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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.

Clinical Trials Experience

CKD Stages 3 and 4

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 1:

Table 1: Treatment-Emergent Adverse Events by Body System Occurring in ≥ 2% of Subjects in the Zemplar-Treated Group of Three, Double-Blind, Placebo-Controlled, Phase 3, CKD Stages 3 and 4 Studies; All Treated Patients

Adverse Eventa Number (%) of Subjects
Zemplar Capsules
(n = 107)
Placebo
(n = 113)
Overall 88 (82%) 86 (76%)
Ear and Labyrinth Disorders
  Vertigo 5 (4.7%) 0 (0.0%)
Gastrointestinal Disorders
  Abdominal Discomfort 4 (3.7%) 1 (0.9%)
  Constipation 4 (3.7%) 4 (3.5%)
  Diarrhea 7 (6.5%) 5 (4.4%)
  Nausea 6 (5.6%) 4 (3.5%)
  Vomiting 5 (4.7%) 5 (4.4%)
General Disorders and Administration Site Conditions
  Chest Pain 3 (2.8%) 1 (0.9%)
  Edema 6 (5.6%) 5 (4.4%)
  Pain 4 (3.7%) 4 (3.5%)
Immune System Disorders
  Hypersensitivity 6 (5.6%) 2 (1.8%)
Infections and Infestations
  Fungal Infection 3 (2.8%) 0 (0.0%)
  Gastroenteritis 3 (2.8%) 3 (2.7%)
  Infection 3 (2.8%) 3 (2.7%)
  Sinusitis 3 (2.8%) 1 (0.9%)
  Urinary Tract Infection 3 (2.8%) 1 (0.9%)
  Viral Infection 8 (7.5%) 8 (7.1%)
Metabolism and Nutrition Disorders
  Dehydration 3 (2.8%) 1 (0.9%)
Musculoskeletal and Connective Tissue Disorders
  Arthritis 5 (4.7%) 0 (0.0%)
  Back Pain 3 (2.8%) 1 (0.9%)
  Muscle Spasms 3 (2.8%) 0 (0.0%)
Nervous System Disorders
  Dizziness 5 (4.7%) 5 (4.4%)
  Headache 5 (4.7%) 5 (4.4%)
  Syncope 3 (2.8%) 1 (0.9%)
Psychiatric Disorders
  Depression 3 (2.8%) 0 (0.0%)
Respiratory, Thoracic and Mediastinal Disorders
  Cough 3 (2.8%) 2 (1.8%)
  Oropharyngeal Pain 4 (3.7%) 0 (0.0%)
Skin and Subcutaneous Tissue Disorders
  Pruritus 3 (2.8%) 3 (2.7%)
  Rash 4 (3.7%) 1 (0.9%)
  Skin Ulcer 3 (2.8%) 0 (0.0%)
Vascular Disorders
  Hypertension 7 (6.5%) 4 (3.5%)
  Hypotension 5 (4.7%) 3 (2.7%)
a Includes only events more common in the Zemplar treatment group.

The following adverse reactions, with a causal relationship to Zemplar, occurred in < 2% of the Zemplar treated patients in the above double-blind, placebo-controlled clinical trial data set.

Gastrointestinal Disorders: Dry mouth

Investigations: Hepatic enzyme abnormal

Nervous System Disorders: Dysgeusia

Skin and Subcutaneous Tissue Disorders: Urticaria

CKD Stage 5

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 2: Treatment-Emergent Adverse Events by Body System Occurring in ≥ 2% of Subjects in the Zemplar-Treated Group, Double-Blind, Placebo-Controlled, Phase 3, CKD Stage 5 Study; All Treated Patients

Adverse Eventsa Number (%) of Subjects
Zemplar Capsules
(n=61)
Placebo
(n = 27)
Overall 43 (70%) 19 (70%)
Gastrointestinal Disorders
  Constipation 3 (4.9%) 0 (0.0%)
  Diarrhea 7 (11.5%) 3 (11.1%)
  Vomiting 4 (6.6%) 0 (0.0%)
General Disorders and Administration Site Conditions
  Fatigue 2 (3.3%) 0 (0.0%)
  Edema Peripheral 2 (3.3%) 0 (0.0%)
Infections and Infestations
  Nasopharyngitis 5 (8.2%) 2 (7.4%)
  Peritonitis 3 (4.9%) 0 (0.0%)
  Sinusitis 2 (3.3%) 0 (0.0%)
  Urinary Tract Infection 2 (3.3%) 0 (0.0%)
Metabolism and Nutrition Disorders
  Fluid Overload 3 (4.9%) 0 (0.0%)
  Hypoglycemia 2 (3.3%) 0 (0.0%)
Nervous System Disorders
  Dizziness 4 (6.6%) 0 (0.0%)
  Headache 2 (3.3%) 0 (0.0%)
Psychiatric Disorders
  Anxiety 2 (3.3%) 0 (0.0%)
  Insomnia 3 (4.9%) 0 (0.0%)
Renal and Urinary Disorders
  Renal Failure Chronic 2 (3.3%) 0 (0.0%)
a Includes only events more common in the Zemplar treatment group.

The following adverse reactions, with a causal relationship to Zemplar, occurred in < 2% of the Zemplar treated patients in the above double-blind, placebo-controlled clinical trial data set.

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

Postmarketing Experience

The following additional adverse reactions have been reported during post-approval use and post-approval clinical trials with the active ingredient in Zemplar capsules:

Immune System Disorders: Angioedema (including laryngeal edema)

Metabolism and Nutrition Disorders: Hypercalcemia

Investigations: Blood creatinine increased