Zemplar

1 INDICATIONS AND USAGE ZEMPLAR 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. ZEMPLAR 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 ZEMPLAR 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 ZEMPLAR 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 ZEMPLAR intravenously through a hemodialysis vascular access port at any time during dialysis. ZEMPLAR may be administered intravenously if an access port is unavailable. Inspect ZEMPLAR 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 ZEMPLAR 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 ZEMPLAR 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 ZEMPLAR 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 ZEMPLAR 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 ZEMPLAR as an intravenous bolus dose of: ○ 0.04 mcg/kg if baseline intact PTH is less …

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

4 CONTRAINDICATIONS ZEMPLAR 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 ZEMPLAR. 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 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 AbbVie Inc. at 1-800-633-9110 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 ZEMPLAR 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 ZEMPLAR and 2.0% of patients treated with placebo. Adverse reactions occurring with greater frequency in the ZEMPLAR 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) % ZEMPLAR (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 ZEMPLAR 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 ZEMPLAR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency …

7 DRUG INTERACTIONS Table 4 includes clinically significant drug interactions with ZEMPLAR. Table 4. Clinically Significant Drug Interactions with ZEMPLAR 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 ZEMPLAR dose as needed [see Warnings and Precautions ( 5.1 )] . Digitalis Compounds Clinical Impact ZEMPLAR 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 ZEMPLAR in patients receiving digitalis compounds [see Warnings and Precautions ( 5.2 )]. Strong CYP3A Inhibitors Clinical Impact ZEMPLAR is partially metabolized by CYP3A. Exposure of ZEMPLAR 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 ZEMPLAR may be necessary. Monitor intact PTH and serum calcium concentrations closely. Strong CYP3A Inhibitors: Co-administration with strong CYP3A inhibitors (e.g., ketoconazole) increases ZEMPLAR 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 ZEMPLAR 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 ZEMPLAR 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 ZEMPLAR and any potential adverse effects on the breast-fed child from ZEMPLAR or from the underlying maternal condition. Clinical Considerations Infants exposed to ZEMPLAR 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 levels of total radioac …

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, 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. ZEMPLAR (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, 20% (v/v) and propylene glycol, 30% (v/v). structural formula

10 OVERDOSAGE Overdosage of ZEMPLAR 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.

16 HOW SUPPLIED/STORAGE AND HANDLING ZEMPLAR injection is a clear, colorless solution available in cartons of 25 vials as follows: Table 7. ZEMPLAR Presentations Total Strength per Total Volume Strength per mL Total Vial Volume and Vial Type NDC No. 2 mcg/mL 2 mcg/mL 1 mL single-dose vial 0074-4637-01 5 mcg/mL 5 mcg/mL 1 mL single-dose vial 0074-1658-01 10 mcg/2 mL 5 mcg/mL 2 mL multiple-dose vial 0074-1658-05 Store at 25°C (77°F). Excursions permitted between 15° to 30°C (59° to 86°F). 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.