SPL UNCLASSIFIED SECTION.

1.1 Chronic Kidney Disease Stages and . Paricalcitol Capsules are indicated for the prevention and treatment of secondary hyperparathyroidism associated with Chronic Kidney Disease (CKD) Stages and 4.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.. The most common adverse reactions (> 5% and more frequent than placebo) include diarrhea, hypertension, dizziness and vomiting. To report SUSPECTED ADVERSE REACTIONS, contact ECI Pharmaceuticals, LLC at 954-486-8181 X-109 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience CKD Stages and The safety of Paricalcitol Capsules has been evaluated in three 24-week (approximately six-month), double-blind, placebo-controlled, multicenter clinical studies involving 220 CKD Stages and patients. Six percent (6%) of Paricalcitol Capsules treated patients and 4% of placebo treated patients discontinued from clinical studies due to an adverse event. Adverse events occurring in the Paricalcitol Capsules group at frequency of 2% or greater and more frequently than in the placebo group are presented in Table 1: Table 1: Treatment-Emergent Adverse Events by Body System Occurring in >= 2% of Subjects in the Paricalcitol-Treated Group of Three, Double-Blind, Placebo-Controlled, Phase 3, CKD Stages and Studies; All Treated PatientsNumber (%) of SubjectsAdverse Event Includes only events more common in the Paricalcitol treatment group.Paricalcitol Capsules(n=107)Placebo(n=113)Overall 88(82%)86(76%)Ear and Labyrinth Disorders Vertigo (4.7%) (0.0%) Gastrointestinal Disorders Abdominal Discomfort (3.7%) (0.9%) Constipation (3.7%) (3.5%) Diarrhea (6.5%) (4.4%) Nausea (5.6%) (3.5%) Vomiting (4.7%) (4.4%) General Disorders and Administration Site Conditions Chest Pain (2.8%) (0.9%) Edema (5.6%) (4.4%) Pain (3.7%) (3.5%) Immune System Disorders Hypersensitivity (5.6%) (1.8%) Infections and Infestations Fungal Infection (2.8%) (0.0%) Gastroenteritis (2.8%) (2.7%) Infection (2.8%) (2.7%) Sinusitis (2.8%) (0.9%) Urinary Tract Infection (2.8%) (0.9%) Viral Infection (7.5%) (7.1%) Metabolism and Nutrition Disorders Dehydration (2.8%) (0.9%) Musculoskeletal and Connective Tissue Disorders Arthritis (4.7%) (0.0%) Back Pain (2.8%) (0.9%) Muscle Spasms (2.8%) (0.0%) Nervous System Disorders Dizziness (4.7%) (4.4%) Headache (4.7%) (4.4%) Syncope (2.8%) (0.9%) Psychiatric Disorders Depression (2.8%) (0.0%) Respiratory, Thoracic and Mediastinal Disorders Cough (2.8%) (1.8%) Oropharyngeal Pain (3.7%) (0.0%) Skin and Subcutaneous Tissue Disorders Pruritus (2.8%) (2.7%) Rash (3.7%) (0.9%) Skin Ulcer (2.8%) (0.0%) Vascular Disorders Hypertension (6.5%) (3.5%) Hypotension (4.7%) (2.7%) The following adverse reactions, with causal relationship to Paricalcitol, occurred in <2% of the Paricalcitol treated patients in the above double-blind, placebo-controlled clinical trial data set.Gastrointestinal Disorders: Dry mouth Investigations: Hepatic enzyme abnormal Nervous System Disorders: Dysgeusia Skin and Subcutaneous Tissue Disorders: Urticaria CKD Stage The safety of Paricalcitol Capsules has been evaluated in one 12-week, double-blind, placebo-controlled, multicenter clinical study involving 88 CKD Stage patients. Sixty-one patients received Paricalcitol Capsules and 27 patients received placebo.The proportion of patients who terminated prematurely from the study due to adverse events was 7% for Paricalcitol Capsules treated patients and 7% for placebo patients.Adverse events occurring in the Paricalcitol Capsules group at frequency of 2% or greater and more frequently than in the placebo group are as follows: Table 2. Treatment-Emergent Adverse Events by Body System Occurring in >= 2% of Subjects in the Paricalcitol-Treated Group, Double- Blind, Placebo-Controlled, Phase 3, CKD Stage Study; All Treated PatientsNumber (%) of SubjectsAdverse EventsIncludes only events more common in the Paricalcitol treatment group. Paricalcitol Capsules(n=61)Placebo(n=27)Overall 43(70%)19(70%)Gastrointestinal Disorders Constipation (4.9%) (0.0%) Diarrhea (11.5%) (11.1%) Vomiting (6.6%) (0.0%) General Disorders and Administration Site Conditions Fatigue (3.3%) (0.0%) Edema Peripheral (3.3%) (0.0%) Infections and Infestations Nasopharyngitis (8.2%) (7.4%) Peritonitis (4.9%) (0.0%) Sinusitis (3.3%) (0.0%) Urinary Tract Infection (3.3%) (0.0%) Metabolism and Nutrition Disorders Fluid Overload (4.9%) (0.0%) Hypoglycemia (3.3%) (0.0%) Nervous System Disorders Dizziness (6.6%) (0.0%) Headache (3.3%) (0.0%) Psychiatric Disorders Anxiety (3.3%) (0.0%) Insomnia (4.9%) (0.0%) Renal and Urinary Disorders Renal Failure Chronic (3.3%) (0.0%) The following adverse reactions, with causal relationship to Paricalcitol, occurred in <2% of the Paricalcitol treated patients in the above double-blind, placebo-controlled clinical trial data set.Gastrointestinal Disorders: Gastroesophageal reflux disease Metabolism and Nutrition Disorders: Decreased appetite, hypercalcemia, hypocalcemia Reproductive System and Breast Disorders: Breast tenderness Skin and Subcutaneous Tissue Disorders: Acne 6.2 Postmarketing Experience. The following additional adverse reactions have been reported during post-approval use and post-approval clinical trials with the active ingredient in Paricalcitol Capsules:Immune System Disorders: Angioedema (including laryngeal edema) Metabolism and Nutrition Disorders: Hypercalcemia Investigations: Blood creatinine increased.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY Secondary hyperparathyroidism is characterized by an elevation in parathyroid hormone (PTH) associated with inadequate levels of active vitamin hormone. The source of vitamin in the body is from synthesis in the skin as vitamin 3 and from dietary intake as either vitamin 2 or 3. Both vitamin 2 and 3 require two sequential hydroxylations in the liver and the kidney to bind to and to activate the vitamin receptor (VDR). The endogenous VDR activator, calcitriol [1,25(OH) 2D 3], is 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 is diminished, resulting in rise of PTH, subsequently leading to secondary hyperparathyroidism and disturbances in the calcium and phosphorus homeostasis. Decreased levels of 1,25(OH) 2D have been observed in early stages of chronic kidney disease. The decreased levels of 1,25(OH) 2D 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 synthetic, biologically active vitamin 2 analog of calcitriol. Preclinical and in vitro studies have demonstrated that paricalcitols biological actions are mediated through binding of the VDR, which results in the selective activation of vitamin responsive pathways. Vitamin 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 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, dosing regimen of iPTH/80 with 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 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 AbsorptionThe mean absolute bioavailability of Paricalcitol Capsules under low-fat fed condition ranged from 72% to 86% in healthy subjects, CKD Stage patients on HD, and CKD Stage patients on PD. food effect study in healthy subjects indicated that the max and AUC 0- were unchanged when paricalcitol was administered with high fat meal compared to fasting. Food delayed max by about hours. The AUC 0- of paricalcitol increased proportionally over the dose range of 0.06 to 0.48 mcg/kg in healthy subjects. DistributionParicalcitol is extensively bound to plasma proteins (>= 99.8%). The mean apparent volume of distribution following 0.24 mcg/kg dose of paricalcitol in healthy subjects was 34 L. The mean apparent volume of distribution following 4 mcg dose of paricalcitol in CKD Stage and 3 mcg dose in CKD Stage patients is between 44 and 46 L.MetabolismAfter oral administration of 0.48 mcg/kg dose of 3H-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. EliminationParicalcitol 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 to hours in healthy subjects, the mean elimination half-life of paricalcitol in CKD Stages 3, 4, and (on HD and PD) patients ranged from 14 to 20 hours. Table 3. Paricalcitol Capsule Pharmacokinetic Characteristics in CKD Stages 3, 4, and PatientsPharmacokinetic ParametersCKD Stage n 15CKD Stage n 14CKD Stage HDn 14CKD Stage PDn 8C max (ng/mL) 0.11 +- 0.04 0.06 +- 0.01 0.575 +- 0.17 0.413 +- 0.06 AUC 0- (ngoh/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 1/2 16.8 +- 2.65 19.7 +- 7.2 13.9 +- 5.1 17.7 +- 9.6 Four mcg Paricalcitol Capsules were given to CKD Stage patients; three mcg Paricalcitol Capsules were given to CKD Stage patients. CKD Stage HD and PD patients received 0.24 mcg/kg dose of paricalcitol as capsules. Specific PopulationsGeriatric The pharmacokinetics of paricalcitol has not been investigated in geriatric patients greater than 65 years see Use in Specific Populations (8.5)]. Pediatric The pharmacokinetics of paricalcitol has not been investigated in patients less than 18 years of age.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 on HD or PD was comparable to that in CKD or 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 CYP2B6, CYP2C9 or CYP3A. Hence, paricalcitol is neither expected to inhibit nor induce the clearance of drugs metabolized by these enzymes. OmeprazoleThe effect of omeprazole (40 mg capsule), strong inhibitor of CYP2C19, on paricalcitol (four mcg capsules) pharmacokinetics was investigated in single dose, crossover study in healthy subjects. The pharmacokinetics of paricalcitol was not affected when omeprazole was administered approximately hours prior to the paricalcitol dose.KetoconazoleThe effect of multiple doses of ketoconazole, strong inhibitor of CYP3A, administered as 200 mg BID for days on the pharmacokinetics of paricalcitol (4 mcg capsule) has been studied in healthy subjects. The max of paricalcitol was minimally affected, but AUC 0- approximately doubled in the presence of ketoconazole. The mean half-life of paricalcitol was 17.0 hours in the presence of ketoconazole as compared to 9.8 hours, when paricalcitol was administered alone see Drug Interactions (7)].

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES 14.1 Chronic Kidney Disease Stages and . The safety and efficacy of Paricalcitol Capsules were evaluated in three, 24-week, double blind, placebo-controlled, randomized, multicenter, Phase clinical studies in CKD Stages and patients. Two studies used an identical three times week dosing design, and one study used daily dosing design. total of 107 patients received Paricalcitol Capsules and 113 patients received placebo. The mean age of the patients was 63 years, 68% were male, 71% were Caucasian, and 26% were African-American. The average baseline iPTH was 274 pg/mL (range: 145-856 pg/mL). The average duration of CKD prior to study entry was 5.7 years. At study entry 22% were receiving calcium based phosphate binders and/or calcium supplements. Baseline 25-hydroxyvitamin levels were not measured.The initial dose of Paricalcitol Capsules was based on baseline iPTH. If iPTH was <= 500 pg/mL, Paricalcitol Capsules were administered mcg daily or mcg three times week, not more than every other day. If iPTH was 500 pg/mL, Paricalcitol Capsules were administered mcg daily or mcg three times week, not more than every other day. The dose was increased by mcg daily or mcg three times week every to weeks until iPTH levels were reduced by at least 30% from baseline. The overall average weekly dose of Paricalcitol Capsules was 9.6 mcg/week in the daily regimen and 9.5 mcg/week in the three times week regimen.In the clinical studies, doses were titrated for any of the following reasons: if iPTH fell to 60 pg/mL, or decreased 60% from baseline, the dose was reduced or temporarily withheld; if iPTH decreased 30% from baseline and serum calcium was <= 10.3 mg/dL and serum phosphorus was <= 5.5 mg/dL, the dose was increased; and if iPTH decreased between 30 to 60% from baseline and serum calcium and phosphorus were <= 10.3 mg/dL and <= 5.5 mg/dL, respectively, the dose was maintained. Additionally, if serum calcium was between 10.4 to 11.0 mg/dL, the dose was reduced irrespective of iPTH, and the dose was withheld if serum calcium was 11.0 mg/dL. If serum phosphorus was 5.5 mg/dL, dietary counseling was provided, and phosphate binders could have been initiated or increased. If the elevation persisted, the Paricalcitol Capsules dose was decreased. Seventy-seven percent (77%) of the Paricalcitol Capsules treated patients and 82% of the placebo treated patients completed the 24-week treatment. The primary efficacy endpoint of at least two consecutive >= 30% reductions from baseline iPTH was achieved by 91% of Paricalcitol Capsules treated patients and 13% of the placebo treated patients (p 0.001). The proportion of Paricalcitol Capsules treated patients achieving two consecutive >= 30% reductions was similar between the daily and the three times week regimens (daily: 30/33, 91%; three times week: 62/68, 91%).The incidence of hypercalcemia (defined as two consecutive serum calcium values 10.5 mg/dL), and hyperphosphatemia in Paricalcitol Capsules treated patients was similar to placebo. There were no treatment related adverse events associated with hypercalcemia or hyperphosphatemia in the Paricalcitol Capsules group. No increases in urinary calcium or phosphorous were detected in Paricalcitol Capsules treated patients compared to placebo.The pattern of change in the mean values for serum iPTH during the studies is shown in Figure 1. Figure 1. Mean Values for Serum iPTH Over Time in the Three Double-Blind, Placebo-Controlled, Phase 3, CKD Stages and Studies CombinedThe mean changes from baseline to final treatment visit in serum iPTH, calcium, phosphorus, calcium-phosphorus product, and bone-specific alkaline phosphatase are shown in Table 4. Table 4. Mean Changes from Baseline to Final Treatment Visit in Serum iPTH, Bone Specific Alkaline Phosphatase, Calcium, Phosphorus, and Calcium Phosphorus Product in Three Combined Double-Blind, Placebo-Controlled, Phase 3, CKD Stages and StudiesParicalcitol CapsulesPlaceboiPTH (pg/mL) = 104 = 110 Mean Baseline Value 266 279 Mean Final Treatment Value 162 315 Mean Change from Baseline (SE) -104 (9.2) +35 (9.0) Bone Specific Alkaline Phosphatase (mcg/L) = 101 = 107 Mean Baseline 17.1 18.8 Mean Final Treatment Value 9.2 17.4 Mean Change from Baseline (SE) -7.9 (0.76) -1.4 (0.74) Calcium (mg/dL) = 104 = 110 Mean Baseline 9.3 9.4 Mean Final Treatment Value 9.5 9.3 Mean Change from Baseline (SE) +0.2 (0.04) -0.1 (0.04) Phosphorus (mg/dL) = 104 = 110 Mean Baseline 4.0 4.0 Mean Final Treatment Value 4.3 4.3 Mean Change from Baseline (SE) +0.3 (0.08) +0.3 (0.08) Calcium Phosphorus Product (mg 2/dL 2) = 104 = 110 Mean Baseline 36.7 36.9 Mean Final Treatment Value 40.7 39.7 Mean Change from Baseline (SE) +4.0 (0.74) +2.9 (0.72) 6e8fe795-figure-02. 14.2 Chronic Kidney Disease Stage . The safety and efficacy of Paricalcitol Capsules were evaluated in Phase 3, 12-week, double blind, placebo-controlled, randomized, multicenter study in patients with CKD Stage on HD or PD. The study used three times week dosing design. total of 61 patients received Paricalcitol Capsules and 27 patients received placebo. The mean age of the patients was 57 years, 67% were male, 50% were Caucasian, 45% were African-American, and 53% were diabetic. The average baseline iPTH was 701 pg/mL (range: 216-1933 pg/mL). The average time since first dialysis across all subjects was 3.3 years.The initial dose of Paricalcitol Capsules was based on baseline iPTH/60. Subsequent dose adjustments were based on iPTH/60 as well as primary chemistry results that were measured once week. Starting at Treatment Week 2, study drug was maintained, increased or decreased weekly based on the results of the previous weeks calculation of iPTH/60. Paricalcitol Capsules were administered three times week, not more than every other day.The proportion of patients achieving at least two consecutive weekly >= 30% reductions from baseline iPTH was 88% of Paricalcitol Capsules treated patients and 13% of the placebo treated patients. The proportion of patients achieving at least two consecutive weekly >= 30% reductions from baseline iPTH was similar for HD and PD patients.The incidence of hypercalcemia (defined as two consecutive serum calcium values 10.5 mg/dL) in patients treated with Paricalcitol Capsules was 6.6% as compared to 0% for patients given placebo. In PD patients the incidence of hypercalcemia in patients treated with Paricalcitol Capsules was 21% as compared to 0% for patients given placebo. The patterns of change in the mean values for serum iPTH are shown in Figure 2. The rate of hypercalcemia with Paricalcitol Capsules may be reduced with lower dosing regimen based on the iPTH/80 formula as shown by computer simulations. The hypercalcemia rate can be further predicted to decrease, if the treatment is initiated in only those with baseline serum calcium <= 9.5 mg/dL see Clinical Pharmacology (12.2) and Dosage and Administration (2.2)]. Figure 2. Mean Values for Serum iPTH Over Time in Phase 3, Double-Blind, Placebo-Controlled CKD Stage Study. 6e8fe795-figure-03.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS Paricalcitol Capsules should not be given to patients with evidence ofhypercalcemia orvitamin toxicity [see Warnings and Precautions (5.1)]. hypercalcemia or. vitamin toxicity [see Warnings and Precautions (5.1)]. Evidence of hypercalcemia or vitamin toxicity 4).

DESCRIPTION SECTION.

11 DESCRIPTION Paricalcitol, USP, the active ingredient in Paricalcitol Capsules, is synthetically manufactured, metabolically active vitamin analog of calcitriol with modifications to the side chain (D 2) and the (19-nor) ring. Paricalcitol is indicated for the prevention and treatment of secondary hyperparathyroidism in chronic kidney disease. Paricalcitol is available as soft gelatin capsules for oral administration containing microgram, micrograms or micrograms of paricalcitol. Each capsule also contains medium chain triglycerides, alcohol and butylated hydroxytoluene. The medium chain triglycerides are fractionated from coconut oil or palm kernel oil. The capsule shell is composed of gelatin, glycerin, titanium dioxide, iron oxide red (2 microgram capsules only), iron oxide yellow (2 microgram and microgram capsules), iron oxide black (1 microgram capsules only), and water. The components of imprinting ink: shellac, isopropyl alcohol, ferrosoferric oxide, N-butyl alcohol, propylene glycol, ammonium hydroxide.Paricalcitol is white, crystalline powder with the empirical formula of 27H 44O 3, which corresponds to molecular weight of 416.64. Paricalcitol is chemically designated as 19-nor-1,3,25-trihydroxy-9,10-secoergosta-5(Z),7(E),22(E)-triene and has the following structural formula: 6e8fe795-figure-01.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION CKD Stages and 4: Paricalcitol Capsules may be administered once daily or every other day, three times week 2.1). CKD Stage 5: Paricalcitol Capsules are dosed every other day, three times week 2.2). To minimize the risk of hypercalcemia patients should be treated only after their baseline serum calcium has been reduced to 9.5 mg/dL or lower. Initial Dosage CKD Stages 3, CKD Stage Baseline intact parathyroid (iPTH)Level Starting Dose Dose in micrograms is based on baseline iPTH level (pg/mL)/80. Dose three times week(e.g. every other day). <= 500 pg/mL mcg daily or mcg three times week (e.g. every other day) 500 pg/mL mcg daily or mcg three times week (e.g. every other day) Dose Titration CKD Stages 3, CKD Stage iPTH Level Relative to Baseline DosingRecommendation Dose in micrograms is based on most recent iPTH level (pg/mL)/80 with adjustments based on serum calcium and phosphorous levels. Dose three times week (e.g. every other day). Decreased by 30% Increase dose by mcg daily or mcg three times week (e.g. every other day) Decreased by >= 30% and <= 60% Maintain dose Decreased by 60% or iPTH 60 pg/mL Decrease dose by mcg daily or mcg three times week (e.g. every other day) CKD Stages and 4: Paricalcitol Capsules may be administered once daily or every other day, three times week 2.1). CKD Stage 5: Paricalcitol Capsules are dosed every other day, three times week 2.2). To minimize the risk of hypercalcemia patients should be treated only after their baseline serum calcium has been reduced to 9.5 mg/dL or lower. 2.1 Chronic Kidney Disease Stages and . Paricalcitol Capsules may be administered daily or three times week. When dosing three times weekly, the dose should be administered not more frequently than every other day. The total weekly doses for both daily and three times week dosage regimens are similar see Clinical Studies (14.1)]. Paricalcitol Capsules may be taken without regard to food. No dosing adjustment is required in patients with mild and moderate hepatic impairment.Initial DoseThe initial dose of Paricalcitol Capsules for CKD Stages and patients is based on baseline intact parathyroid hormone (iPTH) levels.Baseline iPTH LevelDaily DoseThree Times Week Dose To be administered not more often than every other day<= 500 pg/mL mcg mcg 500 pg/mL mcg mcg Dose TitrationDosing must be individualized and based on serum or plasma iPTH levels, with monitoring of serum calcium and serum phosphorus. The following is suggested approach to dose titration.Dose Adjustment at to Week IntervalsiPTH Level Relative to Baseline Paricalcitol Capsule DoseDaily DosageThree Times Week Dosage To be administered not more often than every other dayThe same, increased or decreased by 30% Increase dose by mcg mcg Decreased by >= 30% and <= 60% Maintain dose - Decreased by 60% or iPTH 60 pg/mL Decrease dose by mcg mcg If patient is taking the lowest dose, mcg, on the daily regimen and dose reduction is needed, the dose can be decreased to mcg three times week. If further dose reduction is required, the drug should be withheld as needed and restarted at lower dosing frequency. If patient is on calcium-based phosphate binder, the phosphate-binder dose may be decreased or withheld, or the patient may be switched to non-calcium-based phosphate binder. If hypercalcemia is observed, the dose of Paricalcitol should be reduced or withheld until these parameters are normalized.Serum calcium and phosphorus levels should be closely monitored 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)]. 2.2 Chronic Kidney Disease Stage . Paricalcitol Capsules are to be administered three times week, not more frequently than every other day.Paricalcitol Capsules may be taken without regard to food. No dosing adjustment is required in patients with mild and moderate hepatic impairment.Initial DoseThe initial dose of Paricalcitol Capsules in micrograms is based on baseline iPTH level (pg/mL)/80. To minimize the risk of hypercalcemia patients should be treated only after their baseline serum calcium has been adjusted to 9.5 mg/dL or lower [see Clinical Pharmacology (12.2) and Clinical Studies (14.2)]. Dose TitrationSubsequent dosing should be individualized and based on iPTH, serum calcium and phosphorus levels. suggested dose titration of Paricalcitol Capsules is based on the following formula:Titration dose (micrograms) most recent iPTH level (pg/ml)/80Serum calcium and phosphorus levels should be closely monitored after initiation, during dose titration periods, and with co-administration of strong P450 3A inhibitors. If an elevated serum calcium is observed and the patient is on calcium-based phosphate binder, the binder dose may be decreased or withheld, or the patient may be switched to non-calcium-based phosphate binder. If serum calcium is elevated, the dose should be decreased by to micrograms lower than that calculated by the most recent iPTH/80. If further adjustment is required, the dose of Paricalcitol Capsules should be reduced or withheld until these parameters are normalized.As iPTH approaches the target range, small, individualized dose adjustments may be necessary in order to achieve stable iPTH. In situations where monitoring of iPTH, Ca or occurs less frequently than once per week, more modest initial and dose titration ratio (e.g., iPTH/100) may be warranted.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS Paricalcitol Capsules are available as mcg, mcg, and mcg soft gelatin capsules.1 mcg: An oval-shaped, gray soft capsule imprinted with the 1 in black ink.2 mcg: An oval-shaped, orange-brown soft capsule imprinted with the 2 in black ink.4 mcg: An oval-shaped, gold soft capsule imprinted with the 3 in black ink.. mcg: An oval-shaped, gray soft capsule imprinted with the 1 in black ink.. mcg: An oval-shaped, orange-brown soft capsule imprinted with the 2 in black ink.. mcg: An oval-shaped, gold soft capsule imprinted with the 3 in black ink.. Capsules: mcg, mcg, and mcg 3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS Strong CYP3A inhibitors (e.g. ketoconazole) will increase the exposure of paricalcitol. Use with caution 7.1). Cholestyramine, Mineral Oil: Intestinal absorption of Paricalcitol may be reduced if administered simultaneously with mineral oil or cholestyramine 7.2, 7.3). Strong CYP3A inhibitors (e.g. ketoconazole) will increase the exposure of paricalcitol. Use with caution 7.1). Cholestyramine, Mineral Oil: Intestinal absorption of Paricalcitol may be reduced if administered simultaneously with mineral oil or cholestyramine 7.2, 7.3). 7.1 CYP3A Inhibitors. Since paricalcitol is partially metabolized by CYP3A, exposure of paricalcitol will be increased while paricalcitol is co-administered with strong CYP3A inhibitors including the following drugs but not limited to: ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Paricalcitol Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if patient initiates or discontinues therapy with strong CYP3A4 inhibitor [see Clinical Pharmacology (12.3)]. 7.2 Cholestyramine. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Paricalcitol Capsules.. 7.3 Mineral Oil. The use of mineral oil or other substances that may affect absorption of fat may influence the absorption of Paricalcitol Capsules.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Paricalcitol Capsules are available as mcg, mcg, and mcg capsules.The mcg capsule is an oval-shaped, gray, soft capsule imprinted with the 1 in black ink, and is available in the following package size: Bottles of 30 (NDC 40051-612-11)The mcg capsule is an oval-shaped, orange-brown, soft capsule imprinted with the 2 in black ink, and is available in the following package size: Bottles of 30 (NDC 40051-613-11)The mcg capsule is an oval-shaped, gold soft capsule imprinted with the 3 in black ink, and is available in the following package size: Bottles of 30 (NDC 40051-614-11)Storage Store Paricalcitol Capsules at 25C (77F). Excursions permitted between 15 to 30C (59 to 86F). [See USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE Paricalcitol is vitamin analog indicated for the prevention and treatment of secondary hyperparathyroidism associated with Chronic kidney disease (CKD) Stages and ( 1.1). CKD Stage in patients on hemodialysis (HD) or peritoneal dialysis (PD) 1.2). Chronic kidney disease (CKD) Stages and ( 1.1). CKD Stage in patients on hemodialysis (HD) or peritoneal dialysis (PD) 1.2). 1.1 Chronic Kidney Disease Stages and . Paricalcitol Capsules are indicated for the prevention and treatment of secondary hyperparathyroidism associated with Chronic Kidney Disease (CKD) Stages and 4.. 1.2 Chronic Kidney Disease Stage . Paricalcitol Capsules are indicated for the prevention and treatment of secondary hyperparathyroidism associated with CKD Stage in patients on hemodialysis (HD) or peritoneal dialysis (PD).

INFORMATION FOR PATIENTS SECTION.

17 INFORMATION FOR PATIENTS. Patients should be advised:of the most common adverse reactions with use of Paricalcitol Capsules, which include diarrhea, hypertension, dizziness and vomiting.to adhere to instructions regarding diet and phosphorus restriction.to contact health care provider if you develop symptoms of elevated calcium, (e.g. feeling tired, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination and weight loss).to return to the physicians office for routine monitoring. More frequent monitoring is necessary during the initiation of therapy, following dose changes or when potentially interacting medications are started or discontinued.to inform their physician of all medications, including prescription and nonprescription drugs, supplements, and herbal preparations they are taking and any change to their medical condition. Patients should also be advised to inform their physicians prescribing new medication that they are taking Paricalcitol Capsules.Manufactured byLotus Pharmaceutical Co., Ltd. Nantou PlantNo. 30 Chenggong 1st Rd., Sinsing Village,Nantou City, Nantou County 54066 TaiwanRevision date: 12/2016. of the most common adverse reactions with use of Paricalcitol Capsules, which include diarrhea, hypertension, dizziness and vomiting.. to adhere to instructions regarding diet and phosphorus restriction.. to contact health care provider if you develop symptoms of elevated calcium, (e.g. feeling tired, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination and weight loss).. to return to the physicians office for routine monitoring. More frequent monitoring is necessary during the initiation of therapy, following dose changes or when potentially interacting medications are started or discontinued.. to inform their physician of all medications, including prescription and nonprescription drugs, supplements, and herbal preparations they are taking and any change to their medical condition. Patients should also be advised to inform their physicians prescribing new medication that they are taking Paricalcitol Capsules.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis and Impairment of Fertility In 104-week carcinogenicity study in CD-1 mice, an increased incidence of uterine leiomyoma and leiomyosarcoma was observed at subcutaneous doses of 1, 3, 10 mcg/kg given three times weekly (2 to 15 times the AUC at human dose of 14 mcg, equivalent to 0.24 mcg/kg based on AUC). The incidence rate of uterine leiomyoma was significantly different than the control group at the highest dose of 10 mcg/kg. In 104-week carcinogenicity study in rats, there was an increased incidence of benign adrenal pheochromocytoma at subcutaneous doses of 0.15, 0.5, 1.5 mcg/kg (< to times the exposure following human dose of 14 mcg, equivalent to 0.24 mcg/kg based on AUC). The increased incidence of pheochromocytomas in rats may be related to the alteration of calcium homeostasis by paricalcitol. Paricalcitol did not exhibit genetic toxicity in vitro with or without metabolic activation in the microbial mutagenesis assay (Ames Assay), mouse lymphoma mutagenesis assay (L5178Y), or human lymphocyte cell chromosomal aberration assay. There was also no evidence of genetic toxicity in an in vivo mouse micronucleus assay. Paricalcitol had no effect on fertility (male or female) in rats at intravenous doses up to 20 mcg/kg/dose (equivalent to 13 times human dose of 14 mcg based on surface area, mcg/m 2).

OVERDOSAGE SECTION.

10 OVERDOSAGE Excessive administration of Paricalcitol Capsules can cause hypercalcemia, hypercalciuria, and hyperphosphatemia, and over suppression of PTH [see Warnings and Precautions (5.1)]. Treatment of OverdosageThe treatment of acute overdosage of Paricalcitol Capsules should consist of general supportive measures. If drug ingestion is discovered within relatively short time, induction of emesis or gastric lavage may be of benefit in preventing further absorption. If the drug has passed through the stomach, the administration of mineral oil may promote its fecal elimination. Serial serum electrolyte determinations (especially calcium), rate of urinary calcium excretion, and assessment of electrocardiographic abnormalities due to hypercalcemia should be obtained. Such monitoring is critical in patients receiving digitalis. Discontinuation of supplemental calcium and institution of low-calcium diet are also indicated in accidental overdosage. Due to the relatively short duration of the pharmacological action of paricalcitol, further measures are probably unnecessary. If persistent and markedly elevated serum calcium levels occur, there are variety of therapeutic alternatives that may be considered depending on the patients underlying condition. These include the use of drugs such as phosphates and corticosteroids, as well as measures to induce an appropriate forced diuresis.Paricalcitol is not significantly removed by dialysis.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL. NDC40051-612-11Paricalcitol Capsules1 mcgNDC40051-613-11Paricalcitol Capsules2 mcgNDC40051-614-11Paricalcitol Capsules4 mcg. 9960175-4537-450c-947e-923c10daacf8. e43f3f5-2bf4-4897-8cdf-37e708dbe550. edd9e96-0f50-4334-934a-427138346988.

RECENT MAJOR CHANGES SECTION.

Warnings and Precautions, Laboratory tests 5.3) 8/2014.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy. Pregnancy Category C.Paricalcitol has been shown to cause minimal decreases in fetal viability (5%) when administered daily to rabbits at dose 0.5 times human dose of 14 mcg or 0.24 mcg/kg (based on body surface area, mcg/m 2), and when administered to rats at dose two times the 0.24 mcg/kg human dose (based on body surface area, mcg/m 2). At the highest dose tested, 20 mcg/kg administered three times per week in rats (13 times the 14 mcg human dose based on surface area, mcg/m 2), there was significant increase in the mortality of newborn rats at doses that were maternally toxic and are known to produce hypercalcemia in rats. No other effects on offspring development were observed. Paricalcitol was not teratogenic at the doses tested.Paricalcitol (20 mcg/kg) has been shown to cross the placental barrier in rats. There are no adequate and well-controlled clinical studies in pregnant women. Paricalcitol Capsules should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.. 8.3 Nursing Mothers. Studies in rats have shown that paricalcitol is present in the milk. It is not known whether paricalcitol is excreted in human milk. In the nursing patient, decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.. 8.4 Pediatric Use. Safety and efficacy of Paricalcitol Capsules in pediatric patients have not been established.. 8.5 Geriatric Use. Of the total number (n 220) of CKD Stages and patients in clinical studies of Paricalcitol Capsules, 49% were age 65 and over, while 17% were age 75 and over. Of the total number (n 88) of CKD Stage patients in the pivotal study of Paricalcitol Capsules, 28% were age 65 and over, while 6% were age 75 and over. No overall differences in safety and effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS Excessive administration of vitamin compounds, including Paricalcitol Capsules, can cause over suppression of PTH, hypercalcemia, hypercalciuria, hyperphosphatemia, and adynamic bone disease.. Hypercalcemia: Excessive administration of Paricalcitol Capsules can cause over suppression of PTH, hypercalcemia, hypercalciuria, hyperphosphatemia, and adynamic bone disease. Prescription-based doses of vitamin and its derivatives should be withheld during Paricalcitol treatment 5.1). Digitalis toxicity: Potentiated by hypercalcemia of any cause. Use caution when Paricalcitol Capsules are prescribed concomitantly with digitalis compounds 5.2). Laboratory tests: Monitor serum calcium, serum phosphorus, and serum or plasma iPTH during initial dosing or following any dose adjustment. Paricalcitol Capsules may increase serum creatinine and therefore decrease the estimated GFR (eGFR) 5.3). Aluminum overload and toxicity: Avoid excessive use of aluminum containing compounds 5.4). Hypercalcemia: Excessive administration of Paricalcitol Capsules can cause over suppression of PTH, hypercalcemia, hypercalciuria, hyperphosphatemia, and adynamic bone disease. Prescription-based doses of vitamin and its derivatives should be withheld during Paricalcitol treatment 5.1). Digitalis toxicity: Potentiated by hypercalcemia of any cause. Use caution when Paricalcitol Capsules are prescribed concomitantly with digitalis compounds 5.2). Laboratory tests: Monitor serum calcium, serum phosphorus, and serum or plasma iPTH during initial dosing or following any dose adjustment. Paricalcitol Capsules may increase serum creatinine and therefore decrease the estimated GFR (eGFR) 5.3). Aluminum overload and toxicity: Avoid excessive use of aluminum containing compounds 5.4). 5.1 Hypercalcemia Progressive hypercalcemia due to overdosage of vitamin and its metabolites may be so severe as to require emergency attention [see Overdosage (10)]. Acute hypercalcemia may exacerbate tendencies for cardiac arrhythmias and seizures and may potentiate the action of digitalis. Chronic hypercalcemia can lead to generalized vascular calcification and other soft-tissue calcification. Concomitant administration of high doses of calcium-containing preparations or thiazide diueretics with Paricalcitol may increase the risk of hypercalcemia. High intake of calcium and phosphate concomitant with vitamin compounds may lead to serum abnormalities requiring more frequent patient monitoring and individualized dose titration. 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. Prescription-based doses of vitamin and its derivatives should be withheld during Paricalcitol treatment to avoid hypercalcemia.. 5.2 Digitalis Toxicity Digitalis toxicity is potentiated by hypercalcemia of any cause. Use caution when Paricalcitol Capsules are prescribed concomitantly with digitalis compounds.. 5.3 Laboratory Tests During the initial dosing or following any dose adjustment of medication, serum calcium, serum phosphorus, and serum or plasma iPTH should be monitored at least every two weeks for months, then monthly for months, and every months thereafter.During the initial dosing or following any dose adjustment of medication, serum calcium, serum phosphorus, and serum or plasma iPTH should be monitored at least every two weeks for months, then monthly for months, and every months thereafter. In pre-dialysis patients, Paricalcitol Capsules may increase serum creatinine and therefore decrease the estimated GFR (eGFR). Similar effects have also been seen with calcitriol.. 5.4 Aluminum Overload and Toxicity Aluminum-containing preparations (e.g., antacids, phosphate binders) should not be administered chronically with Paricalcitol, as increased blood levels of aluminum and aluminum bone toxicity may occur.