Paricalcitol

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).

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 (12.3)]. If hypercalcemia is observed, the dose of Paricalcitol Capsules should be reduced or withheld until these parameters are normalized. 2.5 Administration Paricalcitol Capsules may be taken without regard to food. Initial Dosage:CKD Stage 3 and 4 (2.1) Adult:Baseline iPTH ≤ 500 pg/mL 1 mcg orally daily or 2 mcg three times a week* Adult: Baseline iPTH > 500 pg/mL 2 mcg orally daily or 4 mcg three times a week* Dose Titration : CKD Stage 3 and 4 (2.1) Adult : iPTH same, increased or decreased by <30% relative to baseline Increase dose by 1 mcg daily or 2 mcg three times a week* Adult : iPTH decreased by ≥ 30% and ≤ 60% relative to baseline Maintain dose Adult : iPTH decreased by > 60% or iPTH < 60% pg/mL relative to baseline Decrease dose by 1 mcg daily or 2 mcg three times a week* *Not more frequently than every other day when dosing three times a week Initial dosage : CKD Stage 5 (2.2) Adult Dose (micrograms) = baseline iPTH (pg/mL) divided by 80. Administer dose orally three times a week*. Dose Titration: CKD Stage 5 (2.2) Adult Dose in micrograms is based on most recent iPTH (pg/mL) divided by 80 with adjustments based on serum calcium and phosphorous levels. Dose three times a week* * Not more frequently than every other day. CKD Stage 5: To avoid hypercalcemia only treat patients after their baseline serum calcium has been reduced to 9.5 mg/dL or lower (2.2).

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 Musculoskeletal and Connective Tissue Disorders 3 (3%) 1 (1%) 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%) 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 Capsules- 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 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. 6.2 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 (6). To report SUSPECTED ADVERSE REACTIONS, contact Marksans at 1-877-376-4271 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

12.3 Pharmacokinetics Absorption The mean absolute bioavailability of Paricalcitol Capsules under low-fat fed condition ranged from 72% to 86% in healthy adult volunteers, CKD Stage 5 patients on HD, and CKD Stage 5 patients on PD. A food effect study in healthy adult volunteers indicated that the C max and AUC 0-∞, were unchanged when paricalcitol was administered with a high fat meal compared to fasting. Food delayed T max by about 2 hours. The AUC 0-∞ of paricalcitol increased proportionally over the dose range of 0.06 to 0.48 mcg/kg in healthy adult volunteers. Distribution Paricalcitol is extensively bound to plasma proteins (≥ 99.8%). The mean apparent volume of distribution following a 0.24 mcg/kg dose of paricalcitol in healthy adult volunteers was 34 L. The mean apparent volume of distribution following a 4 mcg dose of paricalcitol in CKD Stage 3 and a 3 mcg dose in CKD Stage 4 patients is between 44 and 46 L. Metabolism After oral administration of a 0.48 mcg/kg dose of 3 H-paricalcitol, parent drug was extensively metabolized, with only about 2% of the dose eliminated unchanged in the feces, and no parent drug was found in the urine. Several metabolites were detected in both the urine and feces. Most of the systemic exposure was from the parent drug. Two minor metabolites, relative to paricalcitol, were detected in human plasma. One metabolite was identified as 24(R)-hydroxy paricalcitol, while the other metabolite was unidentified. The 24(R)-hydroxy paricalcitol is less active than Paricalcitol in an in vivo rat model of PTH suppression. In vitro data suggest that paricalcitol is metabolized by multiple hepatic and non-hepatic enzymes, including mitochondrial CYP24, as well as CYP3A4 and UGT1A4. The identified metabolites include the product of 24(R)-hydroxylation, 24,26- and 24,28-dihydroxylation and direct glucuronidation. Elimination Paricalcitol is eliminated primarily via hepatobiliary excretion; approximately 70% of the radiolabeled dose is recovered in the feces and 18% is recovered in the urine. While the mean elimination half-life of paricalcitol is 4 to 6 hours in healthy adult volunteers,the mean elimination half-life of paricalcitol in CKD Stages 3,4, and 5 (on HD and PD) patients ranged from 14 to 20 hours. Table 6. Paricalcitol Capsule Pharmacokinetic Parameters(mean + SD) in CKD Stages 3, 4, and 5 Adult Patients Pharmacokinetic Parameters(units) CKD Stage 3 n = 15* CKD Stage 4 n = 14* CKD Stage 5 HD** n=14 CKD Stage 5 PD** n=8 C max (ng/mL) 0.11 ± 0.04 0.06 ±0.01 0.575 ± 0.17 0.413 ± 0.06 AUC 0-∞ (ng•h/mL) 2.42 ± 0.61 2.13 ± 0.73 11.67 ± 3.23 13.41 ± 5.48 CL/F(L/h) 1.77 ±0.50 1.52 ± 0.36 1.82 ± 0.75 1.76 ± 0.77 V/F (L) 43.7 ±14.4 46.4 ±12.4 38 ± 16.4 48.7 ± 15.6 t 1/2 16.8 ± 2.65 19.7 ±7.2 13.9 ± 5.1 17.7 ± 9.6 HD:hemodialysis;PD:peritoneal dialysis.*Four mcg Paricalcitol capsules were given to CKD Stage 3 patients; three mcg Paricalcitol capsules were given to CKD Stage 4 patients. **CKD Stage 5 HD and PD patients received a 0.24 mcg/kg dose of paricalcitol as capsules. Specific Populations Geriatric The pharmacokinetics of paricalcitol has not been investigated in geriatric patients greater than 65 years [see Use in Specific Populations (8.5)] . Pediatric 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. Gender The pharmacokinetics of paricalcitol following single doses over the 0.06 to 0.48 mcg/kg dose range was gender independent. Hepatic Impairment The disposition of paricalcitol (0.24 mcg/kg) was compared in patients with mild (n = 5) and moderate (n = 5) hepatic impairment (as indicated by the Child-Pugh method) and subjects with normal hepatic function (n = 10). The pharmacokinetics of unbound paricalcitol was similar across the range of hepatic function evaluated in this study. No dose adjustment is required in patients with mild and moderate hepatic impairment. The influence of severe hepatic impairment on the pharmacokinetics of paricalcitol has not been evaluated. Renal Impairment Following administration of paricalcitol capsules, the pharmacokinetic profile of paricalcitol for CKD Stage 5 on HD or PD was comparable to that in CKD 3 or 4 patients. Therefore, no special dose adjustments are required other than those recommended in the Dosage and Administration section [see Dosage and Administration (2)]. Drug Interactions An in vitro study indicates that paricalcitol is neither an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A nor an inducer of CYP2B6, CYP2C9 or CYP3A. Hence, paricalcitol is neither expected to inhibit nor induce the clearance of drugs metabolized by these enzymes. Omeprazole The effect of omeprazole (40 mg capsule), a strong inhibitor of CYP2C19, on paricalcitol (four 4 mcg capsules) pharmacokinetics was investigated in a single dose, crossover study in healthy subjects. The pharmacokinetics of paricalcitol was not affected when omeprazole was administered approximately 2 hours prior to the paricalcitol dose. Ketoconazole The effect of multiple doses of ketoconazole, a strong inhibitor of CYP3A, administered as 200 mg BID for 5 days on the pharmacokinetics of paricalcitol (4 mcg capsule) has been studied in healthy subjects. The C max of paricalcitol was minimally affected, but AUC o-∞ . approximately doubled in the presence of ketoconazole. The mean half-life of paricalcitol was 17.0 hours in the presence of ketoconazole as compared to 9.8 hours, when paricalcitol was administered alone [see Drug Interactions (7)].