PARICALCITOL (Page 2 of 6)

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 diueretics with Paricalcitol 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 Paricalcitol treatment to avoid hypercalcemia.

5.2 Digitalis Toxicity

Digitalis toxicity is potentiated by hypercalcemia of any cause. Use caution when Paricalcitol 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, Paricalcitol 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 Paricalcitol, 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.

6.1 Clinical Trials Experience

CKD Stages 3 and 4

The safety of Paricalcitol 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 Paricalcitol Capsules treated patients and 4% of placebo treated patients discontinued from clinical studies due to an adverse event. Adverse events occurring in the Paricalcitol 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 Paricalcitol-Treated Group of Three, Double-Blind, Placebo-Controlled, Phase 3, CKD Stages 3 and 4 Studies; All Treated Patients
*
Includes only events more common in the Paricalcitol treatment group.
Number (%) of Subjects
Adverse Event * Paricalcitol 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%)

The following adverse reactions, with a causal relationship to Paricalcitol, occurred in <2% of the Paricalcitol 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 Paricalcitol 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 Paricalcitol Capsules and 27 patients received placebo.

The proportion of patients who terminated prematurely from the study due to adverse events was 7% for Paricalcitol Capsules treated patients and 7% for placebo patients.

Adverse events occurring in the Paricalcitol 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 Paricalcitol-Treated Group, Double- Blind, Placebo-Controlled, Phase 3, CKD Stage 5 Study; All Treated Patients
*
Includes only events more common in the Paricalcitol treatment group.
Number (%) of Subjects
Adverse Events * Paricalcitol 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%)

The following adverse reactions, with a causal relationship to Paricalcitol, occurred in <2% of the Paricalcitol 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

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