Paricalcitol (Page 2 of 6)

4 CONTRAINDICATIONS

Paricalcitol capsules should not be given to patients with evidence of

• hypercalcemia or
• vitamin D toxicity [see Warnings and Precautions ( 5.1)].

5 WARNINGS AND PRECAUTIONS

Excessive administration of vitamin D compounds, including paricalcitol capsules, can cause over suppression of PTH, hypercalcemia, hypercalciuria, hyperphosphatemia, and adynamic bone disease.

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 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

Adults

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 3:

Table 3. Adverse Reactions by Body System Occurring in ≥ 2% of Subjects in the Paricalcitol-Treated Group of Three, Double-Blind, Placebo-Controlled CKD Stages 3 and 4 Studies

	Number (%) of Subjects
Adverse Event a	Paricalcitol 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 paricalcitol treatment group.

Additional Adverse Reactions

The following additional adverse reactions occurred in <2% of the paricalcitol-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 paricalcitol 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 paricalcitol capsules.

During the 12-week blinded phase, a total of 18 patients received paricalcitol capsules and 18 patients received placebo. Adverse events occurring more frequently in the paricalcitol 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	Paricalcitol 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 paricalcitol treatment group.

Additional Adverse Reactions

The following adverse reactions have occurred in paricalcitol-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 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 5. Adverse Reactions by Body System Occurring in ≥ 2% of Subjects in the Paricalcitol-Treated Group, Double-Blind, Placebo-Controlled CKD Stage 5 Study

	Number (%) of Subjects
Adverse Events a	Paricalcitol 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 paricalcitol treatment group.

Additional Adverse Reactions

The following adverse reactions occurred in <2% of the paricalcitol-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 paricalcitol 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).