Paricalcitol Drug Information

Chronic Kidney Disease Stage 5 Paricalcitol Capsules are indicated in adults for the prevention and treatment of secondary hyperparathyroidism associated with CKD Stage 5 in patients on hemodialysis (HD) or peritoneal dialysis (PD). Pediatric use information for patients 10 to 16 years of age is approved for AbbVie Inc.’s Zemplar (Paricalcitol) capsules. However, due to AbbVie Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Paricalcitol is a vitamin D analog indicated in adults for the prevention and treatment of secondary hyperparathyroidism associated with: Chronic kidney disease (CKD) Stages 3 and 4.

Chronic Kidney Disease Stages 3 and 4 in Adults Administer Paricalcitol Capsules orally once daily or three times a week. When dosing three times weekly, do not administer more frequently than every other day. Initial Dose Table 1.

Recommended Paricalcitol Capsules Starting Dose Based upon Dose Titration Table 2. Recommended Paricalcitol Capsules Dose Titration Base upon iPTH Level 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.

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 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. Dose Titration Individualize the dose of Paricalcitol Capsules based on iPTH, serum calcium and phosphorus level.

Titrate Paricalcitol Capsules dose based on 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.

Pediatric use information for patients 10 to 16 years of age is approved for AbbVie Inc.’s Zemplar (Paricalcitol) capsules. However, due to AbbVie Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Monitoring

Monitor serum calcium and phosphorus levels closely after initiation of Paricalcitol Capsules during dose titration periods and during co-administration with strong CYP3A inhibitors. If hypercalcemia is observed, the dose of Paricalcitol Capsules should be reduced or withheld until these parameters are normalized.

Administration Paricalcitol Capsules may be taken without regard to food. Initial Dosage:CKD Stage 3 and 4 *Not more frequently than every other day when dosing three times a week Initial dosage: CKD Stage 5 Adult Dose (micrograms) = baseline iPTH (pg/mL) divided by 80. Dose Titration: CKD Stage 5 Adult Dose in micrograms is based on most recent iPTH (pg/mL) divided by 80 with adjustments based on serum calcium and phosphorous levels.

CKD Stage 5: To avoid hypercalcemia only treat patients after their baseline serum calcium has been reduced to 9.5 mg/dL or lower.

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 Capsules-Treated Group of Three, Double-Blind, Placebo-Controlled CKD Stages 3 and 4 Studies Additional Adverse Reactions The following additional adverse reactions, occurred in <2% of the Paricalcitol-treated adult 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 use information for patients 10 to 16 years of age is approved for AbbVie Inc.’s Zemplar (Paricalcitol) capsules.

However, due to AbbVie Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 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. 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 use information for patients 10 to 16 years of age is approved for AbbVie Inc.’s Zemplar (Paricalcitol) capsules.

Postmarketing Experience

The following additional adverse reactions have been reported during post-approval use of Paricalcitol 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 casual relationship to drug exposure. Immune System Disorders: Angioedema (including laryngeal edema) Investigations: Blood creatinine increased The most common adverse reactions (> 5% and more frequent than placebo) include diarrhea, nasopharyngitis, dizziness, vomiting, hypertension, hypersensitity, nausea, and edema.

To report SUSPECTED ADVERSE REACTIONS, contact Marksans at 1-877-376-4271 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

Table 5 shows the clinically significant drug interactions with Paricalcitol capsules. Table 5: Clinically Significant Drug Interactions with Paricalcitol Strong CYP3A inhibitors (e.g. ketoconazole) will increase the exposure of paricalcitol. Use with caution.

Cholestyramine, Mineral Oil: Intestinal absorption of paricalcitol may be reduced if administered simultaneously with cholestyramine or mineral oil. Take paricalcitol capsules at least one hour before or 4 to 6 hours after taking cholestyramine or mineral oil.

Pregnancy Risk Summary Limited data with Paricalcitol capsules in pregnant women are insufficient to inform a drug- associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with chronic kidney disease in pregnancy. In animal reproduction studies, slightly increased embryofetal loss was observed in pregnant rats and rabbits administered paricalcitol intravenously during the period of organogenesis at doses 2 and 0.5 times, respectively, the maximum recommended human dose (MRHD).

Adverse reproductive outcomes were observed at doses that caused maternal toxicity. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Chronic kidney disease in pregnancy increases the maternal risk for hypertension, spontaneous abortion, preterm labor, and preeclampsia. Chronic kidney disease increases the fetal risk for intrauterine growth restriction (IUGR), prematurity, polyhydramnios, still birth, and low birth weight.

Data Animal Data Pregnant rats and rabbits were treated with paricalcitol by once-daily intravenous (IV) injection during the period of organogenesis (in rats, from gestation day (GD) 6 to 17; in rabbits, from GD 6 to 18). Rats were dosed at mcg/kg/day and rabbits at mcg/kg/day, representing up to 2 or 0.5 times, respectively, the maximum recommended human dose (MRHD) of 0.24 mcg/kg, based on body surface area (mg/m 2 ). Slightly decreased fetal viability was observed in both studies at the highest doses representing 2 and 0.5 times, respectively, the MRHD in the presence of maternal toxicity (decreased body weight and food consumption).

Pregnant rats were administered paricalcitol by IV injection three times per week at doses of mcg/kg/day throughout gestation, parturition and lactation (GD 6 to lactation day (LD) 20) representing exposures up to 13 times the MHRD. A small increase in stillbirths and pup deaths from parturition to LD 4 were observed at the high dose when compared to the control group (9.2% versus 3.3% in controls) at 13 times the MRHD, which occurred at a maternally toxic dose known to cause hypercalcemia in rats. Surviving pups were not adversely affected; body weight gains, developmental landmarks, reflex ontogeny, learning indices, and locomotor activity were all within normal parameters.

F1 reproductive capacity was unaffected.

Pediatric Use Safety and effectiveness of Paricalcitol Capsules in pediatric patients under the age of 10 years have not been established. Pediatric use information for patients 10 to 16 years of age is approved for AbbVie Inc.’s Zemplar (Paricalcitol) capsules. However, due to AbbVie Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Paricalcitol Capsules should not be given to patients with evidence of hypercalcemia or vitamin D toxicity. Evidence of hypercalcemia. Evidence of vitamin D toxicity.

Excessive administration of Paricalcitol Capsules can cause hypercalcemia, hypercalciuria, and hyperphosphatemia, and over suppression of PTH. Treatment of Overdosage The treatment of acute overdosage of Paricalcitol Capsules should consist of general supportive measures. If drug ingestion is discovered within a relatively short time, induction of emesis or gastric lavage may be of benefit in preventing further absorption.

If the drug has passed through the stomach, the administration of mineral oil may promote its fecal elimination. Serial serum electrolyte determinations (especially calcium), rate of urinary calcium excretion, and assessment of electrocardiographic abnormalities due to hypercalcemia should be obtained. Such monitoring is critical in patients receiving digitalis.

Discontinuation of supplemental calcium and institution of a low-calcium diet are also indicated in accidental overdosage. Due to the relatively short duration of the pharmacological action of paricalcitol, further measures are probably unnecessary. If persistent and markedly elevated serum calcium levels occur, there are a variety of therapeutic alternatives that may be considered depending on the patient's underlying condition.

These include the use of drugs such as phosphates and corticosteroids, as well as measures to induce an appropriate forced diuresis. Paricalcitol is not significantly removed by dialysis.