PARICALCITOL

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

Paricalcitol Injection is an active vitamin D 2 analogue indicated for the prevention and treatment of secondary hyperparathyroidism associated with chronic kidney disease (CKD) Stage 5. Paricalcitol Injection is an active vitamin D 2 analog indicated for the prevention and treatment of secondary hyperparathyroidism associated with chronic kidney disease Stage 5. ( 1 )

For intravenous use through hemodialysis vascular access port only. The recommended starting dose of Paricalcitol Injection is 0.04 mcg/kg to 0.1 mcg/kg (2.8 – 7 mcg) administered through a hemodialysis vascular access port as a bolus dose at any time during dialysis. Dosing should not occur more frequently than every other day. The drug product should not be injected directly into a vein. Dosage should be individualized. If a satisfactory parathyroid hormone (PTH) lowering response is not observed using the recommended starting dose, the dose may be increased by 2 to 4 mcg every 2 to 4 weeks based on PTH levels (refer to Table 1). Table 1: Suggested Dosage Adjustment PTH Level at Follow-up Visit Dosage Adjustment Above target and PTH increased Increase Above target and PTH decreased by less than 30% Increase Above target and PTH decreased by 30 to 60% No Change Above target and PTH decreased by more than 60% Decrease At target and PTH stable No Change When initiating Paricalcitol Injection or adjusting Paricalcitol Injection dose, measure serum calcium and phosphorus frequently (e.g., twice weekly) and PTH every 2 to 4 weeks. Once a maintenance dose has been established, serum calcium and phosphorus should be measured at least monthly and plasma PTH every 3 months. The recommended starting dose is 0.04 mcg/kg to 0.1 mcg/kg (2.8 – 7 mcg). Administer Paricalcitol Injection as a bolus through a hemodialysis vascular access port at any time during dialysis. Dosing should not occur more frequently than every other day. Do not inject Paricalcitol Injection directly into a vein. Paricalcitol Injection dose should be individualized. If a satisfactory PTH lowering response is not observed with the initial dose, the dose may be increased by 2 to 4 mcg at 2- to 4- week intervals based on parathyroid hormone (PTH) levels. ( 2 ) Suggested Dosage Adjustment PTH Level at Follow-up Visit Dosage Adjustment Above target and PTH increased Increase Above target and PTH decreased by less than 30% Increase Above target and PTH decreased by 30 to 60% No Change Above target and PTH decreased by more than 60% Decrease At target and PTH stable No Change

Paricalcitol Injection is contraindicated in patients with evidence of: Hypercalcemia [see Warnings and Precautions ( 5.1 ) ] Vitamin D toxicity [see Warnings and Precautions ( 5.1 ) ] or Hypersensitivity to paricalcitol or any inactive ingredient in this product [see Adverse Reactions ( 6.2 ) ] Evidence of hypercalcemia, vitamin D toxicity or hypersensitivity. ( 4 )

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 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 another paricalcitol injection product. 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 including rash, urticaria, and angioedema (including laryngeal edema) have been reported.

Co-administration with strong CYP3A inhibitors (e.g. ketoconazole) increases paricalcitol blood levels. See WARNINGS AND PRECAUTIONS. ( 5.3 , 7.1 ) 7.1 Strong CYP3A Inhibitors Paricalcitol is partially metabolized by CYP3A. Paricalcitol blood levels will be increased when paricalcitol is co-administered with strong CYP3A inhibitors. If a patient initiates or discontinues therapy with a strong CYP3A inhibitor, monitor both PTH and serum calcium more frequently and adjust Paricalcitol Injection dose as required [see Clinical Pharmacology ( 12.3 ) ].