Paricalcitol

FDA Drug Information • Also known as: Paricalcitol, Zemplar

Brand Names: Paricalcitol, Zemplar
Drug Class: Vitamin D2 Analog [EPC], Vitamin D Analog [EPC]
Route: INTRAVENOUS
Dosage Form: INJECTION, SOLUTION
Product Type: HUMAN PRESCRIPTION DRUG

Description

11 DESCRIPTION Paricalcitol, USP, the active ingredient in Paricalcitol Capsules, is a synthetically manufactured, metabolically active vitamin D analog of calcitriol with modifications to the side chain (D 2 ) and the A (19-nor) ring. Paricalcitol is available as soft gelatin capsules for oral administration containing 1 microgram, 2 micrograms, and 4 micrograms of paricalcitol. Each capsule also contains medium chain triglycerides, alcohol, and butylated hydroxytoluene. ..The capsule shell is composed of gelatin, glycerin, Noncrystallizing Sorbitol solution, titanium dioxide, iron oxide red (2 microgram capsules only), iron oxide yellow (2 microgram and 4 microgram capsules), iron oxide black (1 microgram capsules only) and water. The soft gelatin capsules are printed with black ink Opacode Black (S-1-17823) containing Isopropyl alcohol, Black iron oxide, N-Butyl alcohol, Propylene glycol, Ammonium hydroxide and Shellac. Paricalcitol is a white, crystalline powder with the empirical formula of C 27 H 44 O 3 , which corresponds to a molecular weight of 416.64. Paricalcitol is chemically designated as 19-nor-1α,3β,25-trihydroxy-9,10-secoergosta-5(Z),7(E),22(E)- triene and has the following structural formula: structure

What Is Paricalcitol Used For?

1 INDICATIONS & USAGE 1.1 Chronic Kidney Disease Stages 3 and 4 Paricalcitol Capsules are indicated in adults for the prevention and treatment of secondary hyperparathyroidism associated with Chronic Kidney Disease (CKD) Stages 3 and 4. 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. 1.2 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 (1.1). CKD Stage 5 in patients on hemodialysis or peritoneal dialysis (1.2).

Dosage and Administration

2 DOSAGE & 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 Capsules 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 Capsules 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 or decreased 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% or iPTH 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 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 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. 2.4 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 [see Warnings and Precautions (5.3), Drug Interactions (7), and Clinical Pharmacology...

Side Effects (Adverse Reactions)

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

Drug Interactions

7 DRUG INTERACTIONS Table 5 shows the clinically significant drug interactions with Paricalcitol capsules. Table 5: Clinically Significant Drug Interactions with Paricalcitol CYP3A Inhibitors Clinical Impact Paricalcitol is partially metabolized by CYP3A. Hence, exposure of paricalcitol will increase upon coadministration with strong CYP3A inhibitors such as but not limited to: boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole. Intervention Dose adjustment of Paricalcitol capsules may be necessary. Monitor closely for iPTH and serum calcium concentrations, if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor. Cholestyramine Clinical Impact Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of paricalcitol. Intervention Recommend to take Paricalcitol capsules at least 1 hour before or 4 to 6 hours after taking cholestyramine (or at as great an interval as possible) to avoid impeding absorption of paricalcitol. Mineral Oil Clinical Impact Mineral oil or other substances that may affect absorption of fat may influence the absorption of paricalcitol. Intervention Recommend to take Paricalcitol capsules at least 1 hour before or 4 to 6 hours after taking mineral oil (or at as great an interval as possible) to avoid affecting absorption of paricalcitol. Strong CYP3A inhibitors (e.g. ketoconazole) will increase the exposure of paricalcitol. Use with caution (7). 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 (7).

Contraindications

4 CONTRAINDICATIONS Paricalcitol Capsules should not be given to patients with evidence of hypercalcemia or vitamin D toxicity [see Warnings and Precautions (5.1)]. Evidence of hypercalcemia (4). Evidence of vitamin D toxicity (4).

Pregnancy and Breastfeeding

8.1 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 [see Clinical Considerations] . 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 [see Data] . 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 0, 0.3, 1.0 or 3.0 mcg/kg/day and rabbits at 0, 0.03, 0.1 or 0.3 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,...

Overdosage

10 OVERDOSAGE Excessive administration of Paricalcitol Capsules can cause hypercalcemia, hypercalciuria, and hyperphosphatemia, and over suppression of PTH [ see Warnings and Precautions (5.1) ]. 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.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING Paricalcitol Capsules are available as 1 mcg, 2 mcg, and 4 mcg capsules. The 1 mcg capsule is gray colour oval shaped soft gelatin capsule imprinted with ‘12’ in black ink and is available in the following package size. Bottles of 30 (NDC 49483-687-03) The 2 mcg capsule is brown colour oval shaped soft gelatin capsule imprinted with ‘14’ in black ink and is available in the following package size. Bottles of 30 (NDC 49483-688-03) The 4 mcg capsule is Light yellow colour oval shaped soft gelatin capsules imprinted with '17' in black ink and is available in the following package size. Bottles of 30 (NDC 49483-699-03) STORAGE Store Paricalcitol Capsules at 20°C to 25°C (68°F to77°F). See USP Controlled Room Temperature.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.