Doxercalciferol by Winthrop U.S. / Genzyme Corporation / Catalent Pharma Solutions LLC / AndersonBrecon Inc. (PCI) / Assia Chemical Industries, Ltd. DOXERCALCIFEROL capsule

Doxercalciferol by

Drug Labeling and Warnings

Doxercalciferol by is a Prescription medication manufactured, distributed, or labeled by Winthrop U.S., Genzyme Corporation, Catalent Pharma Solutions LLC, AndersonBrecon Inc. (PCI), Assia Chemical Industries, Ltd.. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • 1 INDICATIONS AND USAGE

    • Doxercalciferol capsules are indicated for the treatment of secondary hyperparathyroidism in adult patients with Stage 3 or Stage 4 chronic kidney disease (CKD) and adult patients with CKD on dialysis.
    • HECTOROL injection is indicated for the treatment of secondary hyperparathyroidism in adult patients with CKD on dialysis.
  • 2 DOSAGE AND ADMINISTRATION

    2.1 Prior to Initiation of Doxercalciferol Capsules or Injection

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

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

    • Initiate doxercalciferol capsules at a dose of 1 mcg orally once daily.
    • Target the maintenance dose of doxercalciferol 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 Doxercalciferol 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 Doxercalciferol 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.

    2.3 Dosage Recommendations for Doxercalciferol Capsules in Patients with CKD on Dialysis

    • Initiate Doxercalciferol 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 doxercalciferol 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 Doxercalciferol 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 doxercalciferol 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.

    2.4 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)].

    2.5 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.

    2.6 Drug Interactions that May Require Dosage Adjustments of Doxercalciferol

    • Increased monitoring of serum calcium and dose adjustment of doxercalciferol 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 doxercalciferol may be necessary when given concomitantly with cytochrome P450 inhibitors or enzyme inducers [see Drug Interactions (7)].
  • 3 DOSAGE FORMS AND STRENGTHS

    Capsules: soft gelatin, oval capsules with imprinted "g" available as follows:

    • 0.5 mcg (salmon color)
    • 1 mcg (peach color)
    • 2.5 mcg (butter-yellow color)

    Injection: clear and colorless solution available as follows:

    • 2 mcg/mL single-dose vial
    • 4 mcg/2 mL (2 mcg/mL) single-dose vial
    • 4 mcg/2 mL (2 mcg/mL) multiple-dose vial
  • 4 CONTRAINDICATIONS

    Doxercalciferol is contraindicated in patients with:

  • 5 WARNINGS AND PRECAUTIONS

    5.1 Hypercalcemia

    Hypercalcemia may occur during doxercalciferol 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 doxercalciferol. In these circumstances, frequent serum calcium monitoring and doxercalciferol dose adjustments may be required.

    When initiating doxercalciferol or adjusting doxercalciferol 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 doxercalciferol 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.

    5.2 Digitalis Toxicity

    Doxercalciferol can cause hypercalcemia [see Warnings and Precautions (5.1)] which increases the risk of digitalis toxicity. In patients using doxercalciferol 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 doxercalciferol [see Drug Interactions (7)].

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

    5.4 Adynamic Bone Disease

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

  • 6 ADVERSE REACTIONS

    The following adverse reactions are discussed in greater detail in another section of the label:

    6.1 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.

    Doxercalciferol Capsules

    Adverse reactions in patients with stage 3 or 4 CKD

    Doxercalciferol capsules have been evaluated in two placebo-controlled, double-blind 24 week studies in patients with Stage 3 or 4 CKD. Patients were treated with Doxercalciferol capsules (n=27) or placebo (n=28) [see Clinical Studies (14.1)]. Adverse reactions occurring in the Doxercalciferol capsules group at a frequency of 5% or greater and more frequently than in the placebo group are presented in Table 1.

    Table 1: Adverse Reactions Occurring in ≥5% Doxercalciferol Capsule-Treated Patients with CKD on Predialysis and Greater than Placebo in Two Double-Blind Clinical Studies
    Adverse Reaction*Doxercalciferol (n=27)
    %    		Placebo (n=28)
    %
  • * Pooled data on adverse reactions from clinical study reports (Studies BCI-CH-115 and BCI-CH-119).
    		•
    Infection/bacterial infection/viral infection3025
    Constipation2611
    Rhinitis2211
    Anemia194
    Cough194
    Dyspnea1911
    Paresthesia1511
    Asthenia1511
    Insomnia154
    Hypertonia114
    Angina pectoris80
    Dehydration74
    Depression70
    Dyspepsia74
    Edema74
    Urinary tract infection74
    Leukopenia70
    Chest pain74
    Pruritus74
    Sinusitis74

    Adverse reactions in patients with CKD on dialysis

    Doxercalciferol capsules have been evaluated in two placebo-controlled, double-blind studies in patients with CKD on hemodialysis. Patients were treated with Doxercalciferol capsules (n=61) or placebo (n=61) [see Clinical Studies (14.2)]. 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 Doxercalciferol capsules in an open-label fashion for 16 weeks followed by a double-blind period of 8 weeks during which patients received either Doxercalciferol capsules or placebo. Adverse reactions occurring in the doxercalciferol capsule groups at a frequency of 2% or greater, and more frequently than in the placebo group are presented in Table 2.

    Table 2: Adverse Reactions Occurring in ≥2% Doxercalciferol Capsule-Treated Patients with CKD on Dialysis and Greater than Placebo in Two Double-Blind Clinical Studies
    Adverse Reaction*Doxercalciferol (n=61)
    %    		Placebo (n=61)
    %
  • * A patient who reported the same medical term more than once was counted only once for that medical term.
    • Edema3421
    Malaise2820
    Headache2818
    Nausea/Vomiting2120
    Dizziness1210
    Dyspnea127
    Pruritus87
    Bradycardia75
    Anorexia53
    Dyspepsia52
    Arthralgia50
    Weight increase50
    Abscess30
    Sleep disorder30

    HECTOROL Injection

    Adverse reactions in patients with CKD on hemodialysis

    HECTOROL injection has been studied in 70 patients with CKD on hemodialysis in two 12-week, open-label, single-arm, multicenter studies [see Clinical Studies (14.3)]. The incidence of hypercalcemia and hyperphosphatemia increased during therapy with HECTOROL injection. Patients with higher pretreatment serum levels of calcium (>10.5 mg/dL) or phosphorus (>6.9 mg/dL) were more likely to experience hypercalcemia or hyperphosphatemia.

    There was no placebo group included in the studies of HECTOROL injection. Adverse reactions in patients with CKD on hemodialysis receiving HECTOROL injection are expected to be similar to those reported in placebo-controlled studies of Doxercalciferol capsules presented in Table 2.

    6.2 Postmarketing Experience

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

  • 7 DRUG INTERACTIONS

    Tables 3 and 4 include clinically significant drug interactions with doxercalciferol.

    Table 3: Clinically Significant Drug Interactions with HECTOROL Injection and Doxercalciferol Capsules
    Drugs that May Increase the Risk of Hypercalcemia
    Clinical ImpactConcomitant administration of high doses of calcium-containing preparations or other vitamin D compounds may increase the risk of hypercalcemia. Thiazide diuretics are known to induce hypercalcemia by reducing excretion of calcium in the urine.
    ExamplesCalcium-containing products, other vitamin D compounds or thiazide diuretics
    InterventionMonitor serum calcium concentrations more frequently and adjust doxercalciferol dose as needed [see Warnings and Precautions (5.1)].
    Digitalis Compounds
    Clinical ImpactDoxercalciferol can cause hypercalcemia which can potentiate the risk of digitalis toxicity.
    InterventionMonitor patients for signs and symptoms of digitalis toxicity and increase frequency of serum calcium monitoring when initiating or adjusting the dose of doxercalciferol in patients receiving digitalis compounds [see Warnings and Precautions (5.2)].
    Cytochrome P450 Inhibitors
    Clinical ImpactDoxercalciferol is activated by CYP 27 in the liver. Cytochrome P450 inhibitors may inhibit the 25-hydroxylation of doxercalciferol and thus reduce the formation of active doxercalciferol moiety [see Clinical Pharmacology (12.3)].
    ExamplesKetoconazole and erythromycin
    InterventionIf a patient initiates or discontinues therapy with a cytochrome P450 inhibitor, dose adjustment of doxercalciferol may be necessary. Monitor intact PTH and serum calcium concentrations closely.
    Enzyme Inducers
    Clinical ImpactDoxercalciferol is activated by CYP 27 in the liver. Enzyme inducers may affect the 25-hydroxylation of doxercalciferol [see Clinical Pharmacology (12.3)].
    ExamplesGlutethimide and phenobarbital
    InterventionIf a patient initiates or discontinues therapy with an enzyme inducer, dose adjustment of doxercalciferol may be necessary. Monitor intact PTH and serum calcium concentrations closely.
    Magnesium-containing Products
    Clinical ImpactConcomitant administration of doxercalciferol and high doses of magnesium-containing products may increase the risk of hypermagnesemia.
    ExamplesMagnesium-containing products such as antacids
    InterventionAvoid use of magnesium-containing products and doxercalciferol in patients on chronic renal dialysis.
    Table 4: Clinically Significant Drug Interactions with Doxercalciferol Capsules
    Cholestyramine
    Clinical ImpactCholestyramine has been reported to reduce intestinal absorption of fat-soluble vitamins. Therefore, it may impair intestinal absorption of Doxercalciferol capsules.
    InterventionAdminister Doxercalciferol capsules at least 1 hour before or 4 to 6 hours after taking cholestyramine.
    Mineral Oil or other Substances that May Affect Absorption of Fat
    Clinical ImpactThe use of mineral oil or other substances that may affect absorption of fat may influence the absorption and availability of doxercalciferol.
    InterventionAdminister Doxercalciferol capsules at least 1 hour before or 4 to 6 hours after taking mineral oil or other substances that may affect absorption of fat.
  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Risk Summary

    The limited available data with doxercalciferol in pregnant women are insufficient to identify a drug-associated risk for major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with chronic kidney disease in pregnancy [see Clinical Considerations]. In reproduction studies in rats and rabbits administered doxercalciferol during organogenesis at up to 20 mcg/kg/day and 0.1 mcg/kg/day, respectively (approximately 25 times (rats) and less than (rabbits) the maximum recommended human oral dose of 60 mcg/week based on mcg/m2 body surface area), no adverse developmental effects were observed [see Data].

    The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively.

    Clinical Considerations

    Disease-associated maternal and/or embryo/fetal risk

    Chronic kidney disease in pregnancy increases the risk for maternal hypertension and preeclampsia, miscarriage, preterm delivery polyhydramnios, stillbirth, and low-birth-weight infants.

    Data

    Animal data

    There were no adverse effects on fetal development when doxercalciferol was administered at doses up to 20 mcg/kg/day in pregnant rats or doses up to 0.1 mcg/kg/day in pregnant rabbits during the period of organogenesis.

    8.2 Lactation

    Risk Summary

    There is no information available on the presence of doxercalciferol in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Infants exposed to doxercalciferol through breast milk should be monitored for signs and symptoms of hypercalcemia [see Clinical Considerations].

    The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for doxercalciferol and any potential adverse effects on the breastfed child from doxercalciferol or from the underlying maternal condition.

    Clinical Considerations

    Infants exposed to HECTOROL Injection through breast milk should be monitored for signs and symptoms of hypercalcemia, including seizures, vomiting, constipation and weight loss. Monitoring of serum calcium in the infant should be considered.

    8.4 Pediatric Use

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

    8.5 Geriatric Use

    Clinical studies of doxercalciferol 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.

    8.6 Hepatic Impairment

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

  • 10 OVERDOSAGE

    Overdosage of doxercalciferol may lead to hypercalcemia, hypercalciuria, and hyperphosphatemia [see Warnings and Precautions (5.1)]. The treatment of acute overdosage should consist of supportive measures and discontinuation of doxercalciferol administration. Serum calcium levels should be measured until normal.

    Based on similarities between doxercalciferol and its active metabolite, 1α,25-(OH)2D2, it is expected that doxercalciferol is not removed from the blood by dialysis.

  • 11 DESCRIPTION

    Doxercalciferol capsule contains doxercalciferol, which is a synthetic vitamin D2 analog. Doxercalciferol undergoes metabolic activation in vivo to form 1α,25-dihydroxyvitamin D2 (1α,25-(OH)2D2), a naturally occurring, biologically active form of vitamin D2.

    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. The structural formula is:

    Chemical Structure

    Capsules

    Doxercalciferol 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).

  • 12 CLINICAL PHARMACOLOGY

    12.1 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.

    12.3 Pharmacokinetics

    Absorption

    In healthy volunteers, peak blood levels of 1α,25-(OH)2D2, the major metabolite of doxercalciferol, are attained at 8 hours after a single intravenous dose of HECTOROL and at 11 to 12 hours following capsule doses.

    Elimination

    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.

    Metabolism

    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.

    Specific Populations

    Patients with renal impairment

    The mean elimination half-life of 1α,25-(OH)2D2 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.

  • 13 NONCLINICAL TOXICOLOGY

    13.1 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).

  • 14 CLINICAL STUDIES

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

    The safety and effectiveness of Doxercalciferol 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 Doxercalciferol capsules and the other placebo during the double-blind period of 24 weeks. The initial dose of Doxercalciferol capsules was 1 mcg per day. The dosage of Doxercalciferol 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, Doxercalciferol 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 Doxercalciferol capsules group and by 4 pg/mL in the placebo group (p<0.001). Twenty (74%) of 27 subjects in the Doxercalciferol 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.

    14.2 Clinical Studies of Doxercalciferol Capsules in Patients with CKD on Dialysis

    The safety and effectiveness of Doxercalciferol 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 Doxercalciferol capsules in an open-label fashion for 16 weeks followed by a double-blind period of 8 weeks during which patients received either Doxercalciferol capsules or placebo. The initial dose of Doxercalciferol 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 doxercalciferol 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, doxercalciferol 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 Doxercalciferol 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.

    Table 5: Intact PTH Summary Data for Patients with CKD on Dialysis Receiving Doxercalciferol Capsules in Studies A and B
    Intact PTH (pg/mL)
    means ± SD (n)*
    p-value vs Baseline
    p-value vs Placebo
    Doxercalciferol CapsulesPlacebo
    NA = not applicable
  • * All subjects; last value carried to discontinuation.
    • Study ABaseline797.2 ± 443.8 (30)
    NA
    0.97    		847.1 ± 765.5 (32)
    –
    –
    Week 16
    (open-label)    		384.3 ± 397.8 (24)
    <0.001
    0.72    		526.5 ± 872.2 (29)
    <0.001
    –
    Week 24
    (double-blind)    		404.4 ± 262.9 (21)
    <0.001
    0.008     		672.6 ± 356.9 (24)
    0.70
    –
    Study BBaseline973.9 ± 567.0 (41)
    NA
    0.81    		990.4 ± 488.3 (35)
    –
    –
    Week 16
    (open-label)    		476.1 ± 444.5 (37)
    <0.001
    0.91    		485.9 ± 443.4 (32)
    <0.001
    –
    Week 24
    (double-blind)    		459.8 ± 443.0 (35)
    <0.001
    <0.001    		871.9 ± 623.6 (30)
    <0.065
    –

    Doxercalciferol 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 Doxercalciferol capsules treatment group compared to a return to near baseline in the placebo group.

    14.3 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 Doxercalciferol 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 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.

    Table 6: Intact PTH Summary Data for Patients with CKD on Dialysis Receiving HECTOROL Injection in Studies C and D
    Intact PTH LevelStudy C
    (n=28)    		Study D
    (n=42)    		Combined Protocols
    (n=70)
  • * Values were carried forward for the two patients on study for 10 weeks
  • † Treatment intact PTH minus baseline intact PTH
  • ‡ Wilcoxon one-sample test
    		•
    Baseline (Mean of Weeks -2, -1, and 0)
    Mean (SE)698 (60)762 (65)736 (46)
    Median562648634
    On-treatment (Week 12*)
    Mean (SE)406 (63)426 (60)418 (43)
    Median311292292
    Change from Baseline†
    Mean (SE)-292 (55)-336 (41)-318 (33)
    Median-274-315-304
    P-value‡0.0040.001<0.001

    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.

  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    How Supplied

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

    StrengthCapsule ColorImprint CodePackage sizeNDC
    0.5 mcgsalmongbottle of 50 capsules0955-1720-50
    1 mcgpeachgbottle of 50 capsules0955-1721-50
    2.5 mcgbutter-yellowgbottle of 50 capsules0955-1722-50

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

    Total Strength per Total VolumeStrength per mLFlip-off Cap ColorVial Count per Carton × Total Vial Volume and Vial TypeCarton NDCVial NDC
    2 mcg/mL2 mcg/mLGreen50 × 1 mL single-dose vials58468-0126-158468-0126-0
    4 mcg/2 mL2 mcg/mLYellow50 × 2 mL single-dose vials58468-0123-158468-0123-0
    4 mcg/2 mL2 mcg/mLOrange50 × 2 mL multiple-dose vials58468-0127-158468-0127-0

    Storage and Handling

    Dosage FormStorage temperatureExcursions permitted toIn-use storage
  • * Protect from light. Store unopened vial in original carton.
    		•
    Capsule25°C (77°F)15°C to 30°C (59°F to 86°F)
    [see USP controlled room temperature]     		–
    Single-dose vial*25°C (77°F)15°C to 30°C (59°F to 86°F)
    [see USP controlled room temperature]    		Discard unused portion
    Multiple-dose vial*25°C (77°F)15°C to 30°C (59°F to 86°F)
    [see USP controlled room temperature]    		2°C to 8°C (36°F to 46°F), Discard 3 days after opening
  • 17 PATIENT COUNSELING INFORMATION

    Hypercalcemia

    Advise patients to contact a health care provider if they develop symptoms of elevated calcium (e.g. feeling tired, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination and weight loss) [see Warnings and Precautions (5.1)].

    Hypersensitivity

    Inform patients that hypersensitivity reactions can occur with doxercalciferol [see Warnings and Precautions (5.3)].

    Monitoring

    Inform patients that they will need routine monitoring of laboratory parameters such as calcium and intact PTH while receiving doxercalciferol. Inform patients that more frequent monitoring is necessary during the initiation of therapy, following dose changes or when potentially interacting medications are started or discontinued [see Dosage and Administration (2), Drug Interactions (7)].

    Drug Interactions

    Advise patients to inform their physician of all medications, including prescription and nonprescription drugs, and supplements they are taking. Advise patients to also inform their physician that they are receiving doxercalciferol if a new medication is prescribed [see Drug Interactions (7)].

  • SPL UNCLASSIFIED SECTION

    Doxercalciferol Capsules

    Manufactured by Catalent Pharma Solutions for:
    Winthrop U.S.,
    a business of sanofi-aventis U.S. LLC
    Bridgewater, NJ 08807
    A SANOFI COMPANY

    HECTOROL Injection

    Manufactured by:
    Genzyme Corporation
    Cambridge, MA 02142

  • PRINCIPAL DISPLAY PANEL - 0.5 mcg Capsule Bottle Carton

    NDC: 0955-1720-50
    Rx ONLY

    Winthrop
    A SANOFI COMPANY

    Doxercalciferol
    Capsules

    0.5 mcg

    50 Capsules

    SANOFI

    PRINCIPAL DISPLAY PANEL - 0.5 mcg Capsule Bottle Carton
  • PRINCIPAL DISPLAY PANEL - 1 mcg Capsule Bottle Carton

    NDC: 0955-1721-50
    Rx ONLY

    Winthrop
    A SANOFI COMPANY

    Doxercalciferol
    Capsules

    1 mcg

    50 Capsules

    SANOFI

    PRINCIPAL DISPLAY PANEL - 1 mcg Capsule Bottle Carton
  • PRINCIPAL DISPLAY PANEL - 2.5 mcg Capsule Bottle Carton

    NDC: 0955-1722-50
    Rx ONLY

    Winthrop
    A SANOFI COMPANY

    Doxercalciferol
    Capsules

    2.5 mcg

    50 Capsules

    SANOFI

    PRINCIPAL DISPLAY PANEL - 2.5 mcg Capsule Bottle Carton
  • INGREDIENTS AND APPEARANCE
    DOXERCALCIFEROL 
    doxercalciferol capsule
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 0955-1720
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    DOXERCALCIFEROL (UNII: 3DIZ9LF5Y9) (DOXERCALCIFEROL - UNII:3DIZ9LF5Y9) DOXERCALCIFEROL0.5 ug
    Inactive Ingredients
    Ingredient NameStrength
    MEDIUM-CHAIN TRIGLYCERIDES (UNII: C9H2L21V7U)  
    ALCOHOL (UNII: 3K9958V90M)  
    BUTYLATED HYDROXYANISOLE (UNII: REK4960K2U)  
    GELATIN, UNSPECIFIED (UNII: 2G86QN327L)  
    GLYCERIN (UNII: PDC6A3C0OX)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    FERRIC OXIDE YELLOW (UNII: EX438O2MRT)  
    FD&C RED NO. 40 (UNII: WZB9127XOA)  
    Product Characteristics
    ColorPINK (salmon) Scoreno score
    ShapeOVALSize6mm
    FlavorImprint Code g
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 0955-1720-501 in 1 CARTON04/17/2017
    150 in 1 BOTTLE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDA authorized genericNDA02086204/17/2017
    DOXERCALCIFEROL 
    doxercalciferol capsule
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 0955-1721
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    DOXERCALCIFEROL (UNII: 3DIZ9LF5Y9) (DOXERCALCIFEROL - UNII:3DIZ9LF5Y9) DOXERCALCIFEROL1 ug
    Inactive Ingredients
    Ingredient NameStrength
    MEDIUM-CHAIN TRIGLYCERIDES (UNII: C9H2L21V7U)  
    ALCOHOL (UNII: 3K9958V90M)  
    BUTYLATED HYDROXYANISOLE (UNII: REK4960K2U)  
    GELATIN, UNSPECIFIED (UNII: 2G86QN327L)  
    GLYCERIN (UNII: PDC6A3C0OX)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    FD&C YELLOW NO. 6 (UNII: H77VEI93A8)  
    Product Characteristics
    ColorPINK (peach) Scoreno score
    ShapeOVALSize6mm
    FlavorImprint Code g
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 0955-1721-501 in 1 CARTON04/17/2017
    150 in 1 BOTTLE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDA authorized genericNDA02086204/17/2017
    DOXERCALCIFEROL 
    doxercalciferol capsule
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 0955-1722
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    DOXERCALCIFEROL (UNII: 3DIZ9LF5Y9) (DOXERCALCIFEROL - UNII:3DIZ9LF5Y9) DOXERCALCIFEROL2.5 ug
    Inactive Ingredients
    Ingredient NameStrength
    MEDIUM-CHAIN TRIGLYCERIDES (UNII: C9H2L21V7U)  
    ALCOHOL (UNII: 3K9958V90M)  
    BUTYLATED HYDROXYANISOLE (UNII: REK4960K2U)  
    GELATIN, UNSPECIFIED (UNII: 2G86QN327L)  
    GLYCERIN (UNII: PDC6A3C0OX)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    FERRIC OXIDE YELLOW (UNII: EX438O2MRT)  
    Product Characteristics
    ColorYELLOW (butter yellow) Scoreno score
    ShapeOVALSize6mm
    FlavorImprint Code g
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 0955-1722-501 in 1 CARTON04/17/2017
    150 in 1 BOTTLE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDA authorized genericNDA02086204/17/2017
    Labeler - Winthrop U.S. (824676584)
    Establishment
    NameAddressID/FEIBusiness Operations
    Catalent Pharma Solutions, LLC051762268MANUFACTURE(0955-1720, 0955-1721, 0955-1722)
    Establishment
    NameAddressID/FEIBusiness Operations
    AndersonBrecon Inc.053217022LABEL(0955-1720, 0955-1721, 0955-1722) , PACK(0955-1720, 0955-1721, 0955-1722)
    Establishment
    NameAddressID/FEIBusiness Operations
    Assia Chemical Industries Ltd. - Teva Tech Site514678507ANALYSIS(0955-1720, 0955-1721, 0955-1722) , API MANUFACTURE(0955-1720, 0955-1721, 0955-1722)
    Establishment
    NameAddressID/FEIBusiness Operations
    Genzyme Ireland Limited985127419ANALYSIS(0955-1720, 0955-1721, 0955-1722)
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