PARICALCITOL- paricalcitol_injection, solution

Paricalcitol is a synthetic, biologically active vitamin D 2 in vitro Within two hours after administering paricalcitol injection intravenous doses ranging from 0. 24 mcg/kg, concentrations of paricalcitol decreased rapidly; thereafter, concentrations of paricalcitol declined log-linearly. No accumulation of paricalcitol was observed with three times a week dosing. Distribution Paricalcitol is extensively bound to plasma proteins (>=99. In healthy subjects, the steady state volume of distribution is approximately 23. The mean volume of distribution following a 0. 24 mcg/kg dose of paricalcitol in CKD Stage 5 subjects requiring hemodialysis (HD) and peritoneal dialysis (PD) is between 31 and 35 L. Elimination Metabolism After intravenous administration of a 0. 48 mcg/kg dose of 3 in vivo In vitro Excretion Paricalcitol is excreted primarily by hepatobiliary excretion. Approximately 63% of the radioactivity was eliminated in the feces and 19% was recovered in the urine in healthy subjects. In healthy subjects, the mean elimination half-life of paricalcitol is about five to seven hours over the studied dose range of 0. The pharmacokinetics of paricalcitol has been studied in CKD patients requiring hemodialysis (HD) and peritoneal dialysis (PD). The mean elimination half-life of paricalcitol after administration of 0. 24 mcg/kg paricalcitol IV bolus dose in CKD HD and PD patients is 13. 4 hours, respectively (Table 5). Mean +/- SD Paricalcitol Pharmacokinetic Parameters in CKD Patients on Dialysis Following Single 0. 24 mcg/kg Intravenous Bolus Dose CKD -HD CKD -PD C max 1. 315 AUC 0-infinity 14. 98 beta (1/h) 0. 026 t 1/2 * 13. 5 CL (L/h) 1. 95 Vdbeta (L) 30. 5 * harmonic mean +/- pseudo standard deviation, HD: hemodialysis, PD: peritoneal dialysis. The degree of accumulation was consistent with the half-life and dosing frequency. Specific Populations The pharmacokinetics of paricalcitol has not been investigated in geriatric and pediatric patients. Male and Female Patients The pharmacokinetics of paricalcitol were gender independent. Patients with 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 were similar across the range of hepatic function evaluated in this study. The influence of severe hepatic impairment on the pharmacokinetics of paricalcitol has not been evaluated. Patients with Renal Impairment The pharmacokinetics of paricalcitol have been studied in CKD patients requiring hemodialysis (HD) and peritoneal dialysis (PD). Hemodialysis procedure has essentially no effect on paricalcitol elimination. However, compared to healthy subjects, CKD patients on dialysis showed a decreased CL and increased half-life. Drug Interaction Studies An in vitro Drug interactions with paricalcitol injection have not been studied. The following studies have been performed with oral paricalcitol capsules. Omeprazole The pharmacokinetic interaction between paricalcitol capsule (16 mcg) and omeprazole (40 mg; oral), a strong inhibitor of CYP2C19, was investigated in a single dose, crossover study in healthy subjects. The pharmacokinetics of paricalcitol were unaffected when omeprazole was administrated approximately 2 hours prior to the paricalcitol dose. Strong CYP3A Inhibitors 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 capsule has been studied in healthy subjects. The C max 0-infinity [see Drug Interactions (7).

Paricalcitol injection is indicated for the prevention and treatment of secondary hyperparathyroidism in patients 5 years of age and older with chronic kidney disease (CKD) on dialysis. Paricalcitol injection is a vitamin D analog indicated for the prevention and treatment of secondary hyperparathyroidism in patients 5 years of age and older with chronic kidney disease on dialysis ( 1.

Ensure serum calcium is not above the upper limit of normal before initiating ( 2. 1 Administer paricalcitol injection intravenously through a hemodialysis vascular access at any time during dialysis ( 2. 1 Adult Dose: Initiate at 0. 04 mcg/kg to 0. 1 mcg/kg (2. 8 mcg to 7 mcg) no more frequently than every other day ( 2. 2 Target maintenance dose to intact parathyroid hormone (PTH) levels within the desired therapeutic range and serum calcium within normal limits ( 2. 2 Monitor serum calcium frequently (e. , twice weekly) and intact PTH levels every 2 to 4 weeks after dose initiation or adjustment (2. 2) See Table 1 in the full prescribing information for titration recommendations based upon intact PTH levels ( 2. 2 Suspend or decrease the dose for persistent abnormally low intact PTH or serum calcium consistently above the normal range ( 2. 2 Pediatric Dose: Initiate paricalcitol injection as an intravenous bolus dose of: 0. 04 mcg/kg if baseline intact PTH is less than 500 pg/mL, or 0. 08 mcg/kg if baseline intact PTH is 500 pg/mL or greater ( 2. 3 Target maintenance dose to intact PTH levels within the desired therapeutic range and serum calcium within normal limits ( 2. 3 Monitor serum calcium frequently (e. , twice weekly) and intact PTH levels every 2 to 4 weeks after dose initiation or adjustment ( 2. 3 See Table 2 in the full prescribing information for titration recommendations based upon intact PTH levels ( 2. 3 Suspend or decrease the dose for persistent abnormally low intact PTH or serum calcium consistently above the normal range ( 2. 3 Ensure serum calcium is not above the upper limit of normal before initiating treatment [see Warnings and Precautions ( 5. 1 Administer paricalcitol injection intravenously through a hemodialysis vascular access port at any time during dialysis. Paricalcitol injection may be administered intravenously if an access port is unavailable. Inspect paricalcitol injection visually prior to administration; the solution should appear clear and colorless. Do not use if the solution is not clear or particles are present. Discard unused portion of 2 mcg/mL and 5 mcg/mL single-dose vials. Initiate paricalcitol injection as an intravenous bolus dose of 0. 8 mcg to 7 mcg) no more frequently than every other day at any time during dialysis. Target the maintenance dose of paricalcitol injection to intact parathyroid hormone (PTH) levels within the desired therapeutic range and serum calcium within normal limits. Monitor serum calcium frequently (e. , twice weekly) and intact PTH levels every 2 to 4 weeks after initiation of therapy or dose adjustment. Titrate the dose of paricalcitol injection based on intact PTH (see Table 1). Prior to raising the dose, ensure serum calcium is within normal limits. The maximum daily adult dose is 0. Suspend or decrease the dose if intact PTH is persistently and abnormally low to reduce the risk of adynamic bone disease [see Warnings and Precautions ( 5. 3 [see Warnings and Precautions ( 5. Recommended Paricalcitol Injection Adult Dose Titration Based Upon intact PTH Intact PTH Level At Follow-up Visit Dosage Adjustment Above target and intact PTH increased Increase* by 2 mcg to 4 mcg Above target and intact PTH decreased by less than 30% Increase* by 2 mcg to 4 mcg Above target and intact PTH decreased by 30% to 60% No Change Above target and intact PTH decreased by more than 60% Decrease per clinical judgement At target and intact PTH stable No Change * The maximum daily adult dose is 0. 24 mcg/kg Initiate paricalcitol injection as an intravenous bolus dose of: 0. 08 mcg/kg if baseline intact PTH is 500 pg/mL or greater Administer paricalcitol injection three times per week, no more frequently than every other day, at any time during dialysis. Target the maintenance dose of paricalcitol injection to intact PTH levels within the desired therapeutic range and serum calcium within normal limits. Titrate the dose of paricalcitol injection based on intact PTH (see Table 2 Suspend or decrease the dose if intact PTH is persistently and abnormally low to reduce the risk of adynamic bone disease [see Warnings and Precautions ( 5. Recommended Paricalcitol Injection Pediatric Dose Titration Based Upon intact PTH en dash Patients 5 years of age and older Intact PTH Level At Follow-up Visit Dosage Adjustment Above target and intact PTH Increase by 0. 04 mcg/kg Intact PTH 150 pg/mL or greater and No Change Intact PTH less than 150 pg/mL or Decrease by 0. 04 mcg/kg weekly, or Increased monitoring of serum calcium and dose adjustment of paricalcitol injection may be necessary when given concomitantly with drugs that may increase the risk of hypercalcemia [see Drug Interactions ( 7 Increased monitoring of both serum calcium and intact PTH as well as dose adjustment of paricalcitol injection may be necessary when given concomitantly with strong CYP3A inhibitors [see Drug Interactions ( 7.

The following serious adverse reactions are described below and elsewhere in the labeling: Hypercalcemia [see Warnings and Precautions ( 5. 1 Adynamic Bone Disease [see Warnings and Precautions ( 5. 3 The most common adverse reactions (> 5% and more frequent than placebo) are nausea, vomiting and edema ( 6. 1 To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories Inc. , at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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. Four placebo-controlled, double-blind, multicenter studies were conducted in 113 patients (51% male, 10% Caucasian, 81% African-American and 9% Hispanic, ranging in age from 18 to 90 years). Sixty-two patients were exposed to paricalcitol injection and the average dose at the end of treatment was 0. 12 mcg/kg/dose with a mean number of 55 days of dosing across the studies. Discontinuation of therapy due to any adverse reaction occurred in 6. 5% of patients treated with paricalcitol injection and 2. 0% of patients treated with placebo. Adverse reactions occurring with greater frequency in the paricalcitol injection group and at a frequency of 2% or greater are presented in Table 3. Adverse Reactions Occurring at a Rate of 2% or Greater in Patients with CKD on Dialysis in Four Placebo-Controlled Studies Adverse Reaction Placebo (n = 51) % Paricalcitol Injection (n = 62) % Nausea 8 13 Vomiting 6 8 Edema 0 7 Gastrointestinal Hemorrhage 2 5 Chills 2 5 Pyrexia 2 5 Pneumonia 0 5 Sepsis 2 5 Influenza 4 5 Arthralgia 4 5 Palpitations 0 3 Dry Mouth 2 3 Malaise 0 3 Other Adverse Reactions The following adverse reactions occurred in less than 2% of the paricalcitol injection treated patients in the above mentioned studies and in additional double-blind, active-controlled and open-label studies: Blood and Lymphatic System Disorders: Cardiac Disorders: Ear and Labyrinth Disorders Endocrine Disorders: Eye Disorders Gastrointestinal Disorders General Disorders: Infections: Injection site reactions: Laboratory abnormalities: Metabolism and Nutrition Disorders: Musculoskeletal and Connective Tissue Disorders: Neoplasms Benign, Malignant and Unspecified: Nervous System Disorders: Psychiatric Disorders Reproductive System and Breast Disorders Respiratory, Thoracic and Mediastinal Disorders: Skin and Subcutaneous Tissue Disorders: Vascular Disorders: The following adverse reactions have been identified during post-approval use of paricalcitol injection. 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 causal relationship to drug exposure. Allergic reactions, such as rash, urticaria, and angioedema (including laryngeal edema) have been reported.

Paricalcitol injection is contraindicated in patients with: Hypercalcemia [see Warnings and Precautions ( 5. 1 Vitamin D toxicity [see Warnings and Precautions ( 5. 1 Known hypersensitivity to paricalcitol or any of the inactive ingredients in paricalcitol injection. Hypersensitivity adverse reactions have been reported [e. , angioedema (including laryngeal edema) and urticaria] [see Adverse Reactions ( 6. 2 Hypercalcemia ( 4 Vitamin D toxicity ( 4 Known hypersensitivity to paricalcitol or any inactive ingredient ( 4.

Risk Summary Limited data with paricalcitol injection 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, a human dose of 14 mcg (equivalent to 0. 24 mcg/kg), based on body surface area (mg/m 2 (see Data The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Chronic kidney disease in pregnancy increases the risk for maternal hypertension and preeclampsia, miscarriage, preterm delivery, polyhydramnios, still birth, and low birth weight infants. Data Animal Data Pregnant rats and rabbits were treated with paricalcitol by once-daily intravenous 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 or 3 mcg/kg/day and rabbits at 0, 0. 3 mcg/kg/day, representing up to 2 or 0. 5 times, respectively, a human dose of 0. 24 mcg/kg, based on body surface area (mg/m 2 Risk Summary There is no information available on the presence of paricalcitol in human milk, the effects of the drug on the breastfed infant or the effects of the drug on milk production. Studies in rats have shown that paricalcitol and/or its metabolites are present in the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk (see Data (see Clinical Considerations Clinical Considerations Infants exposed to paricalcitol injection through breast milk should be monitored for signs and symptoms of hypercalcemia, including seizures, vomiting, constipation and weight loss. Monitoring of serum calcium in the infant should be considered. Data Following a single oral administration of 20 mcg/kg of radioactive [ 3 3 3 The safety and efficacy of paricalcitol injection for the prevention and treatment of secondary hyperparathyroidism associated with CKD have been established in pediatric patients 5 years of age and older with CKD on dialysis. Use of paricalcitol injection in pediatric patients 5 years of age and older is supported by evidence from an adequate and well-controlled study in 29 patients, 5 to 19 years of age, with CKD on hemodialysis [see Clinical Studies ( 14 The safety and efficacy of paricalcitol injection have not been established in pediatric patients less than 5 years old. Clinical studies of paricalcitol injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic or cardiac function, and of concomitant disease or other drug therapy. The pharmacokinetics of paricalcitol injection were studied in patients with mild and moderate hepatic impairment and were similar to that of patients with normal hepatic function. No dose adjustment is required in patients with mild or moderate hepatic function. Paricalcitol injection has not been studied in patients with severe hepatic impairment.

Strong CYP3A Inhibitors 2. 4 7 Table 4 includes clinically significant drug interactions with paricalcitol injection. Clinically Significant Drug Interactions with Paricalcitol Injection Drugs that May Increase the risk of Hypercalcemia Clinical Concomitant administration of high doses of calcium-containing preparations or other vitamin D compounds may increase the risk of hypercalcemia. Thiazide diuretics are known to induce hypercalcemia by reducing excretion of calcium in the urine. Examples Calcium-containing products, other vitamin D compounds or thiazide diuretics Intervention Monitor calcium more frequently and adjust paricalcitol injection dose as needed [see Warnings and Precautions ( 5. 1 Digitalis Compounds Clinical Paricalcitol injection can cause hypercalcemia which can potentiate the risk of digitalis toxicity. Intervention Monitor patients for signs and symptoms of digitalis toxicity and increase frequency of serum calcium monitoring when initiating or adjusting the dose of paricalcitol injection in patients receiving digitalis compounds [see Warnings and Precautions ( 5. 2 Strong CYP3A Inhibitors Clinical Paricalcitol injection is partially metabolized by CYP3A. Exposure of paricalcitol injection will increase upon coadministration with strong CYP3A inhibitors [see Clinical Pharmacology ( 12. 3 Examples Boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, and voriconazole Intervention If a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor, dose adjustment of paricalcitol injection may be necessary. Monitor intact PTH and serum calcium concentrations closely.

OVERDOSAGE
Overdosage of paricalcitol injection may lead to hypercalcemia, hypercalciuria, and hyperphosphatemia. [see Warnings and Precautions ( 5.1 The treatment of acute overdosage should consist of supportive measures and discontinuation of drug administration. Serum calcium levels should be measured until normal. Paricalcitol is not significantly removed by dialysis.
NONCLINICAL TOXICOLOGY
In a 104-week carcinogenicity study in CD-1 mice, an increased incidence of uterine leiomyoma and leiomyosarcoma was observed at subcutaneous doses of 1, 3, 10 mcg/kg administered 3 times per week (2 to 15 times the AUC at a human dose of 14 mcg, equivalent to 0.24 mcg/kg based on AUC). The incidence rate of uterine leiomyoma was significantly different than the control group at the highest dose of 10mcg/kg. In a 104-week carcinogenicity study in rats, there was an increased incidence of benign adrenal pheochromocytoma at subcutaneous doses of 0.15, 0.5, 1.5 mcg/kg administered 3 times per week (at less than clinical exposure to 7 times the exposure following a human dose of 14 mcg, equivalent to 0.24 mcg/kg based on AUC). The increased incidence of pheochromocytomas in rats may be related to the alteration of calcium homeostasis by paricalcitol. Paricalcitol did not exhibit genetic toxicity in vitro in vivo Paricalcitol had no effect on fertility (male or female) in rats at intravenous doses up to 20 mcg/kg/dose (13 times a human dose of 14 mcg, equivalent to 0.24 mcg/kg based on surface area, mg/m 2
CLINICAL STUDIES
Adult Studies in CKD on Dialysis Three 12-week, placebo-controlled studies were conducted in 78 patients with CKD on hemodialysis. In these studies, patients ranged in age from 22 to 90 years, 51% were males, 13% were Caucasian, 79% were African-American, and 8% were Hispanic. The most common causes of renal failure were hypertension and diabetes. The dose of paricalcitol injection was started at 0.04 mcg/kg 3 times per week intravenously. The dose was increased by 0.04 mcg/kg every 2 weeks until intact PTH levels were decreased at least 30% from baseline or a fifth escalation brought the dose to 0.24 mcg/kg, or intact PTH fell to less than 100 pg/mL, or the Ca × P product was greater than 75 within any 2 week period, or serum calcium became greater than 11.5 mg/dL at any time. Patients treated with paricalcitol injection achieved a mean intact PTH reduction of 30% within 6 weeks. The results from these studies are as follows: Table 6. Mean Changes from Baseline to Final Evaluation in intact PTH, Alkaline Phosphatase, Phosphorus and Calcium × Phosphorus Product in Adult Patients with CKD on Dialysis in Three 12-Week Placebo-Controlled Studies Group Baseline Mean Mean (SE) Change From intact PTH (pg/mL) Paricalcitol Injection 783 -379 (43.7) placebo (n = 38) 745 -69.6 (44.8) Alkaline Phosphatase (U/L) Paricalcitol Injection 150 (40 en dash 600) -41.5 (10.6) placebo (n = 34) 169 (56 en dash 911) +2.6 (10.1) Phosphorus (mg/dL) Paricalcitol Injection 5.8 (3.7 en dash 10.2) +0.47 (0.3) placebo (n = 38) 6.0 (2.8 en dash 8.8) -0.47 (0.3) Calcium × Phosphorus Product Paricalcitol Injection 54 (32 en dash 106) +7.9 (2.2) placebo (n = 38) 54 (26 en dash 77) -3.9 (2.3) Pediatric Study in CKD on Dialysis Paricalcitol injection was evaluated in a 12-week randomized, double-blind, placebo-controlled study of 29 pediatric patients, aged 5 to 19 years, with CKD on hemodialysis; nearly all had received some form of vitamin D prior to the study. Of the 29 patients, 76% were male, 52% were Caucasian and 45% were African-American. The initial dose of paricalcitol injection was 0.04 mcg/kg 3 times per week, based on baseline intact PTH level of less than 500 pg/mL, or 0.08 mcg/kg 3 times per week, based on baseline intact PTH level of 500 pg/mL or greater. The dose of paricalcitol injection was adjusted in 0.04 mcg/kg increments based on the levels of serum intact PTH, calcium and Ca × P. The mean baseline levels of intact PTH were 841 pg/mL for the 15 paricalcitol injection-treated patients and 740 pg/mL for the 14 placebo-treated patients. The mean dose of paricalcitol injection administered was 4.6 mcg (range: 0.8 mcg to 9.6 mcg). Sixty-seven percent of the paricalcitol injection-treated patients and 14% of the placebo-treated patients completed the trial. Seventy-one percent of the placebo-treated patients discontinued due to excessive elevations in intact PTH levels, as defined by 2 consecutive intact PTH levels greater than 700 pg/mL and greater than baseline after 4 weeks of treatment. The primary efficacy analysis demonstrated that 60% of paricalcitol injection-treated patients and 21% of placebo-treated patients achieved two consecutive greater than or equal to 30% reductions from baseline in intact PTH.

Dr. Reddy's Laboratories, Inc.

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