Prescription Drug Information: Paricalcitol

PARICALCITOL- paricalcitol capsule, liquid filled
Zydus Pharmaceuticals USA Inc

1 INDICATIONS AND USAGE

1.1 Chronic Kidney Disease Stages 3 and 4

Paricalcitol capsules are indicated in adults and pediatric patients 10 years of age and older for the prevention and treatment of secondary hyperparathyroidism associated with Chronic Kidney Disease (CKD) Stages 3 and 4.

1.2 Chronic Kidney Disease Stage 5

Paricalcitol capsules are indicated in adults and pediatric patients 10 years of age and older for the prevention and treatment of secondary hyperparathyroidism associated with CKD Stage 5 in patients on hemodialysis (HD) or peritoneal dialysis (PD).

2 DOSAGE AND ADMINISTRATION

2.1 Chronic Kidney Disease Stages 3 and 4 in Adults

Administer paricalcitol capsules orally once daily or three times a week [see Clinical Studies ( 14.1)]. When dosing three times weekly, do not administer more frequently than every other day.

Initial Dose

Table 1. Recommended Paricalcitol Starting Dose Based upon Baseline iPTH Level

Baseline iPTH Level Daily Dose Three Times a Week Dose*
Less than or equal to 500 pg/mL 1 mcg 2 mcg
More than 500 pg/mL 2 mcg 4 mcg
* To be administered not more often than every other day

Dose Titration

Table 2. Recommended Paricalcitol Dose Titration Base upon iPTH Level

Dose Adjustment at 2 to 4 Week Intervals
iPTH Level Relative to Baseline Paricalcitol Capsule Dose Daily Dosage Three Times a Week Dosage*
The same, increased ordecreased by less than 30% Increase dose by 1 mcg 2 mcg
Decreased by more than or equal to 30% and less than or equal to 60% Maintain dose
Decreased by more than 60% oriPTH less than 60 pg/mL Decrease dose by 1 mcg 2 mcg
* To be administered not more often than every other day

If a patient is taking the lowest dose, 1 mcg, on the daily regimen and a dose reduction is needed, the dose can be decreased to 1 mcg three times a week. If a further dose reduction is required, the drug should be withheld as needed and restarted at a lower dosing frequency.

2.2 Chronic Kidney Disease Stage 5 in Adults

Initial Dose

Administer the dose of paricalcitol capsules orally three times a week, no more frequently than every other day based upon the following formula:

Dose (micrograms) = baseline iPTH (pg/mL) divided by 80

Treat patients only after their baseline serum calcium has been adjusted to 9.5 mg/dL or lower to minimize the risk of hypercalcemia [see Clinical Pharmacology ( 12.2) and Clinical Studies ( 14.2)].

Dose Titration

Individualize the dose of paricalcitol based on iPTH, serum calcium and phosphorus levels. Titrate paricalcitol dose based on the following formula:

Dose (micrograms) = most recent iPTH level (pg/ml) divided by 80

If serum calcium is elevated, the dose should be decreased by 2 to 4 micrograms.

As iPTH approaches the target range, small, individualized dose adjustments may be necessary in order to achieve a stable iPTH. In situations where monitoring of iPTH, Ca or P occurs less frequently than once per week, a more modest initial and dose titration ratio (e.g., iPTH divided by 100) may be warranted.

2.3 Pediatric Patients (Ages 10 to 16 Years)

CKD Stages 3 and 4

Initial Dose

Administer paricalcitol 1 mcg capsule orally three times a week, no more frequently than every other day.

Dose Titration

Individualize and titrate paricalcitol dose based on iPTH, serum calcium and phosphorus levels to maintain an iPTH level within target range.

Every 4 weeks, each administered paricalcitol dose may be increased in 1 mcg increments, maintaining the three times per week regimen (e.g., increase from 1 mcg three times per week to 2 mcg three times per week). At any time, each administered dose may be decreased by 1 mcg. Paricalcitol may be stopped if the patient requires reduction while receiving 1 mcg three times per week, resuming when appropriate.

CKD Stage 5

Initial Dose

Administer the dose of paricalcitol capsules orally three times a week, no more frequently than every other day based upon the following formula:

Dose* (micrograms) = baseline iPTH (pg/mL) divided by 120

* Round down to the nearest whole number

Dose Titration

Subsequent dosing should be individualized and based on iPTH, serum calcium and phosphorus levels to maintain an iPTH level within target range.

Every 4 weeks, each administered paricalcitol dose may be increased in 1 mcg increments, maintaining the three times per week regimen (e.g., increase from 1 mcg three times per week to 2 mcg three times per week). At any time, each administered dose may be decreased by 2 mcg. Paricalcitol may be stopped if the patient requires reduction while receiving 2 mcg three times per week or 1 mcg three times per week, resuming when appropriate.

2.4 Monitoring

Monitor serum calcium and phosphorus levels closely after initiation of paricalcitol, during dose titration periods and during co-administration with strong CYP3A inhibitors [see Warnings and Precautions ( 5.3) , Drug Interactions ( 7) , and Clinical Pharmacology ( 12.3)].

If hypercalcemia is observed, the dose of paricalcitol should be reduced or withheld until these parameters are normalized.

2.5 Administration

Paricalcitol capsules may be taken without regard to food.

3 DOSAGE FORMS AND STRENGTHS

Paricalcitol capsules are available as 1 mcg and 2 mcg soft gelatin capsules.

  • 1 mcg: oval, gray capsule imprinted with “ZA”
  • 1 mcg: oval, gray capsule imprinted with the “a” logo and “ZA”
  • 2 mcg: oval, orange-brown capsule imprinted with “ZF”
  • 2 mcg: oval, orange-brown capsule imprinted with the “a” logo and “ZF”

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).

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