PARICALCITOL

Paricalcitol, USP, is a synthetically manufactured active vitamin D 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: Molecular formula is C 27 H 44 O 3 . Molecular weight is 416.64. Paricalcitol Injection is a sterile, clear, colorless, aqueous solution for intravenous use. Each mL contains paricalcitol, 2 mcg or 5 mcg and the following inactive ingredients: alcohol, 35% (v/v) and propylene glycol, 30% (v/v). 1

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.

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 ) Do not inject Paricalcitol Injection directly into a vein ( 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. Do not inject Paricalcitol Injection directly into a vein. 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 Pediatric Patients 5 Years of Age and Above 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 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. 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 2). Prior to raising the dose, ensure serum calcium is within normal limits. 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 2: Recommended Paricalcitol Injection Pediatric Dose Titration Based Upon intact PTH – Patients 5 years of age and older Intact PTH Level At Follow-up Visit Dosage Adjustment Above target and intact PTH decreased by less than 30% Increase by 0.04 mcg/kg every 2 to 4 weeks Intact PTH 150 pg/mL or greater and decreased by 30% to 60% No Change Intact PTH less than 150 pg/mL or decreased by more than 60% Decrease by 0.04 mcg/kg weekly, or by 50% if decreased dose equals zero 2.4 Drug Interactions that May Require Dosage Adjustments of Paricalcitol Injection 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) ] .

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 other inactive ingredient. ( 4 )

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 Accord Healthcare Inc. at 1-866-941-7875 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. The safety of Paricalcitol Injection has been established from adequate and well-controlled studies of another paricalcitol injection product [see Clinical Studies (14) ] . Below is a display of the adverse reactions of paricalcitol injection in these adequate and well-controlled studies. 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. 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: Anemia, lymphadenopathy Cardiac Disorders: Arrhythmia, atrial flutter, irregular heart rate, cardiac arrest, chest discomfort, chest pain, edema peripheral 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: Asthenia, condition aggravated, fatigue, feeling abnormal, pain, swelling Infections: Nasopharyngitis, upper respiratory tract infection, vaginal infection Injection site reactions: Injection site extravasation, injection site pain Laboratory abnormalities: Hypercalcemia, hyperkalemia, hyperphosphatemia, hypocalcemia, increased aspartate aminotransferase, prolonged bleeding time Metabolism and Nutrition Disorders: Decreased appetite, thirst, decreased weight 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, gait disturbance Psychiatric Disorders: Agitation, confusional state, delirium, insomnia, nervousness, restlessness Reproductive System and Breast Disorders: Breast pain, erectile dysfunction Respiratory, Thoracic and Mediastinal Disorders: Cough, dyspnea, orthopnea, pulmonary edema, wheezing Skin and Subcutaneous Tissue Disorders: Alopecia, blister, hirsutism, night sweats, rash pruritic, pruritus, skin burning sensation Vascular Disorders: Hypertension, hypotension 6.2 Postmarketing Experience 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.

Table 4 includes clinically significant drug interactions with Paricalcitol Injection. Table 4: Clinically Significant Drug Interactions with Paricalcitol Injection 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 Injection dose as needed [see Warnings and Precautions (5.1) ] . Digitalis Compounds Clinical Impact 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 Impact 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 Clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, 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. Strong CYP3A Inhibitors: Co-administration with strong CYP3A inhibitors (e.g., ketoconazole) increases Paricalcitol Injection exposure. Dose adjustment may be necessary. Closely monitor intact PTH and serum calcium. ( 2.4 , 7 )