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DOSAGE AND ADMINISTRATION

2.1 Chronic Kidney Disease Stages 3 and 4

Paricalcitol capsules may be administered daily or three times a 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 a 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 Dose

The initial dose of paricalcitol capsules for CKD Stages 3 and 4 patients is based on baseline intact parathyroid hormone (iPTH) levels.

Dose Titration

Dosing must be individualized and based on serum or plasma iPTH levels, with monitoring of serum calcium and serum phosphorus. The following is a suggested approach to dose titration.

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. If a patient is on a calcium-based phosphate binder, the phosphate-binder dose may be decreased or withheld, or the patient may be switched to a non-calcium-based phosphate binder. If hypercalcemia or an elevated Ca x P 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) ].

DOSAGE FORMS AND STRENGTHS

Paricalcitol capsules are available as 1 mcg, 2 mcg, and 4 mcg hard gelatin capsules.

• 1 mcg: Clear to opalescent solution filled in size '3' hard gelatin capsules with white colored cap and white colored body, imprinted 'RDY663' on cap and '1 mcg' on body.

• 2 mcg: Clear to opalescent solution filled in size '3' hard gelatin capsules with white colored cap and white colored body, imprinted 'RDY664' on cap and '2 mcg' on body.

• 4 mcg: Clear to opalescent solution filled in size '3' hard gelatin capsules with white colored cap and white colored body, imprinted 'RDY665' on cap and '4 mcg' on body.

CONTRAINDICATIONS

Paricalcitol capsules should not be given to patients with evidence of

• hypercalcemia or

• vitamin D toxicity [see Warnings and Precautions ( 5.1) ].

WARNINGS AND PRECAUTIONS

Excessive administration of vitamin D compounds, including paricalcitol capsules, can cause over suppression of PTH, hypercalcemia, hypercalciuria, hyperphosphatemia, and adynamic bone disease.

5.1 Hypercalcemia

Progressive hypercalcemia due to overdosage of vitamin D 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 Zemplar may increase the risk of hypercalcemia. High intake of calcium and phosphate concomitant with vitamin D 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 D 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 3 months, then monthly for 3 months, and every 3 months thereafter.

5.4 Aluminum Overload and Toxicity

TAluminum-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.

DRUG INTERACTIONS

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 a patient initiates or discontinues therapy with a 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.

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 a dose 0.5 times a human dose of 14 mcg or 0.24 mcg/kg (based on body surface area, mcg/m2), and when administered to rats at a dose two times the 0.24 mcg/kg human dose (based on body surface area, mcg/m2). 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/m2), there was a 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, a 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 3 and 4 patients in clinical studies of paricalcitol capsules, 49% were age 65 and over, while 17% 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.

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 Overdosage

The treatment of acute overdosage of paricalcitol capsules should consist of general supportive measures. If drug ingestion is discovered within a 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 a 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 a variety of therapeutic alternatives that may be considered depending on the patient's 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.

DESCRIPTION

Paricalcitol USP, the active ingredient in paricalcitol capsules, is a synthetically manufactured, metabolically active vitamin D analog of calcitriol with modifications to the side chain (D2) and the A (19-nor) ring. Paricalcitol capsules are indicated for the prevention and treatment of secondary hyperparathyroidism in chronic kidney disease. Paricalcitol capsules are available as hard gelatin capsules for oral administration containing 1 microgram, 2 micrograms or 4 micrograms of paricalcitol. Each capsule also contains butylated hydroxytoluene, dehydrated ethanol, medium chain triglycerides and polyoxyl 35 castor oil. The medium chain triglycerides are fractionated from coconut oil or palm kernel oil. The capsule shell is composed of gelatin, sodium lauryl sulfate and titanium dioxide. The gelatin solution is composed of gelatin (210 bloom), red iron oxide (for 1 micrograms and 2 micrograms), yellow iron oxide (for 2 micrograms and 4 micrograms) and polysorbate 80.

Paricalcitol is a white to almost white powder with the molecular formula of C27H44O3, which corresponds to a molecular weight of 416.64. Paricalcitol is chemically designated as 19-nor-1a,3b,25-trihydroxy-9,10-secoergosta-5(Z),7(E),22(E)-triene and has the following structural formula:

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 D3 and from dietary intake as either vitamin D2 or D3. Both vitamin D2 and D3 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)2D3], 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)2D3 have been observed in early stages of chronic kidney disease. The decreased levels of 1,25(OH)2D3 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 D2 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

Further lowering of hypercalcemia rates was predicted if the treatment with paricalcitol is initiated in patients with lower serum calcium levels at screening.

12.3 Pharmacokinetics

Absorption

A food effect study in healthy subjects indicated that the Cmax and AUC0-[?] were unchanged when paricalcitol was administered with a high fat meal compared to fasting. Food delayed Tmax by about 2 hours. The AUC0-[?] of paricalcitol increased proportionally over the dose range of 0.06 to 0.48 mcg/kg in healthy subjects.

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 subjects 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 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.

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.

Table 3. Paricalcitol Capsule Pharmacokinetic Characteristics in CKD Stages 3, 4 Patients

* Four mcg paricalcitol capsules were given to CKD Stage 3 patients; three mcg paricalcitol capsules were given to CKD Stage 4 patients.

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

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 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 CYP2B6, CYP2C9 or CYP3A. Hence, paricalcitol is neither expected to inhibit nor induce the clearance of drugs metabolized by these enzymes.

Omeprazole

The effect of omeprazole (40 mg capsule), a strong inhibitor of CYP2C19, on paricalcitol (four 4 mcg capsules) pharmacokinetics was investigated in a single dose, crossover study in healthy subjects. The pharmacokinetics of paricalcitol was not affected when omeprazole was administered approximately 2 hours prior to the paricalcitol dose.

Ketoconazole

The effect of multiple doses of ketoconazole, a strong inhibitor of CYP2C19, administered as 200 mg BID for 5 days on the pharmacokinetics of paricalcitol (4 mcg capsule) has been studied in healthy subjects. The Cmax of paricalcitol was minimally affected, but AUC0-[?] approximately doubled in the presence of ketoconazole. The mean half-life of paricalcitol was 17 hours in the presence of ketoconazole as compared to 9.8 hours, when paricalcitol was administered alone [see Drug Interactions ( 7 )].

NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis and Impairment of Fertility

In a 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 a 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 a 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 (< 1 to 7 times the exposure following a 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 a 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 a human dose of 14 mcg based on surface area, mcg/m2).

CLINICAL STUDIES

14.1 Chronic Kidney Disease Stages 3 and 4

The safety and efficacy of paricalcitol capsules were evaluated in three, 24-week, double blind, placebo-controlled, randomized, multicenter, Phase 3 clinical studies in CKD Stages 3 and 4 patients. Two studies used an identical three times a week dosing design, and one study used a daily dosing design. A 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 to 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 D 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 1 mcg daily or 2 mcg three times a week, not more than every other day. If iPTH was > 500 pg/mL, paricalcitol capsules were administered 2 mcg daily or 4 mcg three times a week, not more than every other day. The dose was increased by 1 mcg daily or 2 mcg three times a week every 2 to 4 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 a 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 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 a week regimens (daily: 30/33, 91%; three times a week: 62/68, 91%).

The incidence of hypercalcemia (defined as two consecutive serum calcium values > 10.5 mg/dL), hyperphosphatemia and elevated Ca x P product 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 3 and 4 Studies Combined

The mean changes from baseline to final treatment visit in serum iPTH, calcium, phosphorus, calcium-phosphorus product (Ca x P), and bone-specific alkaline phosphatase are shown in Table 4.

HOW SUPPLIED/STORAGE AND HANDLING

Paricalcitol capsules are available as 1 mcg, 2 mcg, and 4 mcg capsules.

The 1 mcg capsule is a clear to opalescent solution filled in size '3' hard gelatin capsules with white colored cap and white colored body, imprinted 'RDY663' on cap and '1 mcg' on body with black ink and banded with light to dark pink color gelatin mass and is available in the following package size:

Bottles of 30 NDC 55111-663-30

Bottles of 100 NDC 55111-663-01

Bottles of 500 NDC 55111-663-05

Unit dose package of 30 (3 x 10) NDC 55111-663-81

The 2 mcg capsule is a clear to opalescent solution filled in size '3' hard gelatin capsules with white colored cap and white colored body, imprinted 'RDY664' on cap and '2 mcg' on body with black ink and banded with light to dark orange brown color gelatin mass and is available in the following package size:

Bottles of 30 NDC 55111-664-30

Bottles of 100 NDC 55111-664-01

Bottles of 500 NDC 55111-664-05

Unit dose package of 30 (3 x 10) NDC 55111-664-81

The 4 mcg capsule is a clear to opalescent solution filled in size '3' hard gelatin capsules with white colored cap and white colored body, imprinted 'RDY665' on cap and '4 mcg' on body with black ink and banded with light to dark gold color gelatin mass and is available in the following package size:

Bottles of 30 NDC 55111-665-30

Bottles of 100 NDC 55111-665-01

Bottles of 500 NDC 55111-665-05

Unit dose package of 30 (3 x 10) NDC 55111-665-81

Storage

Store paricalcitol capsules at 20deg-25degC (68deg-77degF) [see USP Controlled Room Temperature].Protect from light.

PATIENT COUNSELING INFORMATION

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 a 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 physician's 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 a new medication that they are taking paricalcitol capsules.

Rx Only

Manufactured by:

Dr. Reddy's Laboratories Limited

Bachupally - 500 090 INDIA

Issued: 0213

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION

1 mcg - Container label 30's count

1 mcg - Blister carton label (3x10's)

2 mcg - Container label 30's count

2 mcg - Blister carton label (3x10's)

4 mcg - Container label 30's count

4 mcg - Blister carton label (3x10's)