Doxercalciferol

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. Doxercalciferol Capsules is a synthetic vitamin D 2 analog: 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.

Before initiating treatment, ensure serum calcium is not above the upper limit of normal. Dosage for doxercalciferol capsules in patients with: Stage 3 or 4 CKD: Initiate dosing at 1 mcg orally once daily. Maximum dose is 3.5 mcg once daily. CKD 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 a total of 60 mcg weekly. Target the maintenance dose of doxercalciferol to intact parathyroid hormone (PTH) levels within the desired therapeutic range and serum calcium within normal limits. See Full Prescribing Information for dose titration, laboratory monitoring, and important administration instructions.

2.1Prior to Initiation of Doxercalciferol Capsules Ensure

serum calcium is not above the upper limit of normal before initiating treatment with doxercalciferol capsules .

2.2Dosage 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 or if serum calcium is consistently above the normal range to reduce the risk of hypercalcemia . If suspended, the drug should be restarted after one week at a dose that is at least 0.5 mcg lower.

2.3Dosage 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 or if serum calcium is consistently above the normal range to reduce the risk of hypercalcemia . If suspended, the drug should be restarted one week later at a dose that is at least 2.5 mcg lower.

2.6Drug 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 . 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 .

Hypercalcemia: 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 D compounds. Monitor serum calcium prior to initiation and during treatment and adjust dose accordingly. ( 2 , 5.1 ) Digitalis 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. Serious 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 a reaction occur, discontinue and treat. 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.

5.1Hypercalcemia 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 . 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 . 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 . 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.

5.2Digitalis Toxicity Doxercalciferol

can cause hypercalcemia 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 .

5.3Serious Hypersensitivity Reactions 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 .

5.4Adynamic 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 .

Doxercalciferol is contraindicated in patients with: Hypercalcemia Vitamin D toxicity Known hypersensitivity to doxercalciferol or any of the inactive ingredients of doxercalciferol capsules; serious hypersensitivity reactions including anaphylaxis and angioedema have been reported . Hypercalcemia Vitamin D toxicity Know hypersensitivity to doxercalciferol or any of the inactive ingredients of doxercalciferol capsules

8.1Pregnancy 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 . 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/m 2 body surface area), no adverse developmental effects were observed . 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.

The following adverse reactions are discussed in greater detail in another section of the label: Hypercalcemia Serious Hypersensitivity Reactions Adynamic Bone Disease The most common adverse reactions in patients with Stage 3 or 4 CKD (incidence >5%) were infection, urinary tract infection, chest pain, angina pectoris, constipation, dyspepsia, anemia, leukopenia, dehydration, edema, depression, hypertonia, insomnia, asthenia, paresthesia, cough increased, dyspnea, pruritus, sinusitis, and rhinitis. The most common adverse reactions in patients with CKD on dialysis (incidence >5%) were headache, malaise, edema, nausea/vomiting, dyspnea, dizziness, pruritus, and bradycardia. To report SUSPECTED ADVERSE REACTIONS, contact Avet Pharmaceuticals Inc. at 1-866-901-DRUG or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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. 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) . 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 Pooled 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 infection 30 25 Constipation 26 11 Rhinitis 22 11 Anemia 19 4 Cough 19 4 Dyspnea 19 11 Paresthesia 15 11 Asthenia 15 11 Insomnia 15 4 Hypertonia 11 4 Angina pectoris 8 0 Dehydration 7 4 Depression 7 0 Dyspepsia 7 4 Edema 7 4 Urinary tract infection 7 4 Leukopenia 7 0 Chest pain 7 4 Pruritus 7 4 Sinusitis 7 4 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) . 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 A patient who reported the same medical term more than once was counted only once for that medical term. 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

6.2Postmarketing 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 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.