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 Pediatric…

5 WARNINGS AND PRECAUTIONS Hypercalcemia : Can occur during treatment with paricalcitol and can lead to cardiac arrhythmias and seizures. Severe hypercalcemia may require emergency attention. The risk may be increased when paricalcitol is used concomitantly with high dose calcium preparations, thiazide diuretics, or vitamin D compounds. Inform patients about symptoms of hypercalcemia and monitor serum calcium prior to initiation and during treatment and adjust dose accordingly ( 2 , 5.1 ). Digitalis toxicity : Risk increases with hypercalcemia. In patients using digitalis compounds, monitor both serum calcium and patients for signs and symptoms of digitalis toxicity. Monitor more frequently when initiating or adjusting the dose of paricalcitol ( 5.2 ). Adynamic Bone Disease : May develop and increase risk of fractures if intact PTH levels are suppressed to abnormally low levels. Monitor intact PTH levels and adjust dose if needed ( 5.3 ). 5.1 Hypercalcemia Hypercalcemia may occur during paricalcitol treatment. Acute hypercalcemia may increase the risk of cardiac arrhythmias and seizures and may potentiate the effect of digitalis on the heart [see Warnings and Precautions (5.2) ] . Chronic hypercalcemia can lead to generalized vascular calcification and other soft-tissue calcification. Severe hypercalcemia may require emergency attention. Hypercalcemia may be exacerbated by concomitant administration of high doses of calcium-containing preparations, thiazide diuretics, or other vitamin D compounds [see Drug Interactions (7) ]. In addition, high intake of calcium and phosphate concomitantly with vitamin D compounds may lead to hypercalciuria and hyperphosphatemia. Patients with a history of hypercalcemia prior to initiating therapy may be at increased risk for development of hypercalcemia with paricalcitol. In these circumstances, frequent serum calcium monitoring and paricalcitol dose adjustments may be required. When initiating paricalcitol or adjusting paricalcitol dose, measure serum calcium frequently (e.g., twice weekly). Once a maintenance dose has been established, measure serum calcium at least monthly . If hypercalcemia occurs, reduce the dose or discontinue paricalcitol until serum calcium is normal [see Dosage and Administration (2.2 , 2.3) ] . Inform patients about the symptoms of elevated calcium (feeling tired, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination and weight loss) and instruct them to report new or worsening symptoms when they occur. 5.2 Digitalis Toxicity Paricalcitol can cause hypercalcemia [see Warnings and Precautions (5.1) ] which increases the risk of digitalis toxicity. In patients using paricalcitol concomitantly with digitalis compounds, monitor serum calcium and patients for signs and symptoms of digitalis toxicity. Increase the frequency of monitoring when initiating or adjusting the dose of paricalcitol [see Drug Interactions (7) ] . 5.3 Adynamic Bone Disease Adynamic bone disease with subsequent increased risk of fractures may develop if intact PTH levels are suppressed by paricalcitol to abnormally low levels. Monitor intact PTH levels to avoid over suppression and adjust paricalcitol dose, if needed [see Dosage and Administration (2.2 , 2.3) ] .

4 CONTRAINDICATIONS Paricalcitol 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. 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 ).

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 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 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 ).

8.1 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 (mg/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 (mg/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.

6 ADVERSE REACTIONS 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 Eugia US LLC at 1-866-850-2876 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. 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 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 and 2.0% of patients treated with placebo. Adverse reactions occurring with greater frequency in the paricalcitol 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 (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 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. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reli…