Date of Revision:

November 21, 2007

Submission Control No: 110441

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 7 DRUG INTERACTIONS 13 DOSAGE AND ADMINISTRATION 14 OVERDOSAGE 17 ACTION AND CLINICAL PHARMACOLOGY 17 STORAGE AND STABILITY 23 SPECIAL HANDLING INSTRUCTIONS 24 DOSAGE FORMS, COMPOSITION AND PACKAGING 24

PART II: SCIENTIFIC INFORMATION 25

PHARMACEUTICAL INFORMATION 25 CLINICAL TRIALS 26 DETAILED PHARMACOLOGY 38 TOXICOLOGY 39 REFERENCES 42

PART III: CONSUMER INFORMATION. 43

ZEMPLAR(r)

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

• Paricalcitol should not be given to patients with evidence of Vitamin D toxicity, hypercalcemia (defined as two consecutive measurements of > 2.88 mmol/L), or hypersensitivity to any ingredient in this product.

For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph.

WARNINGS AND PRECAUTIONS

General

Over suppression of PTH may result in elevations of serum calcium levels (defined as two consecutive measurements of > 2.88 mmol/L) and may lead to low-turnover bone disease. Patient monitoring and individualized dose titration is required to reach appropriate physiological endpoints (see Monitoring and Laboratory Tests). ZEMPLAR(r) (paricalcitol injection USP) contains 20% v/v of ethanol. Dosing is variable dependent on the severity of disease and response to treatment, however each dose may contain up to 1.3 g of ethanol based on the maximum dose seen in clinical trials. Ethanol may be harmful for those suffering from liver disease, alcoholism, epilepsy, brain injury or disease as well as for pregnant women and children, and may modify or increase the effect of other medicines. Hypercalcemia During dose adjustment, serum calcium and phosphate levels should be monitored closely (e.g., twice weekly). If hypercalcemia (defined as two consecutive measurements of > 2.88 mmol/L) develops, the dose should be reduced or interrupted. Chronic administration of paricalcitol may place patients at risk of hypercalcemia, elevated Ca x P product, and metastatic calcification. Hypercalcemia related to Vitamin D intoxication may be asymptomatic; however, it may also present with the following signs and symptoms:

Early

: Weakness, headache, somnolence, nausea, vomiting, dry mouth, constipation, muscle pain, bone pain and metallic taste.

Late

: Anorexia, weight loss, conjunctivitis (calcific), pancreatitis, photophobia, rhinorrhea, pruritus, hyperthermia, decreased libido, elevated urea nitrogen (BUN), hypercholesterolemia, elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT), ectopic calcification, hypertension, cardiac arrhythmias, somnolence, death, and rarely, overt psychosis.

Treatment of patients with clinically significant hypercalcemia consists of immediate dose reduction or interruption of paricalcitol therapy and includes a low calcium diet, withdrawal of calcium supplements, patient mobilization, attention to fluid and electrolyte imbalances, assessment of electrocardiographic abnormalities (critical in patients receiving digitalis), and hemodialysis or peritoneal dialysis against a calcium-free dialysate, as warranted. Serum calcium levels should be monitored frequently until normocalcemia ensues. If clinically significant hypercalcemia develops, and the patient is receiving a calcium-based phosphate binder, the dose of the calcium-based phosphate binder should be reduced or interrupted. Adynamic bone lesions (low-turnover bone disease) may develop if PTH levels are suppressed to abnormal levels. Acute overdose of paricalcitol may cause hypercalcemia and require emergency attention.

Carcinogenesis and Mutagenesis

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 to 10 mcg/kg (< 1 to 3 times the maximum recommended human weekly dose of 0.72 mcg/kg, based on body surface area, mg/m2). 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 to 1.5 mcg/kg (<= 1 times the maximum recommended human weekly dose of 0.72 mcg/kg, based on body surface area, mg/m2). The increased incidence of pheochromocytomas in rats may be related to the alteration of calcium homeostasis by paricalcitol. Preclinical effects were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. 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 the highest recommended human dose (0.24 mcg/kg) based on surface area, mg/m2].

Neurologic

Paricalcitol injection USP contains 30% v/v of propylene glycol as an excipient. Isolated cases of central nervous system depression, hemolysis and lactic acidosis have been reported as toxic effect associated with propylene glycol administration at high doses. Although they are not expected to be found with paricalcitol injection administration as propylene glycol is eliminated during the hemodialysis process, the risk of toxic effects in overdosing situations has to be taken into account.

Special Populations

Pregnant Women: TOXICOLOGY

There are no adequate and well-controlled studies in pregnant women. Animal studies have shown reproductive toxicity. Potential risk in human use is not known. Paricalcitol should be used during pregnancy only if the potential benefit to the mother outweighs the potential risk for the fetus (see

).

Paricalcitol (20 mcg/kg) has been shown to cross the placental barrier in rats, however the concentration of paricalcitol in the rat fetus was lower than in maternal plasma, suggesting some degree of placental barrier. There is no experience of exposure in pregnancy during clinical trials as one of the criteria for inclusion was that the female subjects were not pregnant and were taking contraceptive precautions if they were of child-bearing age at the time of the study.

Nursing Women:

Studies in rats have shown that paricalcitol is present in the milk. It is not known whether paricalcitol is excreted in human milk. Therefore, in the nursing patient, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatrics (birth to 18 years of age)CLINICAL TRIALS, Pediatric Patients

: There is limited experience with the use of paricalcitol injection USP in patients less than 18 years of age (see

).

Geriatrics (>= 65 years of age)

: Of the total number (n=88) of patients with Chronic Kidney Disease (CKD) Stage 5 in the pivotal study of paricalcitol capsules, 28% were age 65 and over, while 6% were 75 and over. No overall differences in safety and effectiveness were observed between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Of the 40 patients receiving paricalcitol injection USP in the three Phase III placebo-controlled chronic renal failure (CRF) studies, ten patients were 65 years or over. In these studies, no overall differences in efficacy or safety were observed between patients 65 years or older and younger patients.

Monitoring and Laboratory Tests ZEMPLAR(r) (paricalcitol capsules)

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 after initiation of oral paricalcitol therapy or following dose-adjustments in oral paricalcitol therapy, then monthly for 3 months, and at least every 3 months thereafter.

ZEMPLAR(r) (paricalcitol injection USP)

In placebo-controlled studies, paricalcitol injection USP reduced serum total alkaline phosphatase levels. During dose adjustment and before dosage is established with paricalcitol, laboratory tests such as serum calcium and phosphorus should be measured frequently (possibly twice a week). Once dosage has been established, serum calcium and phosphorus should be measured at least monthly. Measurement of serum or plasma PTH is recommended every three months.

DRUG INTERACTIONS

Overview

An in vitro study indicates that paricalcitol is not an inhibitor of CYP3A, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP2E1 at concentrations up to 50 nM (21 ng/mL) (approximately 20-fold greater than that obtained after highest tested dose). In fresh primary cultured hepatocytes, the induction observed at paricalcitol concentrations up to 50 nM was less than two-fold for CYP2B6, CYP2C9 or CYP3A, where the positive controls rendered a six- to nineteen-fold induction. Hence, paricalcitol is not expected to inhibit the clearance of drugs metabolized by these enzymes. The pharmacokinetic interaction between paricalcitol capsules (16 mcg) and omeprazole (40 mg; oral) was investigated in a single dose, crossover study in 25 healthy subjects. The pharmacokinetics of paricalcitol were unaffected when co-administered with omeprazole. Ketoconazole is known to be a nonspecific inhibitor of several cytochrome P450 enzymes. The available in vivo and in vitro data suggest that ketoconazole may interact with enzymes that are responsible for the metabolism of paricalcitol and other vitamin D analogs. Although not studied with paricalcitol injection, the effect of ketoconazole on the pharmacokinetics of paricalcitol capsules has been studied in 14 healthy subjects. The Cmax of paricalcitol was minimally affected, but AUC0-[?] approximately doubled in the presence of ketoconazole. The mean t1/2 of paricalcitol was 17.0 hours in the presence of ketoconazole as compared to 9.8 hours, when paricalcitol was administered alone. Caution should be taken while dosing paricalcitol with ketoconazole and other strong CYP3A4 inhibitors.

Drug-Drug Interactions

Specific drug-drug interaction studies in humans have not been performed with paricalcitol injection USP.

Drug-Food Interactions

Paricalcitol capsules may be taken without regard to food.

DOSAGE AND ADMINISTRATION

Dosing Considerations

Hepatic Insufficiency: Unbound concentrations of ZEMPLAR(r) (paricalcitol injection USP) in patients with mild to moderate hepatic impairment are similar to healthy subjects and dose adjustment is not necessary in this patient population. There is no experience in patients with severe hepatic impairment.

Pediatric Use: CLINICAL TRIALS, Pediatric Patients

There is limited experience with the use of paricalcitol injection USP in patients less than 18 years of age (see

).

Geriatric Use:

Of the total number (n=88) of patients with Chronic Kidney Disease (CKD) Stage 5 in the pivotal study of paricalcitol capsules, 28% were age 65 and over, while 6% were 75 and over. No overall differences in safety and effectiveness were observed between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

There is a limited amount of experience with patients 65 years of age or over receiving paricalcitol injection USP in the Phase III studies. In these studies, no overall differences in efficacy or safety were observed between patients 65 years or older and younger patients.

Recommended Dose and Dosage Adjustment ZEMPLAR(r) (paricalcitol capsules)

ZEMPLAR(r) (paricalcitol capsules) may be taken without regard to food. Adults: ZEMPLAR(r) (paricalcitol capsules) are administered three times a week, no more frequently than every other day.

Initial Dose: most recent iPTH level in pmol/L

The initial dose of paricalcitol capsules is based on the following formula: Initial dose (micrograms) =

Dose Titration:

Subsequent dosing should be individualized and based on iPTH, serum calcium and phosphorus levels. A suggested dose titration of paricalcitol capsules is based on the following formula:

Titration dose (micrograms) = most recent iPTH level in pmol/L Serum 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 or elevated Ca x P is observed and the patient is on a calcium-based phosphate binder, the binder dose may be decreased or withheld, or the patient may be switched to a non-calcium- based phosphate binder. If serum calcium > 2.8 mmol/L or Ca x P > 5.6 mmol2/L2, the dose should be decreased by 2 to 4 micrograms lower than that calculated by the most recent iPTH/7 (pmol/L). If further adjustment is required, the dose of paricalcitol capsules should be reduced or interrupted until these parameters are normalized. As PTH approaches the target range, small, individualized dose adjustments may be necessary in order to achieve a stable PTH. In situations where monitoring of PTH, Ca or P occurs less frequently than once per week, a more modest initial and dose titration ratio may be warranted. The mean average TIW dose during the initial week in the clinical study was 11.2 mcg per dose. The mean average overall TIW dose administered in the clinical study was 6.3 mcg per dose. The maximum dose safely administered in the clinical study was 32 mcg per dose.

ZEMPLAR(r) (paricalcitol injection USP)

Adults:

The currently accepted target range for intact parathyroid hormone (iPTH) levels CRF patients is no more than 1.5 to 3 times the non-uremic upper limit of normal (15.9 to 31.8 pmol/L for iPTH).

The recommended initial dose of ZEMPLAR(r) (paricalcitol injection USP) is 0.04 mcg/kg to 0.1 mcg/kg (2.8 to 7 mcg) administered as a bolus dose no more frequently than every other day at any time during dialysis. Single doses as high as 0.24 mcg/kg (16.8 mcg) have been safely administered. If a satisfactory response is not observed, the dose may be increased by 2 to 4 mcg at every 2- to 4-week interval. During any dose adjustment period serum calcium and phosphorous levels should be monitored more frequently, possibly 2 times per week, and if an elevated corrected calcium (Ca) level or a Ca x P product greater than 6.1 is noted, the drug dosage should be immediately reduced or interrupted until these parameters are normalized. Then, paricalcitol administration should be reinitiated at a lower dose. Doses may need to be decreased as the PTH levels decrease in response to therapy. Thus, incremental dosing must be individualized. The following table (Table 5) is a suggested approach for dose titration:

The influence of mild to moderately impaired hepatic function on paricalcitol pharmacokinetics is sufficiently small that no dosing adjustment is required.

Administration

The usual route of administration of paricalcitol solution for injection is via a hemodialysis line. Propylene glycol interacts with heparin and neutralizes its effect. Paricalcitol injection USP contains propylene glycol as an excipient and its administration with heparin must be avoided. Paricalcitol injection USP should not to be mixed with other medicinal products.

OVERDOSAGE

ZEMPLAR(r) (paricalcitol capsules)

Excessive administration of ZEMPLAR(r) (paricalcitol capsules) can cause hypercalcemia (defined as two consecutive measurements of > 2.88 mmol/L) (see WARNINGS AND PRECAUTIONS), hypercalciuria, and hyperphosphatemia, and over suppression of PTH.

ZEMPLAR(r) (paricalcitol injection USP)

Overdosage of ZEMPLAR(r) (paricalcitol injection USP) may lead to hypercalcemia (defined as two consecutive measurements of > 2.88 mmol/L) (see WARNINGS AND PRECAUTIONS). Paricalcitol is not significantly removed by dialysis. The content of propylene glycol as excipient is eliminated by dialysis.

ACTION AND CLINICAL PHARMACOLOGY

The pharmacology of ZEMPLAR(r) (paricalcitol injection USP) has been evaluated in healthy subjects, chronic hepatic insufficiency subjects, and in patients on hemodialysis with secondary hyperparathyroidism. In short-term studies in healthy patients, there were no detectable differences in iPTH levels when paricalcitol injection USP was compared to placebo administration. In patients with secondary hyperparathyroidism, the pharmacodynamic actions of paricalcitol in reducing iPTH levels were as expected of a potent vitamin D analogue. The pharmacokinetics of paricalcitol appear to be linear for the dose range expected to be used in clinical practice. The half-life of paricalcitol is approximately 5 to 7 hours in healthy adults and 11 to 15 hours in hemodialysis patients. Little or no accumulation of the drug is observed in hemodialysis patients in multiple-dose studies of up to 12 weeks in duration. Paricalcitol is eliminated primarily by hepatobiliary excretion; 74% of a radiolabelled dose is recovered in feces and only 16% of a dose is detected in urine. 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; this metabolite is less active than paricalcitol in an in vivo rat model of PTH suppression. In, in vitro studies, paricalcitol had little or no effect on activities catalyzed by CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A at concentrations up to 50 nM (21 ng/mL). No adjustment of paricalcitol dose appears to be required for subjects with mild to moderate hepatic impairment. Paricalcitol is not removed by hemodialyis to a significant extent and therefore can be administered before, during, or after a dialysis session.

Mechanism of Action

Vitamin D has a central role in calcium and phosphate homeostasis and the proper formation and maintenance of bone. These classic effects of the hormone are achieved through the actions of 1,25-dihydroxyvitamin D3 (biologically most active vitamin D) on target cells of the intestine, bone, kidney and parathyroid gland. In the diseased kidney, calcitriol synthesis is diminished. The resultant calcitriol deficiency and altered mineral balance are a major cause of secondary hyperparathyroidism and metabolic bone disease of renal failure. Vitamin D has broader functions in the body that expand the classic actions to include effects on immunity, muscle and vasculature, reproduction, and the growth and differentiation of many cell types. In addition to the classic target organs, vitamin D receptors (VDR) are found in skin, liver, heart, lungs, lymphoid tissue and other organs, suggesting diverse biological roles for this hormone. Paricalcitol is a synthetic vitamin D analog of calcitriol with modifications to the side chain (D2) and the A (19-nor) ring allowing for selective vitamin D receptor (VDR) activation. In rodents, the mechanism of action of paricalcitol appears to differ from calcitriol with respect to the mobilization of calcium and phosphorus from both bone and across the intestine. Paricalcitol does not upregulate the intestinal VDR content in rodents, and is less effective than calcitriol at inducing intestinal calcium and phosphorus absorption. Paricalcitol is also less potent in rodents and in humans than calcitriol in mobilizing calcium and phosphorus from bone. The beneficial effect of paricalcitol in secondary hyperparathyroidism appears to result from correction of vitamin D deficiency, direct inhibition of pre-pro-PTH mRNA synthesis by the parathyroid glands, and anti-proliferative effect on parathyroid cells.

Pharmacodynamics

Secondary hyperparathyroidism is characterized by an elevation in parathyroid hormone (PTH) associated with inadequate levels of active vitamin D hormones. The source of vitamin D is from synthesis in the skin and from dietary intake. Vitamin D requires two sequential hydroxylations in the liver and the kidney to form calcitriol which binds to and to activates 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.4 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 result in renal osteodystrophy.

Pharmacokinetics

ZEMPLAR(r) (paricalcitol capsules) and ZEMPLAR(r) (paricalcitol injection USP) Absorption:

Paricalcitol is well absorbed. In healthy subjects, following oral administration of

paricalcitol at 0.24 mcg/kg, the mean absolute bioavailability was approximately 72%; the maximum plasma concentration (Cmax), time to Cmax (Tmax), and area under the concentration time curve (AUC0-[?]) were 1.512 pmol/mL, 3 hours and 12.60 pmol *h/mL, respectively. The mean absolute bioavailability of paricalcitol in HD and PD patients is 79% and 86%, respectively, with the upper bound of 95% confidence interval of 93% and 112%, respectively. 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. Therefore, paricalcitol capsules may be taken without regard to food. The Cmax and AUC0-[?] of paricalcitol increased proportionally over the dose range of 0.06 to 0.48 mcg/kg in healthy subjects. Following multiple dosing, either as daily or three times a week in healthy subjects, steady-state exposure was reached within seven days and remained constant over time.

Distribution:

Paricalcitol is extensively bound (> 99.8%) to plasma proteins in healthy subjects (or the plasma free fraction < 0.1%) and the percent bound to plasma proteins is constant over the range of 0.25 to 100 ng/mL. The mean apparent volume of distribution following a

0.24 mcg/kg oral dose of paricalcitol in healthy subjects was 34 L. The protein binding is also very high in CKD Stage 5 subjects. Protein binding results were similar in CKD Stage 5 subjects on HD and CPD. The protein binding was reduced at higher paricalcitol concentrations (50 nM; 21.2 ng/mL) in CKD Stage 5 subjects. However, these high concentrations are highly unlikely in CKD Stage 5 subjects based on the dose recommended for this patient population. The pharmacokinetics of paricalcitol have been studied in patients with chronic renal failure (CRF) requiring hemodialysis. Paricalcitol injection USP is administered as an intravenous bolus injection. Within two hours after administering doses ranging from 0.04 to 0.24 mcg/kg, concentrations of paricalcitol decreased rapidly; thereafter, concentrations of paricalcitol declined log-linearly with a mean half-life of about 15 hours. No accumulation of paricalcitol was observed with multiple dosing. 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 found in the urine. Approximately 70% of the radioactivity was eliminated in the feces and 18% was recovered in the urine. 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, as well as 24,26- and 24,28- dihydroxylation and direct glucuronidation. Paricalcitol is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A at concentrations up to 50 nM (21 ng/mL). Less than two-fold induction was noted for CYP2B6, CYP2C9 and CYP3A4 at similar concentrations of paricalcitol.

Excretion:

Paricalcitol is eliminated primarily via hepatobiliary excretion. In healthy subjects, the mean elimination half-life of paricalcitol is five to seven hours over the studies dose range of

0.06 to 0.48 mcg/kg. The degree of accumulation was consistent with the half-life and dosing frequency. Hemodialysis procedure has no effect on paricalcitol elimination. In healthy subjects, a study was conducted with a single 0.16 mcg/kg intravenous bolus dose of 3H-paricalcitol (n=4), plasma radioactivity was attributed to parent drug. Paricalcitol was eliminated primarily by hepatobiliary excretion, as 74% of the radioactive dose was recovered in feces and only 16% was found in urine.

Special Populations and Conditions

Paricalcitol pharmacokinetics have not been investigated in special populations such as geriatric and pediatric. There is a limited amount of experience with patients 65 years of age or over receiving paricalcitol in Phase III studies. In these studies, no overall differences in efficacy or safety were observed between patients 65 years or older and younger patients.

Age: Pediatrics: Geriatrics:

No age related pharmacokinetic differences have been observed in adult patients studied.

Paricalcitol pharmacokinetics have not been investigated in pediatric population.

Paricalcitol pharmacokinetics have not been investigated in geriatric population.

Gender:

No gender related pharmacokinetic differences have been observed in adult patients studied. The pharmacokinetics of paricalcitol following single oral doses over 0.06 to

mcg/kg dose range were gender independent.

Race:

Pharmacokinetic differences due to race have not been identified.

Hepatic Insufficiency:

Following intravenous administration, the disposition of paricalcitol 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). Following administration of a single dose, the pharmacokinetics of unbound paricalcitol were similar across hepatic function groups. Paricalcitol binding to plasma proteins was very high in all hepatic function groups (mean values > 99.7%). The protein binding of paricalcitol was decreased in subjects with moderate (but not mild) hepatic impairment; total paricalcitol concentrations tended to be lower for subjects with moderate hepatic impairment compared to the other two

hepatic function groups. No dosage 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. Unbound concentrations of paricalcitol in patients with mild to moderate hepatic impairment is similar to healthy subjects and dose adjustment is not necessary in this patient population.

Table 6

summarizes the pharmacokinetic results from a Phase I pharmacokinetic study in patients with chronic hepatic insufficiency. Considerable inter-individual variation was apparent.

t

1/2

Renal Insufficiency:

ZEMPLAR(r) (paricalcitol capsules) Paricalcitol pharmacokinetics following single dose oral administration were characterized in patients with Chronic Kidney Disease (CKD) Stage 5 with end-stage renal disease [n = 14 in hemodialysis (HD) and n=8 in peritoneal dialysis (PD)]. Similar to endogenous 1,25(OH)2 D3, the pharmacokinetics of paricalcitol following oral administration were affected significantly by renal impairment, as shown in Table 7. Compared to healthy subjects, CKD Stage 5 patients showed decreased CL/F and increased half-life.

ZEMPLAR(r) (paricalcitol injection USP) In a Phase II study evaluating escalating doses of paricalcitol injection in patients with end stage renal disease (ESRD) undergoing hemodialysis, the paricalcitol pharmacokinetics were in general linear for the dose range of 0.04 to 0.24 mcg/kg. No accumulation of paricalcitol was observed when dosed after each dialysis session. Table 8 summarizes the paricalcitol pharmacokinetic parameters for the data of the first and the last doses combined.

In three (3) Phase III studies evaluating the safety and efficacy of paricalcitol injection USP in end stage renal disease patients undergoing hemodialysis (refer to Table 11 in CLINICAL TRIALS for more information), the distribution of paricalcitol appeared to be essentially complete within 2 hours after the dose. Concentrations of paricalcitol at 2, 24, and 44 hours after the dose also appeared to have declined log-linearly in these studies. Table 9 summarizes the paricalcitol plasma concentrations and half-lives after multiple dosing for these studies.

STORAGE AND STABILITY

ZEMPLAR(r) (paricalcitol capsules) should be stored between 15 and 25oC. ZEMPLAR(r) (paricalcitol injection USP) should be stored between 15 and 25oC. Protect from light, freezing and excessive heat.

SPECIAL HANDLING INSTRUCTIONS

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Discard unused portion.

DOSAGE FORMS, COMPOSITION AND PACKAGING

ZEMPLAR(r) (paricalcitol capsules)

ZEMPLAR(r) (paricalcitol capsules) are available as 1 mcg, 2 mcg, and 4 mcg capsules. The 1 mcg capsule is an oval, gray, soft gelatin capsule imprinted with and ZA. The 2 mcg capsule is an oval, orange-brown, soft gelatin capsule imprinted with and ZF. The 4 mcg capsule is an oval, gold soft gelatin capsule imprinted with and ZK. The capsules are available in high- density polyethylene (HDPE) bottles closed with polypropylene caps in the following package sizes: Bottles containing 30 capsules. Listing of Non-Medicinal Ingredients In addition to the active ingredient paricalcitol, ZEMPLAR(r) capsules also contain the following non-medicinal ingredients: medium chain triglycerides, alcohol, butylated hydroxytoluene, gelatin, glycerin, titanium dioxide, ink, Opacode(r) WB, black, iron oxide red (2 mcg capsules only), iron oxide yellow (2 and 4 mcg capsules), iron oxide black (1 mcg capsules only), purified water.

ZEMPLAR(r) (paricalcitol injection USP)

ZEMPLAR(r) (paricalcitol injection USP) containing 5 mcg/mL paricalcitol is presented in single dose Type I glass ampoule or Flip-top vials as follows: Ampoules containing 1 mL or 2 mL Fliptop vials containing 1 mL or 2 mL Listing of Non-Medicinal Ingredients In addition to the active ingredient paricalcitol, ZEMPLAR(r) (paricalcitol injection USP) contains the following non-medicinal ingredients: ethanol (20 % v/v), propylene glycol (30% v/v), water for injection. Propylene glycol interacts with heparin and neutralizes its effect. Paricalcitol injection USP contains propylene glycol as an excipient and its administration with heparin must be avoided. Paricalcitol injection USP should not to be mixed with other medicinal products.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Paricalcitol Chemical name: (1a,3b,7E,22E)-19-Nor-9,10-secoergosta-5,7,22-triene-1,3,25-triol Molecular formula: C27H44O3 Structural formula:

H

OH

H

HO OH

Molecular mass: 416.64 Physical form: Paricalcitol is a white crystalline powder. Solubility: Paricalcitol is a non-polar compound and is insoluble in water at room temperature, but soluble in most polar solvents e.g., ether, methanol, ethanol, etc.

CLINICAL TRIALS

Study Demographics and Trial Design ZEMPLAR(r) (paricalcitol capsules)

ZEMPLAR(r) (paricalcitol injection USP)

Study Results

ZEMPLAR(r) (paricalcitol capsules)

The safety and efficacy of paricalcitol capsules were evaluated in a Phase III, 12-week, double blind, placebo-controlled, randomized, multicenter study in patients with Chronic Kidney Disease (CKD) Stage 5 on HD or PD. The study used a three times a week dosing design. A total of 61 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 80.6 pmol/L (range: 24.1-215.9 pmol/L). The average time since first dialysis across all subjects is 3.26 years. The initial dose of paricalcitol capsules was based on baseline iPTH/7, up to a maximum initial dose of 32 mcg. Subsequent dose adjustments were based on iPTH/7 as well as primary chemistry results that were measured once a week. Starting at Treatment Week 2, study drug was maintained, increased or decreased weekly based on the results of the previous week's calculation of iPTH/7. If the serum calcium level was > 2.75 mmo/L or Ca x P > 22.6 mmol2/L2 or iPTH < 16.8 pmol/L, the previous week's dose was decreased by 2 mcg or 4 mcg. Paricalcitol capsules were administered three times a week, not more than every other day. The overall average three times a week dose of paricalcitol capsules was 6.3 mcg/dose. Eighty-two percent (82%) of the paricalcitol capsule treated patients and 78% of the placebo patients completed the 12-week treatment. The primary efficacy endpoint of at least two consecutive >= 30% reductions from baseline iPTH was achieved by 88% of paricalcitol capsule treated patients and 13% of the placebo patients (p < 0.001). There were no statistically significant differences between the paricalcitol capsules treated patients and placebo patients in the incidence of hypercalcemia (defined as two consecutive measurements of > 2.88 mmol/L) (p > 0.999), hyperphosphatemia (p=0.073) or elevated calcium-phosphorus product (p=0.669). At baseline, 53 (87%) paricalcitol-treated subjects and 26 (96%) placebo subjects were receiving phosphate binders. At the Final Visit, phosphate binder usage was unchanged from baseline for the majority of subjects in both treatment groups. However when hypercalcemia is defined as one measurement greater than 2.63 mmol/L (ie. greater than the laboratory upper limit of normal) hypercalcemia is significantly more common in the paricalcitol treated group as compared with placebo (see Table 12).

The mean values for serum iPTH, calcium, and phosphorus over time are shown in

Figure 1

, and the pattern of change in the mean values for serum iPTH during the study are shown in

Figure 2Table 13

. The mean changes from baseline to final treatment visit in serum iPTH, calcium, phosphorus, and Ca x P shown in

.

Figure 1

Mean Values for Serum iPTH, Calcium, and Phosphorus Over Time in a Phase 3 Double-Blind, Placebo-Controlled CKD Stage 5 Study

Figure 2

Mean Values for Serum iPTH Over Time in a Phase 3 Double-Blind, Placebo-Controlled CKD Stage 5 Study

ZEMPLAR(r) (paricalcitol injection USP)

Adult Patients

In one Phase II, placebo-controlled study (Study 1) designed to investigate the dose of paricalcitol injection required to achieve at least a 30% decrease in the maximal PTH baseline level in at least 75% of patients undergoing regular hemodialysis demonstrated that patients treated with paricalcitol achieved the PTH endpoint within 2 to 21 days. Table 14 shows the main results of the study. The results showed that increasing the dose of paricalcitol meant a greater and more consistent suppression of PTH.

In three 12-week, placebo-controlled, Phase III studies (Studies 2, 3 and 4) in chronic renal failure patients on dialysis, the dose of paricalcitol injection was started at 0.04 mcg/kg three times per week. The dose was increased by 0.04 mcg/kg every two weeks until intact parathyroid hormone (iPTH) levels were decreased at least 30% from baseline or a fifth escalation brought the dose to 0.24 mcg/kg, or iPTH fell to less than 10.6 pmol/L, or the Ca x P product was greater than 6.1 within any two week period, or serum calcium became greater than 2.88 mmol/L at any time. There was a clear response in PTH suppression in patients treated with paricalcitol for 12 weeks. PTH endpoint results are summarized in Table 15 and Table 16.

Sixty-eight percent (27/40) of active patients had a 30% greater decrease in iPTH levels for 4 consecutive laboratory draws. Eight percent (3/38) of placebo patients demonstrated a similar response. A statistically significant difference (p<0.001) was observed between treatment groups. Patients treated with paricalcitol achieved a mean iPTH reduction of 30% within six weeks. In these studies, there was no significant difference in the incidence of hypercalcemia, as defined in the protocol as 2.88 mmol/L, or hyperphosphatemia between paricalcitol and placebo treated patients. The results from these studies are summarized in Table 16.

Studies 5 and 6 were designed to investigate if paricalcitol injections induce less incidence of hypercalcemia (defined as two consecutive measurements of > 2.88 mmol/L) and Ca x P product episodes than calcitriol injections when using similar starting doses (dose ratio of 4:1, 0.04 mcg/kg for paricalcitol and 0.01 mcg/kg for calcitriol). Study 5 evaluated the drugs for a duration of 12 to 32 weeks, while Study 6 evaluated therapy for 24 weeks. Results of these studies are summarized in Table 17 and Table 18.

Additional analysis of iPTH results indicated that consecutive 50% reductions from baseline iPTH levels occurred in significantly less time in all-treated patients receiving paricalcitol (87 days) than in calcitriol-treated patients (108 days) (p=0.025, Kaplan-Meier survival analysis). The findings suggest that in applications of up to 32 weeks, paricalcitol reduces iPTH levels more rapidly than calcitriol.

Paricalcitol injection reduced iPTH to levels similar to those achieved with calcitriol in ESRD patients on hemodialysis without evidence of a clinically significant difference in its effect on calcium and/or Ca x P product profiles. In addition, the 50% iPTH reduction criterion was met 6 weeks earlier for the paricalcitol group. Also, a statistically significant greater reduction of percent change in iPTH at weeks 11 through 14 occurred in the paricalcitol group. In a Phase IV, double-blind, randomized, multicenter, 12 week study, (Study 7) paricalcitol injection was administered at an initial dose of either 0.04 mcg/kg or baseline iPTH/8 (using intact PTH expressed as pmol/L) three times weekly to chronic renal failure patients on dialysis. The dose was increased by 2 mcg every two weeks until iPTH levels fell between 30% to 60% from baseline, or iPTH fell to less than 10.6 pmol/L, or the Ca x P product was greater than 6.1 for two consecutive occurrences, or serum calcium became greater than 2.88 mmol/L at anytime. This represents a value that is 11% above the published K/DOQI (Kidney Disease Outcomes Quality Initiative) guidelines for the upper limit of normal serum calcium. Patients completed the study by reducing iPTH > 30% from baseline levels for four consecutive measurements, or by having a single incidence of hypercalcemia (defined as two consecutive measurements of > 2.88 mmol/L), or by completing twelve weeks of treatment. No incidence of hypercalcemia was seen for any patients in either treatment group. Both dosing methods were shown to be safe and effective. Results are presented in Table 19.

A long-term, open-label safety study of 164 CRF patients (mean dose of 7.5 mcg three times per week), demonstrated that mean serum Ca, P, and Ca x P remained within clinically appropriate ranges with PTH reduction (mean decrease of 43.4 pmol/L at 13 months) as demonstrated in Figure 3.

Figure 3

Plot of Mean +- SEM for iPTH, Calcium and Phosphorus by Month (All-Treated Patient; N=164)

Pediatric Patients

The safety and effectiveness of paricalcitol injection were examined in a 12-week randomized, double blind, placebo-controlled study of 29 pediatric patients, aged 5 to19 years, with end-stage renal disease on hemodialysis (Study 8). Nearly all patients had received some form of vitamin D prior to the study. Seventy-six percent of the patients were male, 52% were Caucasian and 45% were African-American. The initial dose of paricalcitol was 0.04 mcg/kg 3 times a week, based on baseline iPTH level of < 53 pmol/L, or 0.08 mcg/kg 3 times a week based on baseline iPTH level of $ 53 pmol/L, respectively. The dose of paricalcitol was adjusted in 0.04 mcg/kg increments based on the levels of serum iPTH, calcium, and Ca x P. The mean baseline levels of iPTH were 89.1 pmol/L for the 15 paricalcitol-treated patients and 78.4 pmol/L for the 14 placebo-treated patients. The mean dose of paricalcitol administered was 4.6 mcg (range: 0.8 mcg to 9.6 mcg). Ten of the 15 (67%) paricalcitol-treated patients and 2 of the 14 (14%) placebo-treated patients completed the trial. Ten of the placebo treated patients (71%) were discontinued due to excessive elevations in iPTH levels as defined by 2 consecutive iPTH levels > 74.2 pmol/L and greater than baseline after 4 weeks of treatment In the primary efficacy analysis, 9 of 15 (60%) patients in the paricalcitol group had 2 consecutive 30% decreases from baseline iPTH compared with 3 of 14 (21%) patients in the placebo group (95% CI for the difference between groups -1%, 63%). No patients in either the paricalcitol group or placebo group developed hypercalcemia (defined as at least one calcium value 2.8 mmol/L) during the study.

DETAILED PHARMACOLOGY

Two primary pharmacodynamics studies demonstrated in 5/6 nephrectomized rats that paricalcitol (19-nor-1,25-(OH)2D2) has advantages over calcitriol (1,25-(OH)2D3) at doses that give equivalent or greater reduction of serum PTH. No increase in serum ionized calcium and no increase in serum phosphorus were observed with paricalcitol. In addition there was a reduction of endogenous serum calcitriol levels, a reduction in intestinal vitamin D receptor content and a decrease in parathyroid gland growth. There was also a similar reduction of pre-pro PTH messenger RNA compared with uremic controls. The primary pharmacological activity of paricalcitol was also demonstrated during the repeat dose toxicity evaluations. Pronounced reductions in serum intact PTH occurred at most dosages in all species in subchronic and chronic toxicology studies of paricalcitol. Typically this response was dosage-related, with serum PTH levels approaching zero at higher dosages. In the secondary pharmacodynamic study, it was concluded that paricalcitol is approximately seven-fold less potent than calcitriol in promoting bone mobilization in this animal model. These results support the conclusion of other investigators, using the same animal model but a different statistical method of comparison that the difference in potencies of the two vitamin D analogs was approximately 10-fold. Based on the cumulative information from animal toxicity studies in rodents and dogs and the 8- 10 fold exposure margins achieved in dogs relative to the therapeutic range, the lack of effect of paricalcitol on vital organ function has been well documented in these studies.

TOXICOLOGY

Single Dose Toxicity Study

The acute intravenous toxicity of paricalcitol was evaluated in Crl:CD-1(r) (ICR)BR mice and Crl:CD(r) BR rats of both sexes. No adverse effects were observed in mice and rats treated with paricalcitol at dose levels of 24 and 16 mcg/kg, respectively.

Long- Term Toxicity

Repeat dose toxicity studies of paricalcitol are listed in Table 20. To mimic the clinical dosing regimen, doses were intravenously administered three times per week, two or three days apart, in all of these studies. The toxicology assessment of paricalcitol requires that a distinction be made between effects that were directly or indirectly related its pharmacological actions (suppression of PTH and elevation of serum calcium) and other effects of the vitamin D analog.

The effects seen in repeat-dose toxicity studies in rodents and dogs fell into two general categories: those related and those unrelated to paricalcitol's calcemic activity. Effects not clearly related to hypercalcemia included decreased white blood cell counts and thymic atrophy in dogs, and altered activated partial thromboplastin time (APTT) values (increased in dogs, decreased in rats). Except for reductions in white blood cell counts (WBCs), similar effects were seen in rats and dogs treated with calcitriol. Such WBC changes were not observed in clinical trials of paricalcitol.

Reproductive Toxicity

Paricalcitol has been shown to cause minimal decreases in fetal viability (5%) when administered daily to rabbits at a dose 0.5 times the 0.24 mcg/kg human dose (based on surface area, mg/m2) and when administered to rats at a dose two times the 0.24 mcg/kg human dose (based on plasma levels of exposure). At the highest dose tested (20 mcg/kg three times per week in rats, 13 times the 0.24 mcg/kg human dose based on surface area), there was a significant increase of the mortality of newborn rats at doses that were maternally toxic (hypercalcemia). No other effects on offspring development were observed. Paricalcitol was not teratogenic at the doses tested.

Mutagenicity and Carcinogenicity

Refer to WARNINGS AND PRECAUTIONS. Limitations of the animal models (animals without renal insufficiency) precluded the administration of high doses of paricalcitol in studies on repeated dose toxicity, reproductive toxicity and carcinogenicity. Doses administered and/or systemic exposures to paricalcitol were slightly higher than therapeutic doses/systemic exposures.

REFERENCES

1. Goldenberg MM. Paricalcitol, a new agent for the management of secondary hyperparathyroidism in patients undergoing chromic renal dialysis. Clin Therap 1999; 21:432-41.

2. Drueke TB, McCarron DA. Paricaclitol as compared with calcitriol in patients undergoing hemodialysis. An Editorial. N Eng J Med 2003; 349(5):496-9.

3. Llach F. Paricalcitol: An updated review and guidelines for use. Dialysis & Transplant

2001; 30:654-664. K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. Am J Kidney Dis 2003; Volume 42(4): Supplement 3. Sprague SM, Lerma E, McCormick D, Abraham M, Batlle D. Suppression of parathyroid hormone secretion in hemodialysis patients: Comparison of paricalcitol with calcitriol. Am J Kidney Dis 2001; 38(5 Suppl 5):S51-6. Sprague SM, Llach F, Amdahl M, Taccetta C, Battle D. Paricalcitol versus calcitriol in the treatment of secondary hyperparathyroidism. Kidney International 2003; 63:1483- 1490. Lindberg J, Martin KJ, Gonzalez EA, Acchiardo SR, Valdin JR, Soltanek. A long-term multicentere study of the efficacy and safety of paricalcitol in end-stage renal disease. Clin Nephrol 2001; 56:315-23. Slatopolsky E, Finch JL, Ritter C, et al., A new Analog of calcitriol, 19-nor-1a, 25- (OH)2D2, suppresses parathyroid hormone secretion in uremic rats in the absence of hypercalcemia. Am J Kidney Dis, 1995; 26(5):852-860. Takahashi F, Finch JL, Denda M, et al., A new analog of 1,25-(OH)2D2, 19-nor-1,25- (OH)2D2, suppresses serum PTH and parathyroid gland growth in uremic rats without elevation of intestinal vitamin D receptor content. Am J Kidney Dis 1997; 30(1): 105- 122. Finch JL, Brown AJ, Slatopolsky E. Differential effects of 1a, 25-dihydroxyvitamin D3 and 19-nor-1a,25-dihydroxyvitamin D2 on calcium and phosphorous resorption in bone. J Am Soc Nephrol 1999; 10(5):980-991. Brown AJ. Vitamin D analogues. Am J Kidney Dis 1998; 32(2 Suppl 2):S25-39. IMPORTANT: PLEASE READ

PART III: CONSUMER INFORMATION

PrZEMPLAR(r)

Paricalcitol Capsules

This leaflet is part III of a three-part "Product Monograph" published when ZEMPLAR(r) Capsules was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about ZEMPLAR(r) Capsules. Contact your doctor or pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

ZEMPLAR(r) Capsules are used in the prevention and treatment of secondary hyperparathyroidism (high levels of parathyroid hormone which can cause bone problems) in chronic renal failure

patients on peritoneal or hemodialysis (Chronic Kidney Disease

Stage 5).

What it does:

ZEMPLAR(r) Capsules are a synthetic vitamin D analogue and are used to replace the body's naturally produced active form of

vitamin D. In healthy people, the active form of vitamin D is

naturally produced by the kidneys but in kidney failure, the production of the active vitamin is reduced which can cause low levels of calcium and high levels of parathyroid hormone in the blood.

When it should not be used:

ZEMPLAR(r) Capsules should not be used:

• If you are allergic to vitamin D or have developed evidence of vitamin D toxicity. Symptoms which can occur after receiving too much vitamin D include: confusion, feeling sleepy, weakness, muscle pain, bone pain, constipation, nausea, vomiting, stomach pains, itchy skin, increased thirst, and increased urination.

• If you suffer from hypercalcemia (high levels of calcium in your blood)

• If you are allergic to any of the product's ingredients

What the medicinal ingredient is:

The active substance is paricalcitol.

What the important nonmedicinal ingredients are: ZEMPLAR(r) Capsules also contains medium chain triglycerides, alcohol, butylated hydroxytoluene, gelatin, glycerin, titanium dioxide, ink, Opacode(r) WB, black, iron oxide red (2 mcg capsules only), iron oxide yellow (2 mcg and 4 mcg capsules), iron oxide black (1 mcg capsules only), purified water.

What dosage forms it comes in:

Each capsule contains either 1 mcg, 2 mcg or 4 mcg of paricalcitol. The 1 mcg capsule is an oval, gray, soft gelatin capsule imprinted

with and ZA. The 2 mcg capsule is an oval, orange-brown, soft

gelatin capsule imprinted with and ZF. The 4 mcg capsule is an oval, gold soft gelatin capsule imprinted with and ZK.

ZEMPLAR(r) Capsules is available in bottles containing 30 capsules each.

WARNINGS AND PRECAUTIONS

BEFORE you use ZEMPLAR(r) Capsules talk to your doctor or pharmacist if:

• You are pregnant or if you are breast feeding. Ask your doctor or pharmacist for advice.

INTERACTIONS WITH THIS MEDICATION

Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including the medicine you can buy without a prescription, natural health products, vitamin or mineral supplements.

Drugs that may interact with ZEMPLAR(r) Capsules include:

• Products containing phosphate or vitamin D.

• Products which contain aluminum or magnesium, these would include antacids (stomach medicine) or phosphate binders (used to remove phosphate from the blood).

• Digitalis compound e.g., digoxin or digitoxin (medicines used in certain heart conditions), thiazide diuretics (a type of water tablet) or medicines which contain high levels of calcium.

• Products used to treat fungal infections (e.g., ketoconazole).

PROPER USE OF THIS MEDICATION

Usual dose:

The dosage of ZEMPLAR(r) Capsules varies for each patient. Your doctor will decide on the appropriate dose for you.

ZEMPLAR(r) Capsules are to be taken three times a week (every other day) and may be taken with or without food.

Missed dose:

If you miss a dose, do not take a double dose. The next dose

should be taken as usual.

Overdose:

If you take more ZEMPLAR(r) Capsules than you should, contact your doctor or an emergency room of the nearest hospital.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

HOW TO STORE IT

The most common side effects experienced: These might affect between 1 and 10 in every 100 people. High blood levels of calcium and phosphate; low blood levels of calcium, loss of appetite, diarrhea, dizziness, acne, breast pain, itchy skin and a change in your sense of taste.

Uncommon side effects: These might affect less than 1 in every 100 people. Allergic reaction, constipation, dry mouth, indigestion, gastrointestinal disorder or upset stomach (gastritis), dizziness, rash, hives, leg cramps and unusual taste. The results of blood tests may show raised liver enzymes.

Too much ZEMPLAR(r) Capsules can cause hypercalcemia (higher than normal levels of calcium in the blood, which can be harmful). To help prevent this your blood will be tested frequently early in your treatment, so that your doctor can adjust the dose of ZEMPLAR(r) Capsules to suit you.

Early signs and symptoms of hypercalcemia associate with vitamin D overdose include weakness, headache, feeling sleepy or sick, vomiting, dry mouth, constipation, muscle pain, bone pain and metallic taste.

Symptoms of hypercalcemia associated with vitamin D overdose which may develop over a longer period include a lack of appetite, feeling sleepy, weight loss, sore eyes, runny nose, itchy skin, feeling hot and feverish, decreased sex drive, calcium deposits and severe abdominal pain (due to an inflamed pancreas).

If you experience any other unusual or unexpected symptoms while receiving ZEMPLAR(r) Capsules tell your doctor immediately.

ZEMPLAR(r) Capsules should be stored between 15 and 25oC.

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada collects information on serious and unexpected effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Health Canada by:

toll-free telephone: 866-234-2345

toll-free fax 866-678-6789 By email: cadrmp @hc-sc.gc.ca

By regular mail: National AR Centre

Marketed Health Products Safety and Effectiveness Information Division

Marketed Health Products Directorate Tunney's Pasture, AL 0701C

Ottawa ON K1A 0K9

NOTE: Before contacting Health Canada, you should contact your physician or pharmacist.

MORE INFORMATION

This document plus the full product monograph, prepared for health professionals can be found at: http://www.abbott.ca or by contacting the sponsor, Abbott Laboratories, Limited at

1-800-699-9948.

This leaflet was prepared by Abbott Laboratories, Limited. Last revised: November 2007

This is not a complete list of side effects. For any unexpected effects while taking ZEMPLAR(r), contact your doctor or pharmacist. IMPORTANT: PLEASE READ

PART III: CONSUMER INFORMATION

PrZEMPLAR(r)

Paricalcitol Injection USP

This leaflet is part III of a three-part "Product Monograph" published when ZEMPLAR(r) Injection USP was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about ZEMPLAR(r) Injection USP. Contact your doctor or pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

ZEMPLAR(r) Injection USP is used in the prevention and treatment of secondary hyperparathyroidism (high levels of parathyroid hormone which can cause bone problems) in chronic renal failure

patients on hemodialysis (Chronic Kidney Disease Stage 5).

What it does:

ZEMPLAR(r) Injection USP is a synthetic vitamin D analogue and is used to replace the body's naturally produced active form of vitamin D. In healthy people, the active form of vitamin D is

naturally produced by the kidneys but in kidney failure, the

production of the active vitamin is reduced which can cause low levels of calcium and high levels of parathyroid hormone in the blood.

When it should not be used:

ZEMPLAR(r) Injection USP should not be used:

If you are allergic to vitamin D or have developed evidence of vitamin D toxicity. Symptoms which can occur after receiving too much vitamin D include: confusion, feeling sleepy, weakness, muscle pain, bone pain, constipation, nausea, vomiting, stomach pains, itchy skin, increased thirst, and increased urination.

If you suffer from hypercalcemia (high levels of calcium in your blood)

If you are allergic to any of the product's ingredients

What the medicinal ingredient is:

WARNINGS AND PRECAUTIONS

This product contains 20% ethanol. The amount of ZEMPLAR(r) Injection USP given to you could contain up to 1.3 grams of alcohol. This could be harmful to people who suffer from liver disease, alcoholism, epilepsy, brain injury or disease as well as for pregnant women and children. It may modify or increase the effect of other medicines.

BEFORE you use ZEMPLAR(r) Injection USP talk to your doctor or pharmacist if:

• You are pregnant or if you are breast feeding. Ask your

doctor or pharmacist for advice.

You have liver disease

You drink alcohol

You have seizures (epilepsy or brain injury)

INTERACTIONS WITH THIS MEDICATION

Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including the medicine you can buy without a prescription, natural health products, vitamin or mineral supplements.

Drugs that may interact with ZEMPLAR(r) Injection USP include:

• Products containing phosphate or vitamin D.

• Products which contain aluminum or magnesium, these would include antacids (stomach medicine) or phosphate binders (used to remove phosphate from the blood).

• Digitalis compound e.g., digoxin or digitoxin (medicines used in certain heart conditions), thiazide diuretics (a type of water tablet) or medicines which contain high levels of calcium.

• Products used to treat fungal infections (e.g., ketoconazole).

PROPER USE OF THIS MEDICATION

Usual dose:

*

The active substance is paricalcitol.

The dosage of ZEMPLAR

Injection USP varies for each patient.

Your doctor will decide on the appropriate dose for you.

*

What the important nonmedicinal ingredients are:

ZEMPLAR

ZEMPLAR(r) Injection USP also contains alcohol (20% v/v), propylene glycol and water for injection.

What dosage forms it comes in:

ZEMPLAR(r) Injection USP is available as a liquid (containing

the hemodialysis line. You should not receive ZEMPLAR

Injection USP any more frequently than every other day during dialysis.

Overdose:

5 micrograms of paricalcitol per 1 mL) and packaged in ampoules

If you think you are given too much ZEMPLAR(r)

Injection USP

or Fliptop vials as follows:

• Ampoules containing 1 mL or 2 mL

• Fliptop vials containing 1 mL or 2 mL

than you should, talk to your nurse, doctor, or contact an

emergency room of the nearest hospital.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

The most common side effects experienced: These might affect between 1 and 10 in every 100 people. High blood levels of calcium and phosphate; parathyroid disorder; itchy skin and a change in your sense of taste.

Uncommon side effects: These might affect less than 1 in every 100 people. Blood disorders; enlargement of lymph nodes; taking longer for your blood to clot; blood pressure problems; irregular heart beat; heart attack; stroke; fainting; tissue swelling; fluid retention; loss of appetite; weight loss; constipation; dry mouth; feeling thirsty; diarrhea; feeling sick; vomiting; bleeding from your bottom; difficulty swallowing; indigestion. The results of blood tests may show raised liver enzymes. Unsteadiness; confusion; sleep disturbance; feeling anxious; dizziness; behavioural disorders; shaking; muscle twitches; numbness; eye (glaucoma); breathing difficulties; cough; nose bleeds; fluid on the lungs; chest infection; asthma; sore throat; rash; altered hair growth; sweating; feeling tired; joint pain; muscle pain; twitching; breast cancer; breast pain; impotence; inflammation of vagina; allergic reaction; aches and pains; feeling tired; fever; pain around the injection site; infections; flu-like symptoms, swelling of the face and mouth.

Too much ZEMPLAR(r) Injection USP can cause hypercalcemia (higher than normal levels of calcium in the blood, which can be harmful). To help prevent this your blood will be tested frequently early in your treatment, so that your doctor can adjust the dose of ZEMPLAR(r) Injection USP to suit you.

Early signs and symptoms of hypercalcemia associate with vitamin D overdose include weakness, headache, feeling sleepy or sick, vomiting, dry mouth, constipation, muscle pain, bone pain and metallic taste.

Symptoms of hypercalcemia associated with vitamin D overdose which may develop over a longer period include a lack of appetite, feeling sleepy, weight loss, sore eyes, runny nose, itchy skin, feeling hot and feverish, decreased sex drive, calcium deposits and severe abdominal pain (due to an inflamed pancreas).

The results of blood and urine tests may show high cholesterol, urea nitrogen (BUN) and raised levels of liver enzymes. Your blood pressure may be affected and heart beat irregularities can occur. ZEMPLAR(r) Injection USP may rarely cause mental changes including confusion, drowsiness, insomnia or nervousness.

If you experience any other unusual or unexpected symptoms while receiving ZEMPLAR(r) Injection USP tell your doctor immediately.

This is not a complete list of side effects. For any unexpected effects while taking ZEMPLAR(r) Injection USP, contact your doctor or pharmacist.

HOW TO STORE IT

ZEMPLAR(r) Injection USP should be stored between 15 and 25oC. Protect from light, freezing and excessive heat. IMPORTANT: PLEASE READ

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada collects information on serious and unexpected effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Health Canada by:

toll-free telephone: 866-234-2345

toll-free fax 866-678-6789 By email: cadrmp @hc-sc.gc.ca

By regular mail: National AR Centre

Marketed Health Products Safety and Effectiveness Information Division

Marketed Health Products Directorate Tunney's Pasture, AL 0701C

Ottawa ON K1A 0K9

NOTE: Before contacting Health Canada, you should contact your physician or pharmacist.

MORE INFORMATION

This document plus the full product monograph, prepared for health professionals can be found at: http://www.abbott.ca or by contacting the sponsor, Abbott Laboratories, Limited at

1-800-699-9948.

This leaflet was prepared by Abbott Laboratories, Limited. Last revised: November 21, 2007