djusting the dose of doxercalciferol in patients receiving digitalis compounds [see warnings and precautions (5.2) ]. cytochrome p450 inhibitors clinical impact doxercalciferol 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) ]. examples ketoconazole and erythromycin intervention if 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 impact doxercalciferol is activated by cyp 27 in the liver. enzyme inducers may affect the 25-hydroxylation of doxercalciferol [see clinical pharmacology (12.3) ]. examples glutethimide and phenobarbital intervention if 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 impact concomitant administration of doxercalciferol and high doses of magnesium-containing products may increase the risk of hypermagnesemia. examples magnesium-containing products such as antacids intervention avoid use of magnesium-containing products and doxercalciferol in patients on chronic renal dialysis. cytochrome 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 ) enzyme inducers : formation of the active doxercalciferol moiety may be affected and may necessitate dosage adjustment. monitor intact pth and serum calcium concentrations closely. ( 7 ) magnesium-containing products : combined use may cause hypermagnesemia. monitor serum magnesium concentrations more frequently and adjust dose as needed. ( 7 )

upon treatment initiation for hypersensitivity reactions. should a reaction occur, discontinue and treat. ( 5.3 ) adynamic 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 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). 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 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 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) ].

injection intravenously as a bolus dose at the end of dialysis. inspect doxercalciferol 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 doxercalciferol injection in patients with ckd on dialysis initiate doxercalciferol 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 doxercalciferol injection 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 doxercalciferol 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 injection increased monitoring of serum calcium and dose adjustment of doxercalciferol injection 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 injection may be necessary when given concomitantly with cytochrome p450 inhibitors or enzyme inducers [see drug interactions (7) ].

ercalciferol 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). 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 * a patient who reported the same medical term more than once was counted only once for that medical term. adverse reaction* doxercalciferol (n=61) % placebo (n=61) % edema 34 21 malaise 28 20 headache 28 18 nausea/vomiting 21 20 dizziness 12 10 dyspnea 12 7 pruritus 8 7 bradycardia 7 5 anorexia 5 3 dyspepsia 5 2 arthralgia 5 0 weight increase 5 0 abscess 3 0 sleep disorder 3 0 doxercalciferol 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 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 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.

djusting the dose of doxercalciferol in patients receiving digitalis compounds [see warnings and precautions (5.2) ]. cytochrome p450 inhibitors clinical impact doxercalciferol 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) ]. examples ketoconazole and erythromycin intervention if 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 impact doxercalciferol is activated by cyp 27 in the liver. enzyme inducers may affect the 25-hydroxylation of doxercalciferol [see clinical pharmacology (12.3) ]. examples glutethimide and phenobarbital intervention if 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 impact concomitant administration of doxercalciferol and high doses of magnesium-containing products may increase the risk of hypermagnesemia. examples magnesium-containing products such as antacids intervention avoid use of magnesium-containing products and doxercalciferol in patients on chronic renal dialysis. cytochrome 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 ) enzyme inducers : formation of the active doxercalciferol moiety may be affected and may necessitate dosage adjustment. monitor intact pth and serum calcium concentrations closely. ( 7 ) magnesium-containing products : combined use may cause hypermagnesemia. monitor serum magnesium concentrations more frequently and adjust dose as needed. ( 7 )

% 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 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 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.

al 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.

ent of the kidneys. specific populations patients with renal impairment the mean elimination half-life of 1α,25-(oh) 2 d 2 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) 2 d 2 mean concentrations, presumably due to volume contraction. 1α,25-(oh) 2 d 2 is not removed from blood during hemodialysis.

ood during hemodialysis.

imately 3 times the maximum recommended human oral dose of 60 mcg/week based on mcg/m 2 body surface area).

m recommended human oral dose of 60 mcg/week based on mcg/m 2 body surface area).

e 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 doxercalciferol 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, doxercalciferol 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 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 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 doxercalciferol injection in studies c and d * values were carried forward for the two patients on study for 10 weeks † treatment intact pth minus baseline intact pth ‡ wilcoxon one-sample test intact pth level study 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) median 562 648 634 on-treatment (week 12*) mean (se) 406 (63) 426 (60) 418 (43) median 311 292 292 change from baseline† mean (se) -292 (55) -336 (41) -318 (33) median -274 -315 -304 p-value‡ 0.004 0.001 <0.001 doxercalciferol 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.

e-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 the vial stopper is not made with natural rubber latex.

on 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) ] . distributed by: auromedics pharma llc 279 princeton-hightstown rd. e. windsor, nj 08520 manufactured by: eugia pharma specialities limited hyderabad - 500032 india