1 ML paricalcitol 0.005 MG/ML Injection [Zemplar]

INDICATIONS AND USAGE Paricalcitol is a vitamin D analog indicated in adults for the prevention and treatment of secondary hyperparathyroidism associated with. · Chronic kidney disease (CKD) Stages 3 and 4 ( 1.1 ). · CKD Stage 5 in patients on hemodialysis or peritoneal dialysis ( 1.2 ). 1.1 Chronic Kidney Disease Stages 3 and 4 Paricalcitol capsules are indicated in adults for the prevention and treatment of secondary hyperparathyroidism associated with Chronic Kidney Disease (CKD) Stages 3 and 4. Pediatric use information for patients 10 to 16 years of age is approved for AbbVie Inc.’s Zemplar (paricalcitol) capsules. However, due to AbbVie Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 1.2 Chronic Kidney Disease Stage 5 Paricalcitol capsules are indicated in adults for the prevention and treatment of secondary hyperparathyroidism associated with CKD Stage 5 in patients on hemodialysis (HD) or peritoneal dialysis (PD). Pediatric use information for patients 10 to 16 years of age is approved for AbbVie Inc.’s Zemplar (paricalcitol) capsules. However, due to AbbVie Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information

DOSAGE AND ADMINISTRATION Initial Dosage: CKD Stages 3 and 4 ( 2.1 , 2.3 ) Adult: Baseline iPTH ≤ 500 pg/mL 1 mcg orally daily or 2 mcg three times a week* Adult: Baseline iPTH > 500 pg/mL 2 mcg orally daily or 4 mcg three times a week* Pediatric: Ages 10 to 16 years 1 mcg orally three times a week* Dose Titration: CKD Stages 3 and 4 ( 2.1 , 2.3 ) Adult: iPTH same, increased or decreased by < 30% relative to baseline Increase dose by 1 mcg daily or 2 mcg three times a week* Adult: iPTH decreased by ≥ 30% and ≤ 60% relative to baseline Maintain dose Adult: iPTH decreased by > 60% or iPTH < 60 pg/mL relative to baseline Decrease dose by 1 mcg daily or 2 mcg three times a week* Pediatric: Ages 10 to 16 years Increase each dose by 1 mcg three times a week every 4 weeks or decrease each dose by 1 mcg three times a week at any time based on iPTH, serum calcium and phosphorus levels.* * Not more frequently than every other day when dosing three times a week. Initial Dosage: CKD Stage 5 ( 2.2 , 2.3 ) Adult Dose (micrograms) = baseline iPTH (pg/mL) divided by 80. Administer dose orally three times a week.* Pediatric: Ages 10 to 16 years Dose (micrograms) = baseline iPTH (pg/mL) divided by 120. Administer dose orally three times a week.* Dose Titration: CKD Stage 5 ( 2.2 , 2.3 ) Adult Dose in micrograms is based on most recent iPTH (pg/mL) divided by 80 with adjustments based on serum calcium and phosphorous levels. Dose three times a week.* Pediatric: Ages 10 to 16 years Increase each dose by 1 mcg three times a week every 4 weeks or decrease each dose by 2 mcg three times a week at any time based on iPTH, serum calcium and phosphorus levels.* * Not more frequently than every other day. CKD Stage 5: To avoid hypercalcemia only treat patients after their baseline serum calcium has been reduced to 9.5 mg/dL or lower ( 2.2 ). 2.1 Chronic Kidney Disease Stages 3 and 4 in Adults Administer paricalcitol capsules orally once daily or three times a week [see Clinical Studies (14.1) ]. When dosing three times weekly, do not administer more frequently than every other day. Initial Dose Table 1. Recommended Paricalcitol Capsules Starting Dose Based upon Baseline iPTH Level * To be administered not more often than every other day Baseline iPTH Level Daily Dose Three Times a Week Dose* Less than or equal to 500 pg/mL 1 mcg 2 mcg More than 500 pg/mL 2 mcg 4 mcg Dose Titration Table 2. Recommended Paricalcitol Capsules Dose Titration Base upon iPTH Level * To be administered not more often than every other day Dose Adjustment at 2 to 4 Week Intervals iPTH Level Relative to Baseline Paricalcitol Capsule Dose Daily Dosage Three Times a Week Dosage* The same, increased or decreased by less than 30% Increase dose by 1 mcg 2 mcg Decreased by more than or equal to 30% and less than or equal to 60% Maintain dose - - Decreased by more than 60% or iPTH less than 60 pg/mL Decrease dose by 1 mcg 2 mcg If a patient is taking the lowest dose, 1 mcg, on the daily regimen and a dose reduction is needed, the dose can be decreased to 1 mcg three times a week. If a further dose reduction is required, the drug should be withheld as needed and restarted at a lower dosing frequency. 2.2 Chronic Kidney Disease Stage 5 in Adults Initial Dose Administer the dose of paricalcitol capsules orally three times a week, no more frequently than every other day based upon the following formula: Dose (micrograms) = baseline iPTH (pg/mL) divided by 80 Treat patients only after their baseline serum calcium has been adjusted to 9.5 mg/dL or lower to minimize the risk of hypercalcemia [see Clinical Pharmacology (12.2) and Clinical Studies (14.2) ] . Dose Titration Individualize the dose of paricalcitol capsules based on iPTH, serum calcium and phosphorus levels. Titrate paricalcitol capsules dose based on the following formula: Dose (micrograms) = most recent iPTH level (pg/mL) divided by 80 If serum calcium is elevated, the dose should be decreased by 2 to 4 micrograms. As iPTH approaches the target range, small, individualized dose adjustments may be necessary in order to achieve a stable iPTH. In situations where monitoring of iPTH, Ca or P occurs less frequently than once per week, a more modest initial and dose titration ratio (e.g., iPTH divided by 100) may be warranted. 2.3 Pediatric Patients (Ages 10 to 16 Years) CKD Stages 3 and 4 Initial Dose Administer paricalcitol 1 mcg capsule orally three times a week, no more frequently than every other day. Dose Titration Individualize and titrate paricalcitol capsules dose based on iPTH, serum calcium and phosphorus levels to maintain an iPTH level within target range. Every 4 weeks, each administered paricalcitol capsules dose may be increased in 1 mcg increments, maintaining the three times per week regimen (e.g., increase from 1 mcg three times per week to 2 mcg three times per week). At any time, each administered dose may be decreased by 1 mcg. Paricalcitol capsules may be stopped if the patient requires reduction while receiving 1 mcg three times per week, resuming when appropriate. CKD Stage 5 Initial Dose Administer the dose of paricalcitol capsules orally three times a week, no more frequently than every other day based upon the following formula: Dose* (micrograms) = baseline iPTH (pg/mL) divided by 120 * Round down to the nearest whole number Dose Titration Subsequent dosing should be individualized and based on iPTH, serum calcium and phosphorus levels to maintain an iPTH level within target range. Every 4 weeks, each administered paricalcitol capsules dose may be increased in 1 mcg increments, maintaining the three times per week regimen (e.g., increase from 1 mcg three times per week to 2 mcg three times per week). At any time, each administered dose may be decreased by 2 mcg. Paricalcitol capsules may be stopped if the patient requires reduction while receiving 2 mcg three times per week or 1 mcg three times per week, resuming when appropriate. 2.4 Monitoring Monitor serum calcium and phosphorus levels closely after initiation of paricalcitol capsules, during dose titration periods and during co-administration with strong CYP3A inhibitors [see Warnings and Precautions (5.3) , Drug Interactions (7) , and Clinical Pharmacology (12.3) ] . If hypercalcemia is observed, the dose of paricalcitol capsules should be reduced or withheld until these parameters are normalized. 2.5 Administration Paricalcitol capsules may be taken without regard to food.

WARNINGS AND PRECAUTIONS Hypercalcemia : The risk may be increased when Paricalcitol Injection is used concomitantly with high dose calcium preparations, thiazide diuretics, or metabolically inactive or active forms of vitamin D. Monitor serum calcium when using Paricalcitol Injection and adjust dose accordingly. ( 5.1 ) Digitalis Toxicity : Hypercalcemia increases the risk of digitalis toxicity. In patients using Paricalcitol Injection concomitantly with digitalis compounds, monitor both serum calcium and patients for signs and symptoms of digitalis toxicity and increase frequency of monitoring when initiating or adjusting the dose of Paricalcitol Injection. ( 5.2 ) Risk of Increased Paricalcitol Levels With Concomitant Use of Strong CYP3A Inhibitors : Use of Paricalcitol Injection with strong CYP3A inhibitors increases the concentration of paricalcitol in the blood. In patients on Paricalcitol Injection who are initiating or discontinuing drugs known to be strong CYP3A inhibitors, monitor serum calcium and PTH more frequently and adjust Paricalcitol Injection dose as required. ( 5.3 ) Adynamic Bone Disease : May develop if PTH levels are suppressed to abnormally low levels. Monitor PTH levels and adjust Paricalcitol Injection accordingly. ( 5.4 ) 5.1 Hypercalcemia Hypercalcemia may occur during Paricalcitol Injection treatment and may be exacerbated by concomitant administration of high doses of calcium containing preparations, thiazide diuretics, or vitamin D (i.e., all forms). Acute hypercalcemia may exacerbate tendencies for cardiac arrhythmias and seizures and may potentiate the effect of digitalis on the heart. Chronic hypercalcemia can lead to generalized vascular calcification and other soft-tissue calcification. Hypercalcemia may be so severe as to require emergency attention. High intake of calcium and phosphate concomitantly with vitamin D compounds may lead to hypercalcemia, hypercalciuria, and hyperphosphatemia. Prevention of such adverse reactions requires frequent serum calcium monitoring and careful Paricalcitol Injection dose adjustments. Concomitant use with other active vitamin D analogues should be avoided during Paricalcitol Injection treatment to prevent hypercalcemia. Patients also should be informed about the symptoms of elevated calcium, which include feeling tired, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination and weight loss. 5.2 Digitalis Toxicity Hypercalcemia of any cause increases the risk of digitalis toxicity. In patients using Paricalcitol Injection concomitantly with digitalis compounds, monitor both serum calcium and patients for signs and symptoms of digitalis toxicity and increase frequency of monitoring when initiating or adjusting the dose of Paricalcitol Injection [see Dosage and Administration ( 2 ) ]. 5.3 Risk of Increased Paricalcitol Levels With Concomitant Use of Strong CYP3A Inhibitors Concomitant use of Paricalcitol Injection with strong CYP3A inhibitors will increase the levels of paricalcitol in the blood. In patients on Paricalcitol Injection who are initiating or discontinuing therapy with drugs known to be strong CYP3A inhibitors, monitor serum calcium and PTH more frequently and adjust Paricalcitol Injection dose as required [see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 ) ]. 5.4 Adynamic Bone Disease Adynamic bone disease with subsequent increased risk of fractures may develop if PTH levels are suppressed to abnormally low levels. Monitor PTH levels and adjust Paricalcitol Injection dose [see Dosage and Administration ( 2 ) ].

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 other inactive ingredient. ( 4 )

CLINICAL PHARMACOLOGY Secondary hyperparathyroidism is characterized by an elevation in parathyroid hormone (PTH) associated with inadequate levels of active vitamin D hormone. The source of vitamin D in the body is from synthesis in the skin as vitamin D 3 and from dietary intake as either vitamin D 2 or D 3 . Both vitamin D 2 and D 3 require two sequential hydroxylations in the liver and the kidney to bind to and to activate the vitamin D receptor (VDR). The endogenous VDR activator, calcitriol [1,25(OH) 2 D 3 ], is a hormone that binds to VDRs that are present in the parathyroid gland, intestine, kidney, and bone to maintain parathyroid function and calcium and phosphorus homeostasis, and to VDRs found in many other tissues, including prostate, endothelium and immune cells. VDR activation is essential for the proper formation and maintenance of normal bone. In the diseased kidney, the activation of vitamin D is diminished, resulting in a rise of PTH, subsequently leading to secondary hyperparathyroidism and disturbances in the calcium and phosphorus homeostasis. Decreased levels of 1,25(OH) 2 D 3 have been observed in early stages of chronic kidney disease. The decreased levels of 1,25(OH) 2 D 3 and resultant elevated PTH levels, both of which often precede abnormalities in serum calcium and phosphorus, affect bone turnover rate and may result in renal osteodystrophy. 12.1 Mechanism of Action Paricalcitol is a synthetic, biologically active vitamin D 2 analog of calcitriol. Preclinical and in vitro studies have demonstrated that paricalcitol's biological actions are mediated through binding of the VDR, which results in the selective activation of vitamin D responsive pathways. Vitamin D and paricalcitol have been shown to reduce parathyroid hormone levels by inhibiting PTH synthesis and secretion. 12.2 Pharmacodynamics Paricalcitol decreases serum intact parathyroid hormone (iPTH) and increases serum calcium and serum phosphorous in both HD and PD patients. This observed relationship was quantified using a mathematical model for HD and PD patient populations separately. Computer-based simulations of 100 trials in HD or PD patients (N = 100) using these relationships predict slightly lower efficacy (at least two consecutive ≥ 30% reductions from baseline iPTH) with lower hypercalcemia rates (at least two consecutive serum calcium ≥ 10.5 mg/dL) for lower iPTH-based dosing regimens. Further lowering of hypercalcemia rates was predicted if the treatment with paricalcitol is initiated in patients with lower serum calcium levels at screening. Based on these simulations, a dosing regimen of iPTH/80 with a screening serum calcium ≤ 9.5 mg/dL, approximately 76.5% (95% CI: 75.6% – 77.3%) of HD patients are predicted to achieve at least two consecutive weekly ≥ 30% reductions from baseline iPTH over a duration of 12 weeks. The predicted incidence of hypercalcemia is 0.8% (95% CI: 0.7% – 1.0%). In PD patients, with this dosing regimen, approximately 83.3% (95% CI: 82.6% – 84.0%) of patients are predicted to achieve at least two consecutive weekly ≥ 30% reductions from baseline iPTH. The predicted incidence of hypercalcemia is 12.4% (95% CI: 11.7% - 13.0%) [ see Clinical Studies ( 14.2 ) and Dosage and Administration ( 2.2 )]. 12.3 Pharmacokinetics Absorption The mean absolute bioavailability of paricalcitol capsules under low-fat fed condition ranged from 72% to 86% in healthy adult volunteers, CKD Stage 5 patients on HD, and CKD Stage 5 patients on PD. A food effect study in healthy adult volunteers indicated that the C max and AUC 0-∞ were unchanged when paricalcitol was administered with a high fat meal compared to fasting. Food delayed T max by about 2 hours. The AUC 0-∞ of paricalcitol increased proportionally over the dose range of 0.06 to 0.48 mcg/kg in healthy adult volunteers. Distribution Paricalcitol is extensively bound to plasma proteins (≥ 99.8%). The mean apparent volume of distribution following a 0.24 mcg/kg dose of paricalcitol in healthy adult volunteers was 34 L. The mean apparent volume of distribution following a 4 mcg dose of paricalcitol in CKD Stage 3 and a 3 mcg dose in CKD Stage 4 patients is between 44 and 46 L. Metabolism After oral administration of a 0.48 mcg/kg dose of 3 H-paricalcitol, parent drug was extensively metabolized, with only about 2% of the dose eliminated unchanged in the feces, and no parent drug was found in the urine. Several metabolites were detected in both the urine and feces. Most of the systemic exposure was from the parent drug. Two minor metabolites, relative to paricalcitol, were detected in human plasma. One metabolite was identified as 24(R)-hydroxy paricalcitol, while the other metabolite was unidentified. The 24(R)-hydroxy paricalcitol is less active than paricalcitol in an in vivo rat model of PTH suppression. In vitro data suggest that paricalcitol is metabolized by multiple hepatic and non-hepatic enzymes, including mitochondrial CYP24, as well as CYP3A4 and UGT1A4. The identified metabolites include the product of 24(R)-hydroxylation, 24,26- and 24,28-dihydroxylation and direct glucuronidation. Elimination Paricalcitol is eliminated primarily via hepatobiliary excretion; approximately 70% of the radiolabeled dose is recovered in the feces and 18% is recovered in the urine. While the mean elimination half-life of paricalcitol is 4 to 6 hours in healthy adult volunteers, the mean elimination half-life of paricalcitol in CKD Stages 3, 4, and 5 (on HD and PD) patients ranged from 14 to 20 hours. Table 7. Paricalcitol Capsule Pharmacokinetic Parameters (mean ± SD) in CKD Stages 3, 4, and 5 Adult Patients Pharmacokinetic Parameters CKD Stage 3 n = 15* CKD Stage 4 n = 14* CKD Stage 5 HD** n = 14 CKD Stage 5 PD** n = 8 HD: hemodialysis; PD: peritoneal dialysis. * Four mcg paricalcitol capsules were given to CKD Stage 3 patients; three mcg paricalcitol capsules were given to CKD Stage 4 patients. ** CKD Stage 5 HD and PD patients received a 0.24 mcg/kg dose of paricalcitol as capsules. C max (ng/mL) 0.11 ± 0.04 0.06 ± 0.01 0.575 ± 0.17 0.413 ± 0.06 AUC 0-∞ (ng • h/mL) 2.42 ± 0.61 2.13 ± 0.73 11.67 ± 3.23 13.41 ± 5.48 CL/F (L/h) 1.77 ± 0.50 1.52 ± 0.36 1.82 ± 0.75 1.76 ± 0.77 V/F (L) 43.7 ± 14.4 46.4 ± 12.4 38 ± 16.4 48.7 ± 15.6 t 1/2 16.8 ± 2.65 19.7 ± 7.2 13.9 ± 5.1 17.7 ± 9.6 Specific Populations Geriatric The pharmacokinetics of paricalcitol has not been investigated in geriatric patients greater than 65 years [ see Use in Specific Populations ( 8.5 ) ]. Pediatric Pediatric use information for patients 10 to 16 years of age is approved for AbbVie Inc.’s Zemplar (paricalcitol) capsules. However, due to AbbVie Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. Gender The pharmacokinetics of paricalcitol following single doses over the 0.06 to 0.48 mcg/kg dose range was gender independent. Hepatic Impairment The disposition of paricalcitol (0.24 mcg/kg) was compared in patients with mild (n = 5) and moderate (n = 5) hepatic impairment (as indicated by the Child-Pugh method) and subjects with normal hepatic function (n = 10). The pharmacokinetics of unbound paricalcitol was similar across the range of hepatic function evaluated in this study. No dose adjustment is required in patients with mild and moderate hepatic impairment. The influence of severe hepatic impairment on the pharmacokinetics of paricalcitol has not been evaluated. Renal Impairment Following administration of paricalcitol capsules, the pharmacokinetic profile of paricalcitol for CKD Stage 5 on HD or PD was comparable to that in CKD 3 or 4 patients. Therefore, no special dose adjustments are required other than those recommended in the Dosage and Administration section [ see Dosage and Administration ( 2 ) ]. Drug Interactions An in vitro study indicates that paricalcitol is neither an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A nor an inducer of