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warnings and cautions
5 WARNINGS AND PRECAUTIONS Excessive administration of vitamin D compounds, including ZEMPLAR capsules, can cause over suppression of PTH, hypercalcemia, hypercalciuria, hyperphosphatemia, and adynamic bone disease. Hypercalcemia: Excessive administration of ZEMPLAR capsules can cause over suppression of PTH, hypercalcemia, hypercalciuria, hyperphosphatemia, and adynamic bone disease. Prescription-based doses of vitamin D and its derivatives should be withheld during ZEMPLAR treatment ( 5.1 ). Digitalis toxicity: Potentiated by hypercalcemia of any cause. Use caution when ZEMPLAR capsules are prescribed concomitantly with digitalis compounds ( 5.2 ). Laboratory tests: Monitor serum calcium, serum phosphorus, and serum or plasma iPTH during initial dosing or following any dose adjustment. ZEMPLAR capsules may increase serum creatinine and therefore decrease the estimated GFR (eGFR) ( 5.3 ). Aluminum overload and toxicity: Avoid excessive use of aluminum containing compounds ( 5.4 ). 5.1 Hypercalcemia Progressive hypercalcemia due to overdosage of vitamin D and its metabolites may be so severe as to require emergency attention [see Overdosage ( 10 )] . Acute hypercalcemia may exacerbate tendencies for cardiac arrhythmias and seizures and may potentiate the action of digitalis. Chronic hypercalcemia can lead to generalized vascular calcification and other soft-tissue calcification. Concomitant administration of high doses of calcium-containing preparations or thiazide diuretics with ZEMPLAR may increase the risk of hypercalcemia. High intake of calcium and phosphate concomitant with vitamin D compounds may lead to serum abnormalities requiring more frequent patient monitoring and individualized dose titration. Patients also should be informed about the symptoms of elevated calcium, which include feeling tired, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination and weight loss. Prescription-based doses of vitamin D and its derivatives should be withheld during ZEMPLAR treatment to avoid hypercalcemia. 5.2 Digitalis Toxicity Digitalis toxicity is potentiated by hypercalcemia of any cause. Use caution when ZEMPLAR capsules are prescribed concomitantly with digitalis compounds. 5.3 Laboratory Tests During the initial dosing or following any dose adjustment of medication, serum calcium, serum phosphorus, and serum or plasma iPTH should be monitored at least every two weeks for 3 months, then monthly for 3 months, and every 3 months thereafter. In pre-dialysis patients, ZEMPLAR capsules may increase serum creatinine and therefore decrease the estimated GFR (eGFR). Similar effects have also been seen with calcitriol. 5.4 Aluminum Overload and Toxicity Aluminum-containing preparations (e.g., antacids, phosphate binders) should not be administered chronically with ZEMPLAR, as increased blood levels of aluminum and aluminum bone toxicity may occur.
6 ADVERSE REACTIONS Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The most common adverse reactions (> 5% and more frequent than placebo) include diarrhea, nasopharyngitis, dizziness, vomiting, hypertension, hypersensitivity, nausea, and edema ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience CKD Stages 3 and 4 Adults The safety of ZEMPLAR capsules has been evaluated in three 24-week (approximately six-month), double-blind, placebo-controlled, multicenter clinical studies involving 220 CKD Stages 3 and 4 patients. Six percent (6%) of ZEMPLAR capsules treated patients and 4% of placebo treated patients discontinued from clinical studies due to an adverse event. Adverse events occurring in the ZEMPLAR capsules group at a frequency of 2% or greater and more frequently than in the placebo group are presented in Table 3: Table 3. Adverse Reactions by Body System Occurring in ≥ 2% of Subjects in the ZEMPLAR-Treated Group of Three, Double-Blind, Placebo-Controlled CKD Stages 3 and 4 Studies Number (%) of Subjects Adverse Event a ZEMPLAR Capsules (n = 107) Placebo (n = 113) Overall 88 (82%) 86 (76%) Ear and Labyrinth Disorders Vertigo 5 (5%) 0 (0%) Gastrointestinal Disorders Abdominal Discomfort 4 (4%) 1 (1%) Constipation 4 (4%) 4 (4%) Diarrhea 7 (7%) 5 (4%) Nausea 6 (6%) 4 (4%) Vomiting 5 (5%) 5 (4%) General Disorders and Administration Site Conditions Chest Pain 3 (3%) 1 (1%) Edema 6 (6%) 5 (4%) Pain 4 (4%) 4 (4%) Immune System Disorders Hypersensitivity 6 (6%) 2 (2%) Infections and Infestations Fungal Infection 3 (3%) 0 (0%) Gastroenteritis 3 (3%) 3 (3%) Infection 3 (3%) 3 (3%) Sinusitis 3 (3%) 1 (1%) Urinary Tract Infection 3 (3%) 1 (1%) Viral Infection 8 (7%) 8 (7%) Metabolism and Nutrition Disorders Dehydration 3 (3%) 1 (1%) Musculoskeletal and Connective Tissue Disorders Arthritis 5 (5%) 0 (0%) Back Pain 3 (3%) 1 (1%) Muscle Spasms 3 (3%) 0 (0%) Nervous System Disorders Dizziness 5 (5%) 5 (4%) Headache 5 (5%) 5 (4%) Syncope 3 (3%) 1 (1%) Psychiatric Disorders Depression 3 (3%) 0 (0%) Respiratory, Thoracic and Mediastinal Disorders Cough 3 (3%) 2 (2%) Oropharyngeal Pain 4 (4%) 0 (0%) Skin and Subcutaneous Tissue Disorders Pruritus 3 (3%) 3 (3%) Rash 4 (4%) 1 (1%) Skin Ulcer 3 (3%) 0 (0%) Vascular Disorders Hypertension 7 (7%) 4 (4%) Hypotension 5 (5%) 3 (3%) a. Includes only events more common in the ZEMPLAR treatment group. Additional Adverse Reactions The following additional adverse reactions occurred in <2% of the ZEMPLAR-treated patients in the above double-blind, placebo-controlled clinical trial. Gastrointestinal Disorders: Dry mouth Investigations: Hepatic enzyme abnormal Nervous System Disorders: Dysgeusia Skin and Subcutaneous Tissue Disorders: Urticaria Pediatric patients 10 to 16 years of age The safety of ZEMPLAR capsules has been evaluated in one multicenter clinical study involving CKD Stages 3 and 4 patients ages 10 to 16 years. A 12-week double-blind, placebo-controlled phase was followed by an open-label phase during which all patients received ZEMPLAR capsules. During the 12-week blinded phase, a total of 18 patients received ZEMPLAR capsules and 18 patients received placebo. Adverse events occurring more frequently in the ZEMPLAR capsules group than in the placebo group are presented in Table 4. Table 4. Adverse Reactions by Body System Occurring in the Double-Blind, Placebo-Controlled, CKD Stages 3 and 4 Study in Patients Ages 10 to 16 Years Number (%) of Subjects Adverse Event a ZEMPLAR Capsules (n = 18) Placebo (n = 18) Overall 7 (39%) 16 (89%) Gastrointestinal Disorders Nausea 1 (6%) 0 (0%) Infections and Infestations Conjunctivitis 1 (6%) 0 (0%) Rhinitis 3 (17%) 0 (0%) Renal and Urinary Disorders Micturition Urgency 1 (6%) 0 (0%) Respiratory, Thoracic and Mediastinal Disorders Asthma 1 (6%) 0 (0%) a. Includes only events more common in the ZEMPLAR treatment group. Additional Adverse Reactions The following adverse reactions have occurred in ZEMPLAR-treated patients: Gastrointestinal Disorders: Abdominal pain, constipation, vomiting Metabolism and Nutrition Disorders: Hypercalcemia and hyperphosphatemia Nervous System Disorders: Headache CKD Stage 5 Adults The safety of ZEMPLAR capsules has been evaluated in one 12-week, double-blind, placebo-controlled, multicenter clinical study involving 88 CKD Stage 5 patients. Sixty-one patients received ZEMPLAR capsules and 27 patients received placebo. The proportion of patients who terminated prematurely from the study due to adverse events was 7% for ZEMPLAR capsules treated patients and 7% for placebo patients. Adverse events occurring in the ZEMPLAR capsules group at a frequency of 2% or greater and more frequently than in the placebo group are as follows: Table 5. Adverse Reactions by Body System Occurring in ≥ 2% of Subjects in the ZEMPLAR-Treated Group, Double-Blind, Placebo-Controlled CKD Stage 5 Study Number (%) of Subjects Adverse Events a ZEMPLAR Capsules (n=61) Placebo (n = 27) Overall 43 (70%) 19 (70%) Gastrointestinal Disorders Constipation 3 (5%) 0 (0%) Diarrhea 7 (11%) 3 (11%) Vomiting 4 (7%) 0 (0%) General Disorders and Administration Site Conditions Fatigue 2 (3%) 0 (0%) Edema Peripheral 2 (3%) 0 (0%) Infections and Infestations Nasopharyngitis 5 (8%) 2 (7%) Peritonitis 3 (5%) 0 (0%) Sinusitis 2 (3%) 0 (0%) Urinary Tract Infection 2 (3%) 0 (0%) Metabolism and Nutrition Disorders Fluid Overload 3 (5%) 0 (0%) Hypoglycemia 2 (3%) 0 (0%) Nervous System Disorders Dizziness 4 (7%) 0 (0%) Headache 2 (3%) 0 (0%) Psychiatric Disorders Anxiety 2 (3%) 0 (0%) Insomnia 3 (5%) 0 (0%) Renal and Urinary Disorders Renal Failure Chronic 2 (3%) 0 (0%) a. Includes only events more common in the ZEMPLAR treatment group. Additional Adverse Reactions The following adverse reactions occurred in <2% of the ZEMPLAR-treated patients in the above double-blind, placebo-controlled clinical trial. Gastrointestinal Disorders: Gastroesophageal reflux disease Metabolism and Nutrition Disorders : Decreased appetite, hypercalcemia, hypocalcemia Reproductive System and Breast Disorders : Breast tenderness Skin and Subcutaneous Tissue Disorders : Acne Pediatric patients 10 to 16 years of age The safety of ZEMPLAR capsules has been evaluated in one 12-week, open-label, single-arm, multicenter clinical studies involving 13 CKD Stage 5 patients ages 10 to 16 years of age receiving peritoneal dialysis or hemodialysis. The following adverse reactions were reported: Gastrointestinal Disorders: Abdominal pain, diarrhea, nausea, vomiting Metabolism and Nutrition Disorders: Hypercalcemia, hyperphosphatemia Three of 13 patients (23%) had hypercalcemia defined as at least 2 consecutive serum calcium values >10.2 mg/dL (2.55 mmol/L). 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ZEMPLAR capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders: Angioedema (including laryngeal edema) Investigations: Blood creatinine increased