabolize HECTOROL appropriately. More frequent monitoring of intact PTH, calcium, and phosphorus levels should be done in patients with hepatic impairment.

 Hypercalcemia

Hypercalcemia may occur during HECTOROL treatment. Acute hypercalcemia may increase the risk of cardiac arrhythmias and seizures and may potentiate the effect of digitalis on the heart [see Warnings and Precautions (5.2)]. Chronic hypercalcemia can lead to generalized vascular calcification and other soft-tissue calcification. Severe hypercalcemia may require emergency attention.

Hypercalcemia may be exacerbated by concomitant administration of high doses of calcium-containing preparations, thiazide diuretics, or other vitamin D compounds [see Drug Interactions (7)]. In addition, high intake of calcium and phosphate concomitantly with vitamin D compounds may lead to hypercalciuria and hyperphosphatemia. Patients with a history of hypercalcemia prior to initiating therapy may be at increased risk for development of hypercalcemia with HECTOROL. In these circumstances, frequent serum calcium monitoring and HECTOROL dose adjustments may be required.

When initiating HECTOROL or adjusting HECTOROL dose, measure serum calcium frequently (weekly in patients with CKD on dialysis or every 2 weeks for patients with stage 3 or 4 CKD). Once a maintenance dose has been established, measure serum calcium monthly for 3 months and then every 3 months. If hypercalcemia occurs, reduce the dose or discontinue HECTOROL until serum calcium is normal [see Dosage and Administration (2)].

Inform patients about the symptoms of elevated calcium (feeling tired, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination and weight loss) and instruct them to report new or worsening symptoms when they occur.

 Digitalis Toxicity

HECTOROL can cause hypercalcemia [see Warnings and Precautions (5.1)] which increases the risk of digitalis toxicity. In patients using HECTOROL concomitantly with digitalis compounds, monitor both serum calcium and patients for signs and symptoms of digitalis toxicity. Increase the frequency of monitoring when initiating or adjusting the dose of HECTOROL [see Drug Interactions (7)].

 Serious Hypersensitivity Reactions

Serious hypersensitivity reactions, including fatal outcome, have been reported post marketing 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, and cardiopulmonary arrest. These reactions may occur separately or together.

Monitor patients receiving HECTOROL upon initiation of treatment for hypersensitivity reactions. Should a hypersensitivity reaction occur, discontinue HECTOROL, monitor and treat if indicated [see Contraindications (4)].

 Adynamic Bone Disease

Adynamic bone disease with subsequent increased risk of fractures may develop if intact PTH levels are suppressed by HECTOROL to abnormally low levels. Monitor intact PTH levels to avoid oversuppression and adjust the HECTOROL dose, if needed [see Dosage and Administration (2)].

 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of HECTOROL. 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.

Capsules

HECTOROL capsules are soft gelatin capsules containing 0.5 mcg, 1 mcg, or 2.5 mcg doxercalciferol for oral use. Each capsule also contains butylated hydroxyanisole (BHA), ethanol, and fractionated triglyceride of coconut oil. The capsule shells contain gelatin, glycerin, and titanium dioxide. In addition, the 0.5 mcg capsule shells contain yellow iron oxide and FD&C Red No. 40, the 1 mcg capsule shells contain FD&C Yellow No. 6, and the 2.5 mcg capsule shells contain yellow iron oxide.

Injection

HECTOROL injection 1 mL single-dose vials contain 2 mcg/mL of doxercalciferol. HECTOROL injection 2 mL single-dose vials contain 4 mcg/2 mL (2 mcg/mL) of doxercalciferol. Each milliliter (mL) of solution contains 2 mcg doxercalciferol and the following inactive ingredients: butylated hydroxytoluene (0.02 mg); disodium edetate (1.1 mg); ethanol, 100% (0.05 mL); polysorbate 20 (10 mg); sodium chloride (1.5 mg); sodium phosphate dibasic, heptahydrate (14.4 mg); and sodium phosphate monobasic, monohydrate (1.8 mg).

HECTOROL injection 2 mL multiple-dose vials contain 4 mcg/2 mL (2 mcg/mL) of doxercalciferol. Each milliliter (mL) of solution contains 2 mcg doxercalciferol and the following inactive ingredients: butylated hydroxytoluene (0.02 mg); disodium edetate (1.1 mg); ethanol, 100% (0.075 mL); polysorbate 20 (10 mg); sodium chloride (1.5 mg); sodium phosphate dibasic, heptahydrate (14.4 mg); and sodium phosphate monobasic, monohydrate (1.8 mg).

Mechanism of Action

Doxercalciferol is a synthetic vitamin D2 analog that requires metabolic activation to form the active 1α,25-(OH)2D2 metabolite, which binds to the vitamin D receptor (VDR) to result in the selective activation of vitamin D responsive pathways. Vitamin D and doxercalciferol have been shown to reduce PTH levels by inhibiting PTH synthesis and secretion.

Pharmacokinetics

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 (less than the maximum recommended human oral dose of 60 mcg/week based on mcg/m2 body surface area). 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 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 oral dose of 60 mcg/week based on mcg/m2 body surface area).

 Clinical Studies of HECTOROL Capsules in Patients with Stage 3 or 4 CKD

The safety and effectiveness of HECTOROL capsules were evaluated in two clinical studies in 55 patients with Stage 3 or 4 CKD. Eighty-two percent of the patients were male, the average age was 65 years, 51% were Caucasian, 40% African-American, and the average serum intact PTH level at baseline was 195 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 19 ± 8 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 capsules and the other placebo during the double-blind period of 24 weeks. The initial dose of HECTOROL capsules was 1 mcg per day. The dosage of HECTOROL capsules was adjusted as necessary by the investigator to reduce intact PTH levels to a target of ≥30% below postwashout baseline. The maximum dosage was limited to 3.5 mcg per day. If at any time during the trial intact PTH fell below 15 pg/mL, HECTOROL capsules were immediately suspended and restarted at a lower dosage the following week.

Decreases in the mean plasma intact PTH 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, intact PTH levels decreased from baseline by an average of 101 pg/mL in the HECTOROL capsules group and by 4 pg/mL in the placebo group (p<0.001). Twenty (74%) of 27 subjects in the HECTOROL capsules group achieved mean plasma intact PTH 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 intact PTH suppression.

 Clinical Studies of HECTOROL Capsules in Patients with CKD on Dialysis

The safety and effectiveness of HECTOROL capsules were evaluated in two double-blind, placebo-controlled, multicenter clinical studies (Study A and Study B) in a total of 138 patients with CKD on hemodialysis. Patients in Study A were an average age of 52 years (range: 22 to 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 to 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 capsules in an open-label fashion for 16 weeks followed by a double-blind period of 8 weeks during which patients received either HECTOROL capsules or placebo. The initial dose of HECTOROL capsules during the open-label phase was 10 mcg 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 to achieve intact PTH levels within 150 pg/mL 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 intact PTH fell below 150 pg/mL, HECTOROL was immediately suspended and restarted at a lower dosage the following week. Mean weekly doses during the 16-week open-label period ranged from 15 mcg to 29 mcg in Study A and from 19 mcg to 28 mcg in Study B.

One hundred and six (77%) of the 138 patients who were treated with HECTOROL capsules during the 16-week open-label phase achieved intact PTH levels ≤300 pg/mL. Ninety-four (68%) of these patients exhibited plasma intact PTH levels ≤300 pg/mL on at least 3 occasions. Eighty-seven (63%) patients had plasma intact PTH levels <150 pg/mL on at least one occasion during the open-label phase of study participation.

Decreases in plasma intact PTH 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 Table 5.

HECTOROL capsules treatment resulted in a statistically significant reduction from baseline in mean intact PTH levels during the 16-week open-label treatment period in more than 94% of the 138 treated patients. During the double-blind period (weeks 17 to 24), the reduction in mean intact PTH levels was maintained in the HECTOROL capsules treatment group compared to a return to near baseline in the placebo group.

 Clinical Studies of HECTOROL Injection in Patients with CKD on Dialysis

The safety and effectiveness of HECTOROL injection were evaluated in two open-label, single-arm, multicenter clinical studies (Study C and Study D) in a total of 70 patients with CKD on hemodialysis. Patients in Study C were an average age of 54 years (range: 23 to 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 to 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 to achieve intact PTH levels (measured weekly) within a targeted range of 150 pg/mL to 300 pg/mL. The dosage was increased by 2 mcg per dialysis session after 8 weeks of treatment if the intact PTH 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 study intact PTH fell below 150 pg/mL, HECTOROL injection was immediately suspended and restarted at a lower dosage the following week. Mean weekly doses ranged from ranged from 9 mcg to 13 mcg in Study C and ranged from 9 mcg to 12 mcg in Study D.

Fifty-two (74%) of the 70 patients who were treated with HECTOROL injection achieved intact PTH levels ≤300 pg/mL. Forty-one (59%) of these patients exhibited plasma intact PTH levels ≤300 pg/mL on at least 3 occasions. Thirty-six (51%) patients had plasma intact PTH levels <150 pg/mL on at least one occasion during study participation. Decreases in plasma intact PTH 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 Table 6.

HECTOROL treatment resulted in at least 30% reduction from baseline in mean intact PTH levels during the 12-week open-label treatment period in more than 92% of the 70 treated patients.

How Supplied

HECTOROL capsules are oval, soft gelatin capsules supplied as follows.

HECTOROL injection is a clear, colorless solution supplied in 2 mL amber glass vials as follows.

Storage and Handling