Paricalcitol

1 INDICATIONS AND USAGE 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 ).

2 DOSAGE AND ADMINISTRATION 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.g., 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.g., 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 ) 2.1 Important Administration Information 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. 2.2 Starting Dose and Dose Titration in Adults Initiate paricalcitol injection as an intravenous bolus dose of 0.04 mcg/kg to 0.1 mcg/kg (2.8 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.g., 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 0.24 mcg/kg. 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) ] or if serum calcium is consistently above the normal range to reduce the risk of hypercalcemia [see Warnings and Precautions (5.1) ] . If dose suspension is necessary, restart at a reduced dose after laboratory values have normalized. Table 1: 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 every 2 to 4 weeks Above target and intact PTH decreased by less than 30% Increase * by 2 mcg to 4 mcg every 2 to 4 weeks 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 2.3 Starting Dose and Dose Titration for Pediat …

3 DOSAGE FORMS AND STRENGTHS Injection: sterile, clear, colorless, aqueous solution available as follows: 2 mcg/mL single-dose vial 5 mcg/mL single-dose vial 10 mcg/2 mL (5 mcg/mL) single-dose vial 10 mcg/2 mL (5 mcg/mL) multiple-dose vial Paricalcitol injection is available as ( 3 ): Injection: 2 mcg/mL single-dose vial Injection: 5 mcg/mL single-dose vial Injection: 10 mcg/2 mL (5 mcg/mL) single-dose vial Injection: 10 mcg/2 mL (5 mcg/mL) multiple-dose vial

4 CONTRAINDICATIONS 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.g., 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 )

6 ADVERSE REACTIONS The most common adverse reactions (greater than 5% and more frequent than placebo) include nausea, vomiting and edema. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceutical Corp. at 1-877-233-2001 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience 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. Safety has been evaluated in clinical studies conducted with another paricalcitol injection product in 609 patients with CKD Stage 5. In four, placebo-controlled, double-blind, multicenter studies, discontinuation of therapy due to any adverse event occurred in 6.5% of 62 patients treated with paricalcitol injection (dosage titrated as tolerated, [see Clinical Studies ( 14 ) ]) and 2% of 51 patients treated with placebo for 1 to 3 months. Adverse reactions occurring with greater frequency in the paricalcitol group and at a frequency of 2% or greater are presented in the following table: Table 2: Adverse Reactions Occurring at a Rate A patient who reported the same medical term more than once was counted only once for that medical term. of 2% or Greater in CKD Stage 5 Patients in Four Placebo-Controlled Studies Adverse Reaction Placebo (n=51) % Paricalcitol Injection (n=62) % Cardiac Disorders Palpitations 0.0 3.2 Gastrointestinal Disorders Nausea 7.8 12.9 Vomiting 5.9 8.1 Gastrointestinal Hemorrhage 2.0 4.8 Dry Mouth 2.0 3.2 General Disorders and Administration Site Conditions Edema 0.0 6.5 Chills 2.0 4.8 Pyrexia 2.0 4.8 Malaise 0.0 3.2 Infections and Infestations Pneumonia 0.0 4.8 Sepsis 2.0 4.8 Influenza 3.9 4.8 Musculoskeletal and Connective Tissue Disorders Arthralgia 3.9 4.8 Specific laboratory parameters [i.e., changes in mean Calcium (Ca), Phosphorus (P), and Calcium Phosphorus product (Ca × P)] were followed in an open-label safety study conducted with another paricalcitol injection product for up to 13 months in duration in this patient population and results are shown below [see Clinical Studies ( 14 ) ]. Other Adverse Reactions Associated with Paricalcitol Injection Use The following adverse reactions occurred in less than 2% of the paricalcitol-treated patients in the above mentioned double-blind, placebo-controlled clinical trials and in additional double-blind, active-controlled and open-label studies: Blood and Lymphatic System Disorders: Anemia, lymphadenopathy Cardiac Disorders: Arrhythmia, atrial flutter, cardiac arrest Ear and Labyrinth Disorders: Ear discomfort Endocrine Disorders: Hypoparathyroidism Eye Disorders: Conjunctivitis, glaucoma, ocular hyperemia Gastrointestinal Disorders: Abdominal discomfort, constipation, diarrhea, dysphagia, gastritis, intestinal ischemia, rectal hemorrhage General Disorders and Administration Site Conditions: Asthenia, chest discomfort, chest pain, condition aggravated, edema peripheral, fatigue, feeling abnormal, gait disturbance, injection site extravasation, injection site pain, pain, swelling, thirst Infections and Infestations: Nasopharyngitis, upper respiratory tract infection, vaginal infection Laboratory Investigations and Vital Signs: Increased aspartate aminotransferase, prolonged bleeding time, irregular heart rate, decreased weight Metabolism and Nutrition Disorders: Decreased appetite, hypercalcemia, hyperkalemia, hyperphosphatemia, hypocalcemia Musculoskeletal and Connective Tissue Disorders: Joint stiffness, muscle twitching, myalgia Neoplasms Benign, Malignant and Unspecified : Breast cancer Nervous System Disorders: Cerebrovascular accident, dizziness, dysgeusia, headache, hypoesthesia, myoclonus, paresthesia, syncope, unresponsive to stimuli Psychiatric Disorders: Agitation, confusional state, delirium, insomnia, nervousness, restlessness Reproductive System and Breast Disord …

7 DRUG INTERACTIONS Table 4 includes clinically significant drug interactions with paricalcitol. Table 4: Clinically Significant Drug Interactions with Paricalcitol Drugs that May Increase the risk of Hypercalcemia Clinical Impact 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 dose as needed [see Warnings and Precautions (5.1) ] . Digitalis Compounds Clinical Impact Paricalcitol 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 in patients receiving digitalis compounds [see Warnings and Precautions (5.2) ] . Strong CYP3A Inhibitors Clinical Impact Paricalcitol is partially metabolized by CYP3A. Exposure of paricalcitol will increase upon co-administration 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 may be necessary. Monitor intact PTH and serum calcium concentrations closely. Strong CYP3A Inhibitors: Co-administration with strong CYP3A inhibitors (e.g., ketoconazole) increases paricalcitol exposure. Dose adjustment may be necessary. Closely monitor intact PTH and serum calcium. ( 2.4 , 7 )

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Limited data with paricalcitol 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 (mcg/m 2 ). 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. In the U.S. 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, 0.03, 0.1 or 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 (mcg/m 2 ). Slightly decreased fetal viability was observed in both studies at the highest doses representing 2 and 0.5 times, respectively, a human dose of 0.24 mcg/kg, in the presence of maternal toxicity (decreased body weight and food consumption). Pregnant rats were administered paricalcitol by intravenous injection three times per week at doses of 0, 0.3, 3 or 20 mcg/kg/day throughout gestation, parturition and lactation (GD 6 to lactation day (LD) 20) representing exposures up to 13 times a human dose of 0.24 mcg/kg. 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 a human dose of 0.24 mcg/kg, 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. 8.2 Lactation 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) . Infants exposed to paricalcitol through breast milk should be monitored for signs and symptoms of hypercalcemia (see Clinical Considerations) . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for paricalcitol and any potential adverse effects on the breast-fed child from paricalcitol or from the underlying maternal condition. Clinical Considerations Infants exposed to paricalcitol 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 H] paricalcitol to lactating rats, the concentrations of total radioactivity was determined. Lower l …

12.1 Mechanism of Action Paricalcitol is a synthetic, biologically active vitamin D 2 analog. Preclinical and in vitro studies have demonstrated that paricalcitol’s biological actions are mediated through binding of the vitamin D receptor (VDR), which results in the selective activation of vitamin D responsive pathways. Vitamin D and paricalcitol have been shown to reduce PTH levels by inhibiting PTH synthesis and secretion.

11 DESCRIPTION Paricalcitol, USP, the active ingredient in Paricalcitol Injection, is a synthetically manufactured active vitamin D 2 analog. It is a white powder 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: Paricalcitol Injection is available as a sterile, clear, colorless, aqueous solution for intravenous injection. Each mL contains paricalcitol 2 mcg or 5 mcg and the following inactive ingredients: alcohol, 35% (v/v) and 70% sorbitol solution 7% (v/v) in water for injection. chemical structure

10 OVERDOSAGE Overdosage of Paricalcitol Injection may lead to hypercalcemia, hypercalciuria, hyperphosphatemia, and oversuppression of PTH resulting in adynamic bone disease. [see Warnings and Precautions ( 5 .1 , 5.4 ) ]. 10.1 Treatment of Overdosage and Hypercalcemia The treatment of acute overdosage should consist of supportive measures, discontinuation of drug administration and supplemental calcium, institution of a low calcium diet. Serum calcium levels should be measured until normocalcemia ensues. When serum calcium levels have returned to within normal limits, Paricalcitol Injection may be reinitiated at a lower dose. Paricalcitol is not significantly removed by dialysis.

16 HOW SUPPLIED/STORAGE AND HANDLING Paricalcitol injection, USP is supplied as a sterile, clear, colorless, aqueous solution for intravenous injection. It is available as follows: 2 mcg/ mL (1 mL) (Each 1 mL single-dose vial contains 2 mcg of paricalcitol, USP) 1 mL Single-Dose Vial NDC 70121-1033-1 25 Vials in a Carton NDC 70121-1033-5 10 Vials in a Carton NDC 70121-1033-7 5 mcg/ mL (1 mL) (Each 1 mL single-dose vial contains 5 mcg of paricalcitol, USP) 1 mL Single-Dose Vial NDC 70121-1034-1 25 Vials in a Carton NDC 70121-1034-5 10 Vials in a Carton NDC 70121-1034-7 10 mcg/2 mL (5 mcg/mL) (2 mL) (Each 2 mL single-dose vial contains 10 mcg of paricalcitol, USP) 2 mL Single-Dose Vial NDC 70121-1035-1 25 Vials in a Carton NDC 70121-1035-5 10 Vials in a Carton NDC 70121-1035-7 10 mcg/2 mL (5 mcg/mL) (2 mL) (Each 2 mL multiple-dose vial contains 10 mcg of paricalcitol, USP) 2 mL Multiple-Dose Vial NDC 70121-1036-1 25 Vials in a Carton NDC 70121-1036-5 10 Vials in a Carton NDC 70121-1036-7 Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Discard any unused portion of the single-dose vial after use. The contents of the multiple-dose vial remain stable up to seven days after initial use when stored at controlled room temperature.