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warnings and cautions
5 WARNINGS AND PRECAUTIONS • Hypercalcemia: Can occur during treatment with Doxercalciferol Injection 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 Injection. ( 5.2 ) • 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 Injection. Monitor patients 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 over suppression and adjust dose if needed. ( 5.4 ) 5.1 Hypercalcemia Hypercalcemia may occur during Doxercalciferol Injection 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 Injection. In these circumstances, frequent serum calcium monitoring and Doxercalciferol Injection dose adjustments may be required. When initiating Doxercalciferol Injection or adjusting Doxercalciferol Injection 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 Injection 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 Injection can cause hypercalcemia [see Warnings and Precautions (5.1)] which increases the risk of digitalis toxicity. In patients using Doxercalciferol Injection 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 Injection [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 Injection upon initiation of treatment for hypersensitivity reactions. Should a hypersensitivity reaction occur, discontinue Doxercalciferol Injection, 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 Injection to abnormally low levels. Monitor intact PTH levels to avoid over suppression and adjust the Doxercalciferol Injection 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: Hypercalcemia [see Warnings and Precautions (5.1)] Serious Hypersensitivity Reactions [see Warnings and Precautions (5.3)] Adynamic Bone Disease [see Warnings and Precautions (5.4)] 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, 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 Alembic Pharmaceuticals Inc., at 1-866-210-9797 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 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 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) % 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 * A patient who reported the same medical term more than once was counted only once for that medical term. 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, multicentre studies [see Clinical Studies (14.3)] . The incidence of hypercalcemia and hyperphosphatemia increased during therapy with Doxercalciferol Injection. Patients with higher pre-treatment 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 capsule presented in Table 2. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval 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.