ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in another section of the label:oHypercalcemia [see Warnings and Precautions (5.1)]oSerious Hypersensitivity Reactions [see Warnings and Precautions (5.3)]oAdynamic Bone Disease [see Warnings and Precautions (5.4)]. oHypercalcemia [see Warnings and Precautions (5.1)]. oSerious Hypersensitivity Reactions [see Warnings and Precautions (5.3)]. oAdynamic Bone Disease [see Warnings and Precautions (5.4)]. The most common adverse reactions in patients with Stage or CKD (incidence >5%) were infection, urinary tract infection, chest pain, angina pectoris, constipation, dyspepsia, anemia, leucopenia, dehydration, edema, depression, hypertonia, insomnia, asthenia, paresthesia, cough increased, dyspnea, pruritus, sinusitis, and rhinitis. (6.1) The most common adverse reactions in patients with CKD on dialysis (incidence >5%) were headache, malaise, edema, nausea/vomiting, dyspnea, dizziness, pruritus, and bradycardia. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 or CKD: Doxercalciferol capsules have been evaluated in two placebo-controlled, double-blind 24 week studies in patients with Stage or 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 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% DoxercalciferolCapsule-Treated Patients with CKD on Predialysis and Greater than Placebo in Two Double-Blind Clinical StudiesAdverse ReactionsPooled data on adverse reactions from clinical study reports (Studies BCI-CH-115 and BCI-CH-119).Doxercalciferol (n=27)%Placebo (n=28)%Infection/Bacterial Infection/Viral Infection3025Constipation2611Rhinitis2211Anemia194Cough194Dyspnea1911Paresthesia1511Asthenia1511Insomnia154Hypertonia114Angina Pectoris80Dehydration74Depression70Dyspepsia74Edema74Urinary Tract Infection74Leukopenia70Chest pain74Pruritus74Sinusitis74Adverse 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 derivatives were administered to either group. Subsequently, all patients received doxercalciferol capsules in an open-label fashion for 16 weeks followed by double-blind period of weeks during which patients received either doxercalciferol capsules or placebo. Adverse reactions occurring in the doxercalciferol capsule groups at 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 ReactionsA patient who reported the same medical term more than once was counted only once for that medical term.Doxercalciferol (n=61)%Placebo (n=61)%Edema3421Malaise2820Headache2818Nausea/Vomiting2120Dizziness1210Dyspnea127Pruritus87Bradycardia75Anorexia53Dyspepsia52Arthralgia50Weight Increase50Abscess30Sleep Disorder30Doxercalciferol Injection: Adverse reactions in patients with CKD on hemodialysis:Doxercalciferol 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 doxercalciferol 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 doxercalciferol injection. Adverse reactions in patients with CKD on hemodialysis receiving doxercalciferol 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 population of uncertain size, it is not always possible to estimate their frequency or to establish causal relationship to drug exposure.Hypersensitivity reactions, including fatal outcome, have been reported in patients on hemodialysis following administration of doxercalciferol 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In 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 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 times the maximum recommended human oral dose of 60 mcg/week based on mcg/m2 body surface area).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Doxercalciferol is synthetic vitamin D2 analog that requires metabolic activation to form the active 1,25-(OH)2D2 metabolite, which binds to the vitamin receptor (VDR) to result in the selective activation of vitamin responsive pathways. Vitamin 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 1,25-(OH)2D2, the major metabolite of doxercalciferol, are attained at hours after single intravenous dose of doxercalciferol and at 11 to 12 hours following capsule doses. Elimination: The mean elimination half-life of 1,25-(OH)2D2 after an oral dose is approximately 32 to 37 hours with range of up to 96 hours. Metabolism: Doxercalciferol is activated by CYP 27 in the liver to form 1,25-(OH)2D2 (major metabolite) and 1,24-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 1,25-(OH)2D2 in patients with end-stage renal disease (ESRD) and in healthy volunteers appears to be similar following an oral dose. Hemodialysis causes temporary increase in 1,25-(OH)2D2 mean concentrations, presumably due to volume contraction. 1,25-(OH)2D2 is not removed from blood during hemodialysis.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES 14.1 Clinical Studies of Doxercalciferol Capsules in Patients with Stage or CKD The safety and effectiveness of doxercalciferol capsules were evaluated in two clinical studies in 55 patients with Stage or 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 were not evaluated at baseline, retrospective assessments of stored serum revealed that the mean +- SD serum 25-(OH) vitamin was 19 +- 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 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 mcg per day. The dosage of doxercalciferol capsules was adjusted as necessary by the investigator to reduce intact PTH levels to 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 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 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 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 and Study B) in total of 138 patients with CKD on hemodialysis. Patients in Study 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 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 derivatives were administered to either group. Subsequently, all patients received doxercalciferol capsules in an open-label fashion for 16 weeks followed by double-blind period of 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 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 lower dosage the following week. Mean weekly doses during the 16-week open-label period ranged from 15 mcg to 29 mcg in Study 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 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 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 and BIntact PTH (pg/mL)means +- SD (n)All subjects; last value carried to discontinuation. NA not applicablep-value vs Baseline p-value vs PlaceboDoxercalciferolCapsulesPlaceboStudy ABaseline797.2 +- 443.8 (30)NA 0.97847.1 +- 765.5 (32)--Week 16 (open-label)384.3 +- 397.8 (24) <0.001 0.72526.5 +- 872.2 (29) <0.001 -Week 24(double-blind)404.4 +- 262.9 (21) <0.001 0.008672.6 +- 356.9 (24) 0.70 -Study BBaseline973.9 +- 567.0 (41) NA 0.81990.4 +- 488.3 (35)--Week 16 (open-label)476.1 +- 444.5 (37) <0.001 0.91485.9 +- 443.4 (32) <0.001 -Week 24(double-blind)459.8 +- 443.0 (35) <0.001 <0.001871.9 +- 623.6 (30) <0.065 -Doxercalciferol capsules treatment resulted in 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 return to near baseline in the placebo group.. 14.3 Clinical Studies of Doxercalciferol Injection in Patients with CKD on Dialysis The safety and effectiveness of doxercalciferol injection were evaluated in two open-label, single-arm, multicenter clinical studies (Study and Study D) in total of 70 patients with CKD on hemodialysis. Patients in Study 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 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 and Study B) received doxercalciferol Injection in an open-label fashion for 12 weeks following an 8-week washout (control) period. Dosing of doxercalciferol injection was initiated at the rate of mcg administered at the end of each dialysis session (3 times weekly) for total of 12 mcg per week. The dosage of doxercalciferol was adjusted to achieve intact PTH levels (measured weekly) within targeted range of 150 pg/mL to 300 pg/mL. The dosage was increased by mcg per dialysis session after 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, doxercalciferol injection was immediately suspended and restarted at lower dosage the following week. Mean weekly doses ranged from ranged from mcg to 13 mcg in Study and ranged from mcg to 12 mcg in Study D. Fifty-two (74%) of the 70 patients who were treated with doxercalciferol 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 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 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 Doxercalciferol Injection in Studies and DIntact PTH LevelStudy C(n=28)Study D(n=42)Combined Protocols(n=70)Baseline (Mean of Weeks -2, -1, and 0)Mean (SE)698 (60)762 (65)736 (46)Median562648634On-treatment (Week 12Values were carried forward for the two patients on study for 10 weeks )Mean (SE)406 (63)426 (60)418 (43)Median311292292Change from BaselineTreatment intact PTH minus baseline intact PTH Mean (SE)-292 (55)-336 (41)-318 (33)Median-274-315-304P-valueWilcoxon one-sample test 0.0040.001<0.001Doxercalciferol 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.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS Doxercalciferol Capsules is contraindicated in patients with:oHypercalcemia [see Warnings and Precautions (5.1)]oVitamin toxicity [see Warnings and Precautions (5.1)]oKnown hypersensitivity to doxercalciferol or any of the inactive ingredients of doxercalciferol capsules or doxercalciferol injection; serious hypersensitivity reactions including anaphylaxis and angioedema have been reported [see Warnings and Precautions (5.3), Adverse Reactions (6.2)].. oHypercalcemia [see Warnings and Precautions (5.1)]. oVitamin toxicity [see Warnings and Precautions (5.1)]. oKnown hypersensitivity to doxercalciferol or any of the inactive ingredients of doxercalciferol capsules or doxercalciferol injection; serious hypersensitivity reactions including anaphylaxis and angioedema have been reported [see Warnings and Precautions (5.3), Adverse Reactions (6.2)].. oHypercalcemia (4)oVitamin toxicity (4)oKnow hypersensitivity to doxercalciferol or any of the inactive ingredients of doxercalciferol capsules (4). oHypercalcemia (4). oVitamin toxicity (4). oKnow hypersensitivity to doxercalciferol or any of the inactive ingredients of doxercalciferol capsules (4).

DESCRIPTION SECTION.

11 DESCRIPTION Doxercalciferol, the active ingredient in Doxercalciferol Capsules, is synthetic vitamin D2 analog that undergoes metabolic activation in vivo to form 1,25-dihydroxyvitamin D2 (1,25-(OH)2D2), naturally occurring, biologically active form of vitamin D2. Doxercalciferol is white to off-white powder with calculated molecular weight of 412.65 and molecular formula of C28H44O2. It is soluble in N,N-dimethylformamide, sparingly soluble in methanol, slightly soluble in acetonitrile and practically insoluble in water. Chemically, doxercalciferol is (1,3,5Z,7E,22E)-9,10-Seco-ergosta-5,7,10(19),22-tetraene-1,3-diol and has the following structural formula:Other names frequently used for doxercalciferol are 1-hydroxyvitamin D2 and 1-hydroxyergocalciferol.Doxercalciferol Capsules are soft gelatin capsules containing 0.5 mcg, mcg, or 2.5 mcg doxercalciferol for oral use. Each capsule also contains butylated hydroxyanisole (BHA), dehydrated alcohol, and medium chain triglyceride. The capsule shells contain D&C Yellow No. 10 (0.5 mcg and 2.5 mcg), FD&C Yellow No. (1 mcg only), FD&C Red No. 40 (0.5 mcg only), gelatin, glycerin, Opacode Black, purified water, and titanium dioxide. Opacode Black contains ammonium hydroxide, iron oxide black, isopropyl alcohol, N-butyl alcohol, propylene glycol, and shellac.. image.JPG.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION oBefore initiating treatment, ensure serum calcium is not above the upper limit of normal. (2.1) oDosage for doxercalciferol capsules in patients with: oStage or CKD: Initiate dosing at mcg orally once daily. Maximum dose is 3.5 mcg once daily. (2.2) oCKD on dialysis: Initiate dosing at 10 mcg orally three times weekly at dialysis (no more frequently than every other day). Maximum dose is 20 mcg three times weekly for total of 60 mcg weekly. (2.3) oTarget the maintenance dose of doxercalciferol to intact parathyroid hormone (PTH) levels within the desired therapeutic range and serum calcium within normal limits. (2) oSee Full Prescribing Information for dose titration, laboratory monitoring, and important administration instructions. (2). oBefore initiating treatment, ensure serum calcium is not above the upper limit of normal. (2.1) oDosage for doxercalciferol capsules in patients with: oStage or CKD: Initiate dosing at mcg orally once daily. Maximum dose is 3.5 mcg once daily. (2.2) oCKD on dialysis: Initiate dosing at 10 mcg orally three times weekly at dialysis (no more frequently than every other day). Maximum dose is 20 mcg three times weekly for total of 60 mcg weekly. (2.3) oTarget the maintenance dose of doxercalciferol to intact parathyroid hormone (PTH) levels within the desired therapeutic range and serum calcium within normal limits. (2) oSee Full Prescribing Information for dose titration, laboratory monitoring, and important administration instructions. (2). 2.1 Prior to Initiation of Doxercalciferol Capsules oEnsure serum calcium is not above the upper limit of normal before initiating treatment with doxercalciferol capsules [see Warnings and Precautions (5.1)].. oEnsure serum calcium is not above the upper limit of normal before initiating treatment with doxercalciferol capsules [see Warnings and Precautions (5.1)].. 2.2 Dosage Recommendations for Doxercalciferol Capsules in Patients with Stage or CKD oInitiate doxercalciferol capsules at dose of mcg orally once daily.oTarget the maintenance dose of doxercalciferol to intact parathyroid hormone (PTH) levels within the desired therapeutic range and serum calcium within normal limits.oMonitor serum calcium, phosphorus, and intact PTH levels at least every two weeks for months after initiation of therapy or dose adjustment, then monthly for months, and every months thereafter.oTitrate 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.oSuspend 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 dose that is at least 0.5 mcg lower.. oInitiate doxercalciferol capsules at dose of mcg orally once daily.. oTarget the maintenance dose of doxercalciferol to intact parathyroid hormone (PTH) levels within the desired therapeutic range and serum calcium within normal limits.. oMonitor serum calcium, phosphorus, and intact PTH levels at least every two weeks for months after initiation of therapy or dose adjustment, then monthly for months, and every months thereafter.. oTitrate 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.. oSuspend 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 dose that is at least 0.5 mcg lower.. 2.3 Dosage Recommendations for Doxercalciferol Capsules in Patients with CKD on Dialysis oInitiate doxercalciferol capsules at dose of 10 mcg orally administered three times weekly at dialysis (no more frequently than every other day).oTarget the maintenance dose of doxercalciferol to intact parathyroid hormone (PTH) levels within the desired therapeutic range and serum calcium within normal limits.oMonitor serum calcium, phosphorus, and intact PTH levels frequently (e.g., weekly) after initiation of therapy or dose adjustment.oTitrate 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 total dose of 60 mcg weekly. Prior to raising the dose, ensure serum calcium is within normal limits.oSuspend 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 dose that is at least 2.5 mcg lower.. oInitiate doxercalciferol capsules at dose of 10 mcg orally administered three times weekly at dialysis (no more frequently than every other day).. oTarget the maintenance dose of doxercalciferol to intact parathyroid hormone (PTH) levels within the desired therapeutic range and serum calcium within normal limits.. oMonitor serum calcium, phosphorus, and intact PTH levels frequently (e.g., weekly) after initiation of therapy or dose adjustment.. oTitrate 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 total dose of 60 mcg weekly. Prior to raising the dose, ensure serum calcium is within normal limits.. oSuspend 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 dose that is at least 2.5 mcg lower.. 2.6 Drug Interactions that May Require Dosage Adjustments of Doxercalciferol oIncreased 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)].oIncreased 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)].. oIncreased 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)].. oIncreased 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)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS Capsules: soft gelatin, oval capsules with imprinted r available as follows o0.5 mcg (orange color)o1 mcg (peach color)o2.5 mcg (yellow color). o0.5 mcg (orange color). o1 mcg (peach color). o2.5 mcg (yellow color). oCapsules: 0.5 mcg, mcg, and 2.5 mcg (3). oCapsules: 0.5 mcg, mcg, and 2.5 mcg (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS Tables and include clinically significant drug interactions with doxercalciferol. Table 3: Clinically Significant Drug Interactions with Doxercalciferol Injection and Doxercalciferol CapsulesDrugs that May Increase the Risk of HypercalcemiaClinical ImpactConcomitant administration of high doses of calcium-containing preparations or other vitamin 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 compounds or thiazide diureticsInterventionMonitor serum calcium concentrations more frequently and adjust doxercalciferol dose as needed [see Warnings and Precautions (5.1)].Digitalis CompoundsClinical 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 InhibitorsClinical 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 erythromycinInterventionIf patient initiates or discontinues therapy with cytochrome P450 inhibitor, dose adjustment of doxercalciferol may be necessary. Monitor intact PTH and serum calcium concentrations closely.Enzyme InducersClinical 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 phenobarbitalInterventionIf 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 ProductsClinical ImpactConcomitant administration of doxercalciferol and high doses of magnesium-containing products may increase the risk of hypermagnesemia.ExamplesMagnesium-containing products such as antacidsInterventionAvoid use of magnesium-containing products and doxercalciferol in patients on chronic renal dialysis.Table 4: Clinically Significant Drug Interactions with Doxercalciferol CapsulesCholestyramineClinical 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 hour before or to hours after taking cholestyramine.Mineral Oil or other Substances that May Affect Absorption of FatClinical 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 hour before or to hours after taking mineral oil or other substances that may affect absorption of fat. oCytochrome P450 inhibitors: Formation of the active doxercalciferol moiety may be hindered and may necessitate dosage adjustment. Monitor intact PTH and serum calcium concentrations closely. (7)oEnzyme inducers: Formation of the active doxercalciferol moiety may be affected and may necessitate dosage adjustment. Monitor intact PTH and serum calcium concentrations closely. (7) oMagnesium-containing products: Combined use may cause hypermagnesemia. Monitor serum magnesium concentrations more frequently and adjust dose as needed. (7) oCholestyramine: May impair absorption of doxercalciferol capsules. Administer doxercalciferol capsules at least hour before or to hours after taking cholestyramine. (7)oMineral oil or other substances that may affect absorption of fat: May impair absorption of doxercalciferol capsules. Administer doxercalciferol capsules at least hour before or to hours after taking substances that may affect absorption.. oCytochrome P450 inhibitors: Formation of the active doxercalciferol moiety may be hindered and may necessitate dosage adjustment. Monitor intact PTH and serum calcium concentrations closely. (7). oEnzyme inducers: Formation of the active doxercalciferol moiety may be affected and may necessitate dosage adjustment. Monitor intact PTH and serum calcium concentrations closely. (7) oMagnesium-containing products: Combined use may cause hypermagnesemia. Monitor serum magnesium concentrations more frequently and adjust dose as needed. (7) oCholestyramine: May impair absorption of doxercalciferol capsules. Administer doxercalciferol capsules at least hour before or to hours after taking cholestyramine. (7). oMineral oil or other substances that may affect absorption of fat: May impair absorption of doxercalciferol capsules. Administer doxercalciferol capsules at least hour before or to hours after taking substances that may affect absorption.

GERIATRIC USE SECTION.

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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING Doxercalciferol Capsules are supplied as clear, oily solution encapsulated in oval shaped, soft gelatin capsules. The 0.5 mcg capsules are orange, opaque with r imprinted in black ink along one side of the capsule. The mcg capsules are light peach, opaque with r imprinted in black ink along one side of the capsule. The 2.5 mcg capsules are yellow, opaque with r imprinted in black ink along one side of the capsule. 0054-0338-19 0.5 mcg, orange capsules, bottle of 500054-0388-19 mcg, light peach capsules, bottle of 500054-0339-19 2.5 mcg, yellow capsules, bottle of 50StorageStore at 25oC (77oF), with excursions permitted between 15o to 30oC (59o to 86oF). [See USP Controlled Room Temperature.].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE oDoxercalciferol capsules are indicated for the treatment of secondary hyperparathyroidism in adult patients with Stage or Stage chronic kidney disease (CKD) and adult patients with CKD on dialysis.. oDoxercalciferol capsules are indicated for the treatment of secondary hyperparathyroidism in adult patients with Stage or Stage chronic kidney disease (CKD) and adult patients with CKD on dialysis.. Doxercalciferol is synthetic vitamin D2 analog: oDoxercalciferol capsules are indicated for the treatment of secondary hyperparathyroidism in adult patients with Stage or Stage chronic kidney disease (CKD) and adult patients with CKD on dialysis. (1). oDoxercalciferol capsules are indicated for the treatment of secondary hyperparathyroidism in adult patients with Stage or Stage chronic kidney disease (CKD) and adult patients with CKD on dialysis. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Hypercalcemia:Advise patients to contact 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 new medication is prescribed [see Drug Interactions (7)].Made in India.Manufactured by: Cipla Limited Kurkumbh, Maharashtra, IndiaManufactured for: West-Ward Pharmaceuticals Corp.Eatontown, NJ 0772421072711Revised April 2019.

LACTATION SECTION.

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 mothers 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 Doxercalciferol 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.

MECHANISM OF ACTION SECTION.

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

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In 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 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 times the maximum recommended human oral dose of 60 mcg/week based on mcg/m2 body surface area).

OVERDOSAGE SECTION.

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, 1,25-(OH)2D2, it is expected that doxercalciferol is not removed from the blood by dialysis.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL Doxercalciferol Capsules, 0.5 mcgNDC 0054-0338-19Rx only. 0-5mcg.jpg.

PEDIATRIC USE SECTION.

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

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Absorption:In healthy volunteers, peak blood levels of 1,25-(OH)2D2, the major metabolite of doxercalciferol, are attained at hours after single intravenous dose of doxercalciferol and at 11 to 12 hours following capsule doses. Elimination: The mean elimination half-life of 1,25-(OH)2D2 after an oral dose is approximately 32 to 37 hours with range of up to 96 hours. Metabolism: Doxercalciferol is activated by CYP 27 in the liver to form 1,25-(OH)2D2 (major metabolite) and 1,24-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 1,25-(OH)2D2 in patients with end-stage renal disease (ESRD) and in healthy volunteers appears to be similar following an oral dose. Hemodialysis causes temporary increase in 1,25-(OH)2D2 mean concentrations, presumably due to volume contraction. 1,25-(OH)2D2 is not removed from blood during hemodialysis.

PREGNANCY SECTION.

8.1 Pregnancy Risk Summary: The limited available data with doxercalciferol in pregnant women are insufficient to identify 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% to 4% and 15% to 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.

SPL UNCLASSIFIED SECTION.

2.1 Prior to Initiation of Doxercalciferol Capsules oEnsure serum calcium is not above the upper limit of normal before initiating treatment with doxercalciferol capsules [see Warnings and Precautions (5.1)].. oEnsure serum calcium is not above the upper limit of normal before initiating treatment with doxercalciferol capsules [see Warnings and Precautions (5.1)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary: The limited available data with doxercalciferol in pregnant women are insufficient to identify 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% to 4% and 15% to 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 mothers 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 Doxercalciferol 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oHypercalcemia: Can occur during treatment with doxercalciferol and can lead to cardiac arrhythmias and seizures. Severe hypercalcemia may require emergency attention. Risk may be increased when used concomitantly with high dose calcium preparations, thiazide diuretics, or vitamin compounds. Monitor serum calcium prior to initiation and during treatment and adjust dose accordingly. (2, 5.1)oDigitalis Toxicity: Hypercalcemia increases the risk of digitalis toxicity. In patients using digitalis compounds, monitor serum calcium and patients for signs and symptoms of digitalis toxicity. Increase frequency of monitoring when initiating or adjusting the dose of doxercalciferol. (5.2) oSerious Hypersensitivity Reactions: Anaphylaxis, with symptoms of angioedema, hypotension, unresponsiveness, chest discomfort, shortness of breath, and cardiopulmonary arrest, has been reported in hemodialysis patients after administration of doxercalciferol. Monitor patients upon treatment initiation for hypersensitivity reactions. Should reaction occur, discontinue and treat. (5.3) oAdynamic Bone Disease: May develop and increase risk of fractures if intact PTH levels are suppressed to abnormally low levels. Monitor intact PTH levels to avoid oversuppression and adjust dose if needed. (5.4). oHypercalcemia: Can occur during treatment with doxercalciferol and can lead to cardiac arrhythmias and seizures. Severe hypercalcemia may require emergency attention. Risk may be increased when used concomitantly with high dose calcium preparations, thiazide diuretics, or vitamin compounds. Monitor serum calcium prior to initiation and during treatment and adjust dose accordingly. (2, 5.1). oDigitalis Toxicity: Hypercalcemia increases the risk of digitalis toxicity. In patients using digitalis compounds, monitor serum calcium and patients for signs and symptoms of digitalis toxicity. Increase frequency of monitoring when initiating or adjusting the dose of doxercalciferol. (5.2) oSerious Hypersensitivity Reactions: Anaphylaxis, with symptoms of angioedema, hypotension, unresponsiveness, chest discomfort, shortness of breath, and cardiopulmonary arrest, has been reported in hemodialysis patients after administration of doxercalciferol. Monitor patients upon treatment initiation for hypersensitivity reactions. Should reaction occur, discontinue and treat. (5.3) oAdynamic Bone Disease: May develop and increase risk of fractures if intact PTH levels are suppressed to abnormally low levels. Monitor intact PTH levels to avoid oversuppression and adjust dose if needed. (5.4). 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 compounds [see Drug Interactions (7)]. In addition, high intake of calcium and phosphate concomitantly with vitamin compounds may lead to hypercalciuria and hyperphosphatemia. Patients with 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 weeks for patients with stage or CKD). Once maintenance dose has been established, measure serum calcium monthly for months and then every 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 doxercalciferol 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 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)].