CCR5 antagonist

Pfizer Canada Inc. 17 300 Trans-Canada Highway Kirkland, Quebec H9J 2M5 Date of Revision: November 18, 2008

Submission Control Number: 124408

* (tm) CELSENTRI is a trademark of Pfizer Products Inc. / Pfizer Canada Inc., licensee

(c)

Pfizer Canada Inc., 2008

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 ADVERSE REACTIONS 7 DRUG INTERACTIONS 12 DOSAGE AND ADMINISTRATION 20 ACTION AND CLINICAL PHARMACOLOGY 22 STORAGE AND STABILITY 24 DOSAGE FORMS, COMPOSITION AND PACKAGING 24

PART II: SCIENTIFIC INFORMATION 26

PHARMACEUTICAL INFORMATION 26 CLINICAL TRIALS 27 DETAILED PHARMACOLOGY 30 TOXICOLOGY 32 REFERENCES 35

PART III: CONSUMER INFORMATION 36

PrCELSENTRI *

(maraviroc)

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

CELSENTRI (maraviroc) is contraindicated in patients with hypersensitivity to maraviroc or any component of this medication. For a complete listing, see the Dosage Forms, Composition and Packaging section of this product monograph.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

Hepatotoxicity has been reported with CELSENTRI use. A systemic allergic reaction, including pruritic rash, eosinophilia or elevated IgE may occur prior to the development of hepatotoxicity. Patients with signs or symptoms of acute hepatitis or allergic reaction should be evaluated immediately and, if required discontinuation of CELSENTRI treatment should be considered. (see WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic below).

General

CELSENTRI (maraviroc) should be taken as part of an antiretroviral combination regimen. As with other antiretrovirals, CELSENTRI should be optimally combined with other antiretrovirals to which the patient's virus is sensitive. Physicians should ensure that appropriate dose adjustment of CELSENTRI is made when CELSENTRI is co-administered with CYP3A4 inhibitors and/or inducers since maraviroc concentrations and its therapeutic effects may be affected (see DRUG INTERACTIONS). Tropism testing should be performed prior to initiation of therapy, however tropism assays may not detect low levels of CXCR4-tropic variants. CELSENTRI did not demonstrate efficacy in a Phase 2 study of patients infected with CXCR4-tropic virus (see CLINICAL TRIALS). The long-term impact of CELSENTRI-mediated inhibition of the CCR5 receptor is the subject of ongoing studies.

Cardiovascular

CELSENTRI should be used with caution in patients with a history of cardiovascular disease or who are at risk for cardiovascular events. Cases of myocardial ischemia and myocardial infarction were reported in 11 subjects (1.3%) receiving CELSENTRI in Phase 3 studies (total exposure 267 patient-years). These events mostly occurred in subjects with pre-existing cardiac disease or cardiac risk factors, which confounded the assessment of CELSENTRI causality.

Postural Hypotension and Syncope

CELSENTRI-related cases of postural hypotension and syncope were reported during Phase 3 studies in HIV-infected patients who received the drug at the recommended dose (see ADVERSE DRUG REACTIONS). At dosing higher than the recommended dose, CELSENTRI-related cases of postural hypotension and syncope were observed during Phase 1 studies in healthy volunteers. Caution should be used when administering CELSENTRI in patients who have a history of postural hypotension or who are on concomitant medications known to lower blood pressure.

Immune

Immune Reconstitution Syndrome

During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as MAC, CMV, PCP and TB), which may necessitate further evaluation and treatment.

Potential Risk of Infection and Malignancy

The antagonistic action of CELSENTRI on the CCR5 receptor may impair immune function and potentially increase the risk of developing infections and/or malignancy. The rates of certain infections (upper respiratory tract and Herpes virus) were higher in subjects receiving CELSENTRI, while others (pneumonia) were lower as compared to those in patients on placebo in Phase 3 studies (see ADVERSE REACTIONS). The overall incidence and severity of infection and AIDS-defining category C infections were similar in the CELSENTRI and placebo treatment arms. Patients on CELSENTRI treatment should be carefully monitored for symptoms of infection. There were no increased reports of malignancies in subjects treated with CELSENTRI during Phase 3 studies. Long-term follow-up is required to assess whether CELSENTRI increases the risk of malignancy.

Hepatic/Biliary/Pancreatic

A case of possible CELSENTRI-induced hepatotoxicity with allergic features has been reported in a study of healthy volunteers. In addition, an increase in hepatic adverse reactions with CELSENTRI was observed during studies of treatment-experienced subjects with HIV infection, although there was no overall increase in ACTG Grade 3/4 liver function test abnormalities. Discontinuation of CELSENTRI should be considered in any patient with signs or symptoms of acute hepatitis, in particular if drug-related hypersensitivity is suspected or with increased liver transaminases combined with rash or other systemic symptoms of potential hypersensitivity (e.g. pruritic rash, eosinophila or elevated IgE). Caution should also be used when administering CELSENTRI to patients with pre-existing liver dysfunction or who are co-infected with viral hepatitis B or C. If there is evidence of worsening of liver disease in such patients, interruption or discontinuation of treatment must be considered. The safety and efficacy of CELSENTRI have not been specifically studied in patients with significant underlying liver disorders. However drug levels were increased in patients with moderate hepatic impairment (see ACTION AND CLINICAL PHARMACOLOGY Special Populations and Conditions - Hepatic Impairment). In Phase 3 studies, approximately 6% of subjects were co-infected with Hepatitis B virus and approximately 6% were co-infected with Hepatitis C virus. Thus, the number of co-infected subjects was too small to assess the risk for hepatic adverse events with CELSENTRI administration in this patient population (see ACTION AND CLINICAL PHARMACOLOGY Special Populations and Conditions - Hepatic Impairment).

Renal

Renal Impairment

The safety and efficacy of maraviroc have not been specifically studied in patients with renal impairment, therefore maraviroc should be used with caution in this population. In the absence of metabolic inhibitors, renal clearance accounts for less than 25% of total clearance of maraviroc. However, in the presence of metabolic inhibitors, renal clearance may account for up to 70% of total clearance of maraviroc, hence renal impairment may result in increased maraviroc exposures in this case. Therefore, maraviroc should be used with caution in patients with renal impairment (CLcr < 80ml/min) who are also taking potent CYP3A4 inhibitors (see DOSAGE AND ADMINISTRATION).

Special Populations

Pregnancy, Fertility and Reproduction: see TOXICOLOGY, Fertility and Reproduction

Embryofetal development studies in rats and rabbits revealed no evidence of harm to the fetus from maraviroc. Pre- and post-natal developmental studies showed a slight increase in motor activity in male offspring at both weaning and as adults at the high dose, while no effects were seen in female offspring. The subsequent development of these offspring, including fertility and reproductive performance, was not affected by the maternal administration of maraviroc (

).

No meaningful clinical data on exposure during pregnancy are available. Because animal reproduction studies are not always predictive of human response, maraviroc should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to CELSENTRI and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263 or via email at http://www.apregistry.com.

Nursing Mothers:

It is recommended that HIV-infected women not breast-feed their infants under any circumstances to avoid the transmission of HIV infection. Studies in lactating rats indicate that maraviroc is extensively secreted into rat milk. It is not known whether maraviroc is secreted into human milk. Mothers should be instructed not to breast-feed if they are receiving CELSENTRI because of both the potential for HIV transmission and any possible undesirable effects in nursing infants.

Pediatrics (<16 years of age):

The pharmacokinetics, safety and efficacy of maraviroc in pediatric patients have not been established. Therefore, maraviroc should not be used in this patient population.

Geriatrics (>65 years of age):

There were insufficient numbers of subjects aged 65 and over in the clinical studies to determine whether they respond differently from younger subjects. In general, caution should be exercised when administering CELSENTRI in elderly patients, also reflecting the greater frequency of decreased hepatic and renal function, of concomitant disease and other drug therapy.

Gender and Race:

Dosage adjustment is not necessary based on gender or race.

Patients co-infected with Hepatitis B and/or Hepatitis C virus:

The safety and efficacy of CELSENTRI have not been studied specifically in patients co-infected with Hepatitis B or Hepatitis C virus. CELSENTRI should be used in caution with this population.

DRUG INTERACTIONS

Overview

Maraviroc is a substrate of cytochrome P450 CYP3A4. Co-administration of CELSENTRI (maraviroc) with medicinal products that induce CYP3A4 may decrease maraviroc concentrations and reduce its therapeutic effects. Co-administration of CELSENTRI with medicinal products that inhibit CYP3A4 may increase maraviroc plasma concentrations. Dose adjustment of CELSENTRI is recommended when CELSENTRI is co-administered with CYP34A inhibitors and/or inducers.

Drug-Drug Interactions

Effect of Maraviroc on the Pharmacokinetics of Concomitant Drugs

Maraviroc is unlikely to inhibit the metabolism of co-administered drugs that are metabolized by cytochrome P450 enzymes because it does not inhibit the seven major cytochrome P450 isoenzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) at clinically relevant concentrations in vitro (IC50 > 30uM). Drug interaction studies were performed with maraviroc and other drugs likely to be co- administered or commonly used as probes for pharmacokinetic interactions (see Tables 3 and 4). Maraviroc had no effect on the pharmacokinetics of zidovudine or lamivudine, suggesting no interactions with renal clearance or non-P450 metabolism. Maraviroc had no clinically relevant effect on the pharmacokinetics of midazolam, the oral contraceptives ethinyloestradiol and levonorgestrel, no effect on the urinary 6b-hydroxycortisol/cortisol ratio, suggesting no induction of CYP3A4 in vivo, and no effect on the debrisoquine metabolic ratio in vivo, suggesting no inhibition of CYP2D6. Maraviroc inhibits P-glycoprotein in vitro (IC50 is 183uM). Systemic effects of P-glycoprotein are unlikely to be of relevance. Maraviroc could inhibit P-glycoprotein in the gut and may thus affect bioavailability of certain drugs.

Effect of Concomitant Drugs on the Pharmacokinetics of Maraviroc

Maraviroc is a substrate of CYP3A4 and Pgp and hence its pharmacokinetics are likely to be modulated by inhibitors and inducers of these enzymes/transporters. The CYP3A4/Pgp inhibitors ketoconazole, lopinavir/ritonavir, ritonavir, saquinavir and atazanavir all increased the Cmax and AUC of maraviroc (see Table 5). The CYP3A4 inducers rifampin and efavirenz decreased the Cmax and AUC of maraviroc (see Table 5). Tipranavir/ritonavir (net CYP3A4 inhibitor/Pgp inducer) did not affect the steady state pharmacokinetics of maraviroc. Substrates and inhibitors of renal clearance (cotrimoxazole and tenofovir) did not affect the pharmacokinetics of maraviroc (see Table 5).

Table 3: Established and Other Potentially Significant Drug Interactions:

Alterations in Dose or Regimen May be Recommended Based on Drug Interaction Studies or Predicted Interaction (see Tables 4 and 5)

Table 4: Drug Interactions: Pharmacokinetic Parameters for Co-Administered Drugs in the Presence of Maraviroc

Table 5: Drug Interactions: Pharmacokinetic Parameters for Maraviroc in the Presence of Co- Administered Drugs

Co-administered drug Dose of

co-administered drug

Dose of Maraviroc

N PK

change

Ratio (90% CI) of maraviroc pharmacokinetic parameters with/without co-administered drug (no effect = 100)

a

in HIV patients, compared to historical controls

Drug-Food Interactions

Coadministration of a 300 mg tablet with a high fat breakfast reduced maraviroc Cmax and AUC by 33% in healthy volunteers. There were no food restrictions in the studies that demonstrated the efficacy and safety of maraviroc (see CLINICAL TRIALS). Therefore, maraviroc can be taken with or without food at the recommended dose (see DOSAGE AND ADMINISTRATION).

Drug-Herb Interactions

Concomitant use of maraviroc and St. John's wort (Hypericum perforatum) or products containing St. John's wort is not recommended. Coadministration of maraviroc with St. John's wort is expected to substantially decrease maraviroc concentrations and may result in suboptimal levels of maraviroc and lead to loss of virologic response and possible resistance to maraviroc.

Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

Dosing Considerations

CELSENTRI (maraviroc) must be given in combination with other antiretroviral agents. The recommended dose is 300 mg twice daily but adjustments are recommended based on the patient's concomitant medications. CELSENTRI can be taken with or without food.

Recommended Dose and Dosage Adjustment

Adults: Table 6 DRUG INTERACTIONS, Drug-Drug Interactions, Table 3

The recommended dose of CELSENTRI is 300 mg twice daily. A dose adjustment may be needed due to the potential for drug interactions (see

and

).

Table 6 gives the recommended dose adjustments (see DRUG INTERACTIONS). Table 6: Recommended Dosing Regimen

Pediatrics (<16 years of age):

The pharmacokinetics, safety and efficacy of maraviroc in pediatric patients have not been established. Therefore, maraviroc should not be used in this patient population.

Geriatrics (>65 years of age):

There were insufficient numbers of subjects aged 65 and over in the clinical studies to determine whether they respond differently from younger subjects. In general, caution should be exercised when administering CELSENTRI in elderly patients, also reflecting the greater frequency of decreased hepatic and renal function, of concomitant disease and other drug therapy.

Renal Impairment: The safety and efficacy of maraviroc have not been specifically studied in patients with renal impairment, therefore maraviroc should be used with caution in this population. In the absence of metabolic inhibitors, renal clearance accounts for less than 25% of total clearance of maraviroc. However, in the presence of metabolic inhibitors, renal clearance may account for up to 70% of total clearance of maraviroc, hence renal impairment may result in increased maraviroc exposures in this case. Therefore, maraviroc should be used with caution in patients with renal impairment (CLcr < 80ml/min) who are also taking potent CYP3A4 inhibitors. Table 7 provides dose interval adjustment guidelines based on simulations of increasing renal impairment in patients being co-administered potent CYP3A4 inhibitors. The safety and efficacy of these dose interval adjustments have not been clinically evaluated. Therefore, clinical response to treatment and renal function should be closely monitored in these patients

Table 7: Dose interval adjustments based on simulations of increasing renal impairment in patients being co-administered potent CYP3A4 inhibitors

Missed Dose

If a dose is missed, patients should take the next dose as soon as possible. A dose should not be doubled.

OVERDOSAGE

For the management of a suspected drug overdose, contact your regional Poison Control Centre. There is no specific antidote for overdose with maraviroc. Treatment of overdose should consist of general supportive measures including keeping the patient in a supine position, careful assessment of patient vital signs, blood pressure and ECG. Administration of activated charcoal may be used to aid in removal of unabsorbed drug. Since maraviroc is moderately protein bound, dialysis may be beneficial in removal of this medicine. The highest dose administered in clinical studies was 1200 mg. The dose limiting adverse event was postural hypotension.

ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics, Effects on Electrocardiogram

Prolongation of the QT interval was seen in dogs and monkeys at plasma concentrations 6 and 12 times, respectively, those expected in humans at the maximum recommended dose of 300 mg twice daily. However, no significant QT prolongation was seen in the Phase 3 clinical studies using the recommended doses of maraviroc or in a specific pharmacokinetic study to evaluate the potential of maraviroc to prolong the QT interval (see

).

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Maraviroc is a member of a therapeutic class called CCR5 antagonists. Maraviroc selectively binds to the human chemokine receptor CCR5 and inhibits the interaction of the envelope glycoprotein (gp120) from CCR5-tropic HIV-1 strains with CCR5. Binding of gp120 to CCR5 is an essential step in the HIV-1 entry process for CCR5-tropic strains. Maraviroc has no activity against viruses that use CXCR4 as their co-receptor (CXCR-4-tropic and dual-tropic viruses).

Pharmacodynamics

Maraviroc inhibits the replication of CCR5-tropic laboratory strains and clinical isolates of HIV-1 in models of acute T-cell infection (see DETAILED PHARMACOLOGY, Pharmacodynamics).

Pharmacokinetics

Table 8: Mean Maraviroc Pharmacokinetic Parameters

*

the estimated exposure is lower compared to other studies possibly due to food effect, compliance and concomitant medications

Absorption:

Peak maraviroc plasma concentrations are attained 0.5-4h following single oral doses of 1-1200 mg administered to uninfected volunteers. The pharmacokinetics of oral maraviroc are not dose proportional over the dose range.

The absolute bioavailability of a 100 mg dose is 23% and is predicted to be 33% at 300 mg. Maraviroc is a substrate for the efflux transporter P-glycoprotein. Effect of Food on Oral Absorption: Coadministration of a 300 mg tablet with a high fat breakfast reduced maraviroc Cmax and AUC by 33% in healthy volunteers. There were no food restrictions in the studies that demonstrated the efficacy and safety of maraviroc (see CLINICAL TRIALS). Therefore, maraviroc can be taken with or without food at the recommended dose (see DOSAGE AND ADMINISTRATION).

Distribution:

Maraviroc is bound (approximately 76%) to human plasma proteins, and shows moderate affinity for albumin and alpha-1 acid glycoprotein. The volume of distribution of maraviroc is approximately 194L.

Preclinical data in the rat indicate CSF exposure with concentrations ~10% of free plasma concentrations.

Metabolism:

Studies in humans and in vitro studies using human liver microsomes and expressed enzymes have demonstrated that maraviroc is principally metabolized by the cytochrome P450 system to metabolites that are essentially inactive against HIV-1. In vitro studies indicate that CYP3A4 is the major enzyme responsible for maraviroc metabolism. In vitro studies also indicate that polymorphic enzymes CYP2C9, CYP2D6 and CYP2C19 do not contribute significantly to the metabolism of maraviroc.

Maraviroc is the major circulating component (~42% drug related radioactivity) following a single oral dose of 300 mg [14C]-maraviroc to healthy male volunteers. The most significant circulating metabolite in humans is a secondary amine (~22% radioactivity) formed by N-dealkylation. This polar metabolite has no significant pharmacological activity. Other metabolites are products of mono-oxidation and are only minor components of plasma drug related radioactivity. Elimination: The terminal half-life of maraviroc following oral dosing to steady-state in healthy subjects was 14-18 hours. A mass balance/excretion study was conducted using a single 300 mg dose of 14C-labeled maraviroc. Approximately 20% of the radiolabel was recovered in the urine and 76% was recovered in the feces over 168 hours. Maraviroc was the major component present in urine (mean of 8% dose) and feces (mean of 25% dose). The remainder was excreted as metabolites.

Effects on Electrocardiogram:

A placebo-controlled, randomized, crossover study to evaluate the effect on the QT interval of healthy male and female volunteers was conducted with 3 single oral doses of maraviroc and moxifloxacin. The placebo-adjusted mean maximum increases in QTc from baseline after 100, 300 and 900 mg of maraviroc were -2.3, -0.6, and 1.0 msec, respectively, and

12.9 msec for moxifloxacin 400 mg. No subject in any group had an increase in QTc of >= 60 msec from baseline. No subject experienced an interval exceeding the potentially clinically relevant threshold of 500 msec.

Special Populations and Conditions

Maraviroc is primarily metabolized and eliminated by the liver. A study compared the pharmacokinetics of a single 300mg dose of CELSENTRI in patients with mild (Child-Pugh Class A, n=8), and moderate (Child-Pugh Class B, n=8) hepatic impairment compared to healthy subjects (n=8). Geometric mean ratios for Cmax and AUClast were 11% and 25% higher respectively for subjects with mild hepatic impairment, and 32% and 46% higher respectively for subjects with moderate hepatic impairment compared to subjects with normal hepatic function. The pharmacokinetics of maraviroc have not been studied in subjects with severe hepatic impairment (see WARNINGS AND PRECAUTIONS).

Renal Impairment:

The safety and efficacy of maraviroc have not been specifically studied in patients with renal impairment, therefore maraviroc should be used with caution in this population. In the absence of metabolic inhibitors, renal clearance accounts for less than 25% of total clearance of maraviroc. However, in the presence of metabolic inhibitors, renal clearance may account for up to 70% of total clearance of maraviroc, hence renal impairment may result in increased maraviroc exposures in this case (see DOSAGE AND ADMINISTRATION).

STORAGE AND STABILITY

CELSENTRI (maraviroc) film-coated tablets should be stored at 15o to 30oC in a USP tight container.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Dosage Form and Packaging:

Dosage Form: 150 and 300 mg tablets are blue, biconvex, oval film-coated tablets debossed with "Pfizer" on one side and "MVC 150" or "MVC 300" on the other. Packaging: High density polyethylene bottles (HDPE) with polypropylene child resistant (CR) closures and an aluminium foil/polyethylene heat induction seal containing 30, 60, 120 and 180 film-coated tablets for the 150 mg and 300 mg strengths. Polyvinyl chloride (PVC) blisters with aluminium foil backing in a carton containing 30, 60, 90 and 180 (2 x 90) film-coated tablets for the 150 mg and 300 mg strengths.

Composition:

CELSENTRI (maraviroc) is available as film-coated tablets for oral administration containing either 150 or 300 mg of maraviroc and the following inactive ingredients: dibasic calcium phosphate (anhydrous), magnesium stearate, microcrystalline cellulose, sodium starch glycolate. The film- coat [Opadry(tm)II Blue (85G20583)] contains FD&C blue #2 aluminum lake, polyethylene glycol (macrogol 3350), polyvinyl alcohol, soya lecithin, talc and titanium dioxide.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Maraviroc Chemical name: 4,4-difluoro-N-{(1S)-3-[exo-3-(3-isopropyl-5-methyl-4H-1,2,4- triazol-4-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl} cyclohexanecarboxamide. Molecular formula: C29H41F2N5O Molecular weight: 513.67 Daltons Structural formula:

F F

NH

N

H3C

N

N

N

CH3 Description: Maraviroc is a white to pale colored powder. It is highly soluble across the physiological pH range (pH 1.0 to 7.5) pka: Maraviroc has pKa values of 3.3 and 7.3. The lower pKa value corresponds to protonation of the 1,2,4-triazole ring. The higher pKa value corresponds to protonation of tropane nitrogen.

CLINICAL TRIALS

Studies in Antiretroviral Experienced Patients

The clinical efficacy and safety of CELSENTRI are derived from analyses of 24-week data from 2 ongoing studies, MOTIVATE 1 and MOTIVATE 2, in antiretroviral treatment-experienced adult patients infected with CCR5 tropic HIV-1. These studies are supported by a 24-week study in antiretroviral treatment-experienced adult patients infected with dual/mixed-tropic HIV-1, 1029.

Studies in CCR5-tropic, Treatment-Experienced Patients

Studies MOTIVATE 1 and MOTIVATE 2 are ongoing, double-blind, randomized, placebo- controlled, multicenter studies in patients infected with CCR5-tropic HIV-1. Patients were required to have an HIV-1 RNA of greater than 5,000 copies/mL despite at least 6 months of prior therapy with at least 1 agent from 3 of the 4 antiretroviral drug classes [>=1 nucleoside reverse transcriptase inhibitors (NRTI), >=1 non-nucleoside reverse transcriptase inhibitors (NNRTI), >=2 protease inhibitors (PI), and/or enfuvirtide] or documented resistance or intolerance to at least 1 member of each class. All patients received an optimized background regimen consisting of 3 to 6 antiretroviral agents (excluding low-dose ritonavir) selected on the basis of the subject's prior treatment history and baseline genotypic and phenotypic viral resistance measurements. In addition to the optimized background regimen, patients were then randomized in a 2:2:1 ratio to maraviroc 300 mg once daily, maraviroc 300 mg twice daily, or placebo. Doses were adjusted based on background therapy (see DOSAGE AND ADMINISTRATION - Table 6). In the pooled analysis for studies, MOTIVATE 1 and MOTIVATE 2, the demographics and baseline characteristics of the treatment groups were comparable (Tables 9 and 10). Table 9 compares the demographic characteristics of the patients in the CELSENTRI + OBT and placebo + OBT arms.

Table 9: Demographic Characteristics of Patients in Studies MOTIVATE 1 and MOTIVATE 2

300 mg dose equivalent

Table 10 compares the baseline characteristics of the patients on CELSENTRI + OBT with those on placebo + OBT.

Table 10: Baseline Characteristics of Patients in Studies MOTIVATE 1 and MOTIVATE 2

a

OSS -Sum of active drugs in OBT based on combined information from genotypic and phenotypic testing.

b

Resistance mutations based on IAS guidelines

300 mg dose equivalent

The week 24 results for the pooled studies MOTIVATE 1 and MOTIVATE 2 are shown in Table 11.

Table 11: Outcomes of Randomized Treatment at Week 24 - Pooled Studies MOTIVATE 1 and MOTIVATE 2

* For all efficacy endpoints, the confidence intervals were 95%, except for HIV-1 RNA change from baseline which

was 97.5%.

* *

300 mg dose equivalent

Tropism

In the majority of cases, treatment failure on maraviroc was associated with detection of CXCR4- using (i.e., CXCR4- or dual/mixed-tropic) virus which was not detected by the tropism assay prior to treatment. CXCR4-using virus was detected at failure in approximately 60% of subjects who failed treatment on maraviroc, as compared to 6% of subjects who experienced treatment failure in the placebo arm. To investigate the likely origin of the on-treatment CXCR4-using virus, a detailed clonal analysis was conducted on virus from 20 representative subjects (16 subjects from the maraviroc arms and 4 subjects from the placebo arm) in whom CXCR4-using virus was detected at treatment failure. From analysis of amino acid sequence differences and phylogenetic data, CXCR4-using virus in these subjects emerged from a low level of pre-existing CXCR4 using virus not detected by the tropism assay (which is population-based) prior to treatment rather than from a co-receptor switch from CCR5-tropic virus to CXCR4-using virus resulting from mutation in the virus. Detection of CXCR4-using virus prior to initiation of therapy has been associated with a reduced virological response to maraviroc. Furthermore, subjects failing maraviroc BID with CXCR4-using virus had a lower median increase in CD4+ cell counts from baseline (+22 cells/mm3) than those subjects failing with CCR5-tropic virus (+149 cells/mm3). The median increase in CD4+ cell count in patients failing in the placebo arm was +5 cells/mm3.

Study in Dual/Mixed-tropic Patients

Study 1029 was an exploratory, randomized, double-blind, multicenter trial to determine the safety and efficacy of maraviroc in patients infected with dual/mixed coreceptor tropic HIV-1. The inclusion/exclusion criteria were similar to those for Studies MOTIVATE 1 and MOTIVATE 2 above and the patients were randomized in a 1:1:1 ratio to CELSENTRI once daily, CELSENTRI twice daily, or placebo. There was no significant difference in the efficacy between the CELSENTRI and placebo arms, however patients receiving CELSENTRI exhibited an increase in their absolute CD4 cell counts from baseline (+62) as compared to subjects on placebo (+36).

DETAILED PHARMACOLOGY

Pharmacodynamics

Antiviral Activity In Vitro

Maraviroc inhibits the replication of CCR5-tropic laboratory strains and clinical isolates of HIV-1 in models of acute T-cell infection. The in vitro IC50 (50% inhibitory concentration) for maraviroc against HIV-1 group M isolates (subtypes A to J) and group O isolates ranged from 0.1 to 8.9 nM (0.05 to 4.56 ng/mL). HIV-1 clinical isolates resistant to nucleoside analogue reverse transcriptase inhibitors (NRTI), non-nucleoside analogue reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI) and enfuvirtide were all susceptible to maraviroc in cell culture. When used with other antiretroviral agents in vitro, the combination of maraviroc produced additive/synergistic antiviral effects with protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir) and was generally additive with the NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine and zidovudine) and the NNRTIs (delavirdine and efavirenz and nevirapine). Maraviroc was additive/synergistic with the HIV fusion inhibitor enfuvirtide. Protein binding studies have shown that the antiviral activity of maraviroc decreases on average 2-fold in conditions where plasma proteins are present. Maraviroc has no activity against viruses that use CXCR4 as their co-receptor (CXCR4-tropic and dual-tropic viruses). The antiviral activity of maraviroc against HIV-2 has not been evaluated.

Resistance In Vitro

HIV-1 variants with reduced susceptibility to maraviroc have been selected in vitro, following serial passage of 2 CCR5-tropic viruses. The maraviroc-resistant viruses remained CCR5-tropic and there was no conversion from a CCR5-tropic virus to a CXCR4-using virus. Two amino acid residue substitutions in the V3-loop region of the HIV-1 envelope glycoprotein (gp160), A316T and I323V (numbering by alignment to the HIV-1 strain HXB2) were identified by site directed mutagenesis and were shown to be necessary for the maraviroc-resistant phenotype in the HIV-1 isolate CC1/85. In contrast, a 3-amino acid residue deletion in the V3 loop, [? ]QAI (positions 315-317, numbering by alignment to the HIV-1 strain HXB2), was associated with the maraviroc-resistant phenotype in the RU570 isolate. Concentration response curves for the maraviroc resistant viruses were characterized phenotypically by curves that did not reach 100% inhibition in drug assays using serial dilutions of maraviroc. The relevance of the specific gp120 mutations observed in isolates CC1/85 and RU570 to maraviroc susceptibility in other viruses is not known.

Resistance In Vivo

The resistance profile in treatment-naive and treatment-experienced subjects has not yet been fully characterized. Preliminary data from 12 treatment-experienced patients failing maraviroc- containing regimens identified 5 viruses that were characterized in drug assays by curves that did not reach 100% inhibition. Unique patterns of multiple amino acid substitutions in the V3-loop of gp120 were detected in each of these viruses, however all had changes at either position 308 or 323. The contribution of mutations in other regions of gp120 to maraviroc resistance has not been investigated.

Cross-resistance In Vitro

Maraviroc-resistant viruses that emerged in vitro remained sensitive to fusion inhibitor enfuvirtide and the protease inhibitor saquinavir (see Resistance In Vitro).

TOXICOLOGY

Acute/Chronic Toxicity

The no observed adverse effect level (NOAEL) was found to be 750 mg/kg in the mouse and 100 mg/kg in the rat. The LD in both rats and mice is >2000 mg/kg.

Repeat-Dose Toxicity Studies

Repeat-dose studies in CD-1 mice were associated with mortality and slight to mild degenerative changes to the superficial epithelium of the cecum at oral daily doses of 1000 and 2000 mg/kg and no adverse effects at 750 mg/kg. The AUC at the NOAEL provides an exposure 68-fold greater than that at the therapeutic dose. Maraviroc was also well tolerated in rasH2 transgenic mice at daily doses of 200, 800 and 1500 mg/kg for up to 6 months. In a 1-month oral range-finding study in male rats at daily doses of 100, 300, and 1500 mg/kg, the dose of 1500 mg/kg induced clinical signs of salivation, diarrhea, decreases in body weight and food consumption, dilatation of colon and cecum (probably secondary to diarrhea) and pituitary vacuolation. In addition, 2 rats had moderate increases in liver enzymes, associated in 1 rat with liver necrosis. The NOAEL was 300 mg/kg. In a 6-month study, dose levels of 30, 100, 300 and 900 mg/kg were well tolerated. Body weight in males treated with 900 mg/kg was reduced at the end of the treatment and reversibility periods. The liver was confirmed as the principal target organ, with changes in the bile duct (vacuolation from 100 mg/kg and hyperplasia from 300 mg/kg) and hepatocytes (altered cell foci and multinucleated cells at 900 mg/kg). Some hepatic changes in males treated with 300 and 900 mg/kg were still present after a 3-month reversibility period. Thyroid follicular cell hypertrophy at 300 and 900 mg/kg was shown to be reversible. An exploratory study to investigate thyroid function in rats showed that liver enzyme induction may have contributed to this change. The NOAEL is 100 mg/kg, providing an AUC exposure 8-fold greater than that at the therapeutic dose. In dogs, maraviroc produced a range of clinical signs: emesis from 5 mg/kg, salivation, reddening of the skin and conjunctiva and mydriasis from 10 mg/kg, protruding nictitating membrane, lacrimation from 15 mg/kg and partially closed eyes from 40 mg/kg. Multiple bouts of emesis from 150 mg/kg and body weight loss at this dose are considered to set the maximum tolerated dose, at an exposure multiple of 23 (Cmax) or 28 (AUC). There were inconsistent reductions in blood pressure in dogs at 50 and 250 mg/kg, and increases in QTc interval from 15 mg/kg. Consequently, the NOAEL is 5 mg/kg in dogs, providing a Cmax exposure 2-fold greater than that at the therapeutic dose. Studies in monkeys indicated that the daily dose of 800 mg/kg was not well tolerated. Animals treated with this dose were euthanized due to severe clinical signs (prostration, decreased activity, loss of balance, and vomiting) and cardiovascular effects (QT prolongation, decreased heart rate, and lowered diastolic blood pressure). Treatment at 400 mg/kg produced similar, though less severe, findings. After treatment for 9 months, body weight in males was reduced at 120 mg/kg (8%) and 400 mg/kg (11%). At 400 mg/kg (given as a divided dose), decreases in blood pressure, heart rate and increases in QTc interval were measured. At this dose, Cmax exposures were 11-12 fold higher than seen at the therapeutic dose. Based on these cardiovascular changes the NOAEL is 120 mg/kg in monkeys, providing a Cmax exposure 5-fold greater than that at the therapeutic dose.

Fertility and Reproduction

A fertility study was conducted to evaluate the effects of maraviroc on mating performance, the fertility of adult male and female rats and the development of the embryos during the pre- and post- implantation stages. The NOAEL for adult male and female rats was 300 mg/kg. There were no effects on fertility up to 1000 mg/kg in either sex. Pre- and post-natal developmental studies were performed in rats at doses up to 27-fold the estimated free clinical AUC for a 300 mg twice daily dose. The only effect in the offspring was a slight increase in motor activity in male offspring rats at both weaning and as adults at the high dose, while no effects were seen in female offspring. The subsequent development of these offspring, including fertility and reproductive performance, was not affected by the maternal administration of maraviroc. Embryofetal development studies were conducted in rats and rabbits at doses up to 39 and 34-fold the estimated free clinical AUC for a 300 mg twice daily dose. In the oral embryofetal development study in rats at daily doses of 100, 300, and 1000 mg/kg, the high dose was slightly toxic to pregnant females (decreased body weight and food consumption). There were no effects on reproductive parameters, embryofetal development or growth. The NOAEL was 300 mg/kg for the pregnant females and 1000 mg/kg for the foetuses. In the oral embryofetal development study in rabbits at daily doses of 30, 75, and 200 mg/kg, death was observed at the high dose. There were no associated clinical signs or macroscopic findings. Treatment with maraviroc had no effect on reproductive parameters. An increased incidence of external anomalies was observed at the high dose. Thus, the NOAEL was 75 mg/kg (approximately 7-fold higher than seen at the therapeutic dose) for the pregnant females and fetuses.

Carcinogenesis and Mutagenesis

Carcinogenic potential was assessed in a 24-month study using Sprague-Dawley rats and in a 6-month study with Tg (rasH2) hemizygous mice. In rats, daily doses of 50, 100, 500 and 900 mg/kg were administered to males for 104 weeks and to females for 96 weeks (due to high mortality in female control rats). There was no adverse treatment effect on survival. Maraviroc produced a toxicologically significant decrease in mean body weight in the males at 500 and 900 mg/kg and in females at 900 mg/kg. An increased incidence of follicular cell adenoma of the thyroid was observed in both males and females of the high dose group (900 mg/kg; 21 times higher than that found at the human therapeutic dose of 300 mg bid). This may be associated with adaptive liver changes. A rare tumour, cholangiocarcinoma, was observed in the liver of 2 male rats at 900 mg/kg. The incidence was slightly higher than that observed in a large database of control animals (3/1850) and in the control group of a concurrent study (1/65). In Tg(rasH2) mice, daily doses of 200, 800 and 1500 mg/kg did not produce hyperplastic, neoplastic inflammatory or degenerative changes. The free plasma AUC exposure in Tg mice at 1500 mg/kg was 54-times higher than that found at the human therapeutic dose. Maraviroc is not considered to be genotoxic based on in vitro (bacterial mutation, chromosome aberration in human lymphocytes) and in vivo (mouse bone marrow micronucleus) tests.

Immunotoxicology

Immunotoxicologic potential was assessed in a 4-week oral immunotoxicology study in monkeys at daily doses of 30, 100 and 300 mg/kg (15, 50, 150 mg/kg BID). Treatment with maraviroc did not affect lymphocyte subset distribution, NK cell activity, phagocytosis activity, oxidative burst or humoral primary (IgM) and secondary (IgG) immune responses against KLH. There were no adverse pathological changes to the immune system.. CCR5 occupancy by maraviroc was complete at all timepoints at 300 mg/kg/day, while at 30 mg/kg/day CCR5 occupancy was complete at the 1 hour post-dose time point only (receptor occupancy was approx. 79% at 7 and 24 hours after dosing).

Local Tolerance

In topical studies, maraviroc produced very slight dermal irritation at 2000 mg/kg in rats, which resolved on day 5, but no dermal irritation in rabbits. Maraviroc produced very slight ocular irritation in an eye irritation study in rabbits and no evidence of skin sensitization in a local lymph node assay in mice.

REFERENCES

1. Brumme ZL, Goodrich J, Mayer HB et al. Molecular and clinical epidemiology of CXCR4- using HIV-1 in a large population of antiretroviral-naive individuals. J Infect Dis 2005; 192:466-74.

2. de Roda Husman AM, Koot M, Cornelissen M et al. Association between CCR5 genotype and the clinical course of HIV-1 infection. Ann Intern Med 1998; 127:882-90.

3. Delobel P, Sandres-Saune K, Cazabat M et al. R5 to X4 Switch of the Predominant HIV-1 Population in Cellular Reservoirs During Effective Highly Active Antiretroviral Therapy. J Acq Imm Def Syndr 2005; 38:382-92.

4. Hunt PW, Harrigan PR, Huang W et al. Prevalence of CXCR4 Tropism among Antiretroviral-Treated HIV-1-Infected Patients with Detectable Viremia. J Infect Dis 2006; 194:926-30.

5. Moore JP, Kitchen S, Pugach P et al. The CCR5 and CXCR4 coreceptors - central to understanding the transmission and pathogenesis of the human immunodeficiency virus type 1 infection. AIDS Res Human Retrovir 2004; 20:111-26.

6. Philpott S. HIV-1 coreceptor usage, transmission, and disease progression. Current HIV Res 2003; 1:217-27.

7. Samson M, Libert F, Doranz BJ et al. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 1996; 382:722-5.

8. Walker DK, Abel S, Comby P, et al. Species differences in the disposition of the CCR5 antagonist, UK-427,857, a new potential treatment for HIV. Drug Metab Disp 2005; 33:587-595.

9. Westby M, Lewis M, Whitcomb J et al. Emergence of CXCR4-using human immunodeficiency virus type 1 (HIV-1) variants in a minority of HIV-1-infected patients following treatment with the CCR5 antagonist maraviroc is from a pretreatment CXCR4- using virus reservoir. J Virol 2006; 80:4909-20.

10. Wood A and Armour D. The Discovery of the CCR5 Receptor Antagonist, UK-427,857, A New Agent for the Treatment of HIV Infection and AIDS. Prog Med Chem 2005; 43:239-71.

PART III: CONSUMER INFORMATION

Pr

CELSENTRI

(maraviroc)

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

Read all of this leaflet carefully before you start taking this medicine.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.

If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

ABOUT THIS MEDICATION

What the medication is used for:

CELSENTRI is an oral tablet used for the treatment of HIV-1 (Human Immunodeficiency Virus type 1) infection in adults, in combination with other anti-HIV drugs. HIV is the virus that causes AIDS (Acquired Immune Deficiency Syndrome). CELSENTRI is a type of anti-HIV drug called a CCR5 antagonist.

CELSENTRI can reduce the amount of HIV in the blood (called "viral load") and increase the number of CD4 (T) cells. This may keep your immune system healthy, so it can help fight infection.

CELSENTRI should be taken in combination with other medicines used to treat HIV.

CELSENTRI does not cure HIV infection or AIDS. People taking CELSENTRI may still develop infections or other conditions associated with HIV infection. Although CELSENTRI is not a cure for HIV or AIDS, CELSENTRI can help reduce your risks of getting illnesses associated with HIV infection (AIDS and opportunistic infection).

CELSENTRI does not lower your chance of passing HIV to other people through sexual contact, sharing needles, or being exposed to your blood. For your health and the health of others, it is important to always practice safer sex by using a latex or polyurethane condom or other barrier method to lower the chance of contact with any body fluids such as semen, vaginal secretions, or blood. Never re-use or share needles.

This medicine is prescribed for your particular condition. Do not use it for any other condition. Do not give CELSENTRI to other people, even if they have the same symptoms you have. It may harm them.

What it does:

CELSENTRI works by blocking a receptor called CCR5 that a type of HIV uses to enter cells in your blood called CD4 or T-cells. This virus type is called CCR5-tropic HIV. Your doctor may take blood samples to determine if you have been infected with CCR5-tropic HIV and that therefore, CELSENTRI is an appropriate treatment for you.

When it should not be used: If you are allergic (hypersensitive) to maraviroc or any of the other ingredients of CELSENTRI (see What the nonmedicinal ingredients are).

CELSENTRI is not recommended for use in children. What the medicinal ingredient is: The active ingredient is

maraviroc.

What the important nonmedicinal ingredients are:

Other non- medicinal ingredients present in CELSENTRI film-coated tablets include: microcrystalline cellulose, dibasic calcium phosphate, sodium starch glycolate, magnesium stearate.

Film-coat: aluminum lake (FD&C blue #2), macrogol 3350, polyvinyl alcohol, soya lecithin, talc and titanium dioxide.

What dosage forms it comes in:

CELSENTRI comes in oval- shaped, blue, film-coated tablets in 150 mg and 300 mg strengths.

WARNINGS AND PRECAUTIONS

Liver problems

Liver problems (liver toxicity) have happened in patients taking CELSENTRI. An allergic reaction may happen before liver problems occur. Stop taking CELSENTRI and call your doctor right away if you get any of the following symptoms:

an itchy rash on your body (allergic reaction)

your skin or eyes look yellow and/or dark (tea-colored) urine

vomiting and/or upper right stomach area (abdominal) pain

You should see your doctor right away but continue taking CELSENTRI if you have any of the following other symptoms: nausea, fever, flu-like symptoms, fatigue.

BEFORE you use CELSENTRI talk to your doctor or pharmacist if:

• You have liver problems or are infected with Hepatitis B or Hepatitis C, as your liver function may need to be closely monitored.

• You have a history of low blood pressure and/or if you are taking any medication to lower blood pressure.

• You have heart disease

• You have a history of any kidney problems.

• You are pregnant, planning to become pregnant, or become pregnant while taking CELSENTRI. It is not known if CELSENTRI can harm your unborn child.

You and your doctor will need to decide if taking

CELSENTRI is right for you. If you take CELSENTRI while you are pregnant, talk to your doctor about how you can be included in the Antiretroviral Pregnancy Registry.

You are breast-feeding. You should not breast-feed if you are HIV-positive because of the chance of passing HIV to your baby. Also, it is not known if

CELSENTRI can pass into your breast milk and if it

can harm your baby. Talk with your doctor about the best way to feed your baby.

Other warnings:

It is very important to take all your anti-HIV medicines as prescribed and at the right times of day. This can help your medicines work better. It also lowers the chance that your medicines will stop working to fight HIV (drug resistance).

When your CELSENTRI supply starts to run low, ask your doctor or pharmacist for a refill. This is very important because the amount of virus in your blood may increase if the medicine is stopped for even a short period of time.

You should never stop taking CELSENTRI or your other HIV medicines without talking with your doctor.

INTERACTIONS WITH THIS MEDICATION

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including prescription and non-prescription medicines, vitamins, and herbal supplements.

Your doctor may need to adjust your dose of CELSENTRI depending on which other medications you are taking. Do not start or stop any other medications without your doctor or pharmacist's approval.

The following medications are known to interact or may interact with CELSENTRI and your doctor may adjust the dosage of Celsentri:

• clarithromycin, ketoconazole, itraconazole, rifampin, telithromycin

• atazanavir, atazanavir/ritonavir, darunavir/ritonavir,

efavirenz, lopinaviz/ritonavir, saquinavir, saquinavir/ritonavir and other anti-HIV combinations

St. John's Wort (Hypericum perforatum) should not be used

as it may reduce the amount of Celsentri in the blood and reduce the effectiveness of this medication.

PROPER USE OF THIS MEDICATION

Usual dose:

The recommended dose of CELSENTRI in adults is 300 mg twice daily. However, a dose adjustment may be needed due to the potential for interactions with other medicinal products. CELSENTRI can be taken with or without food. CELSENTRI comes in a tablet form and should be swallowed. Do not chew the tablets.

Overdose:

Your doctor will monitor your response and condition to determine what CELSENTRI treatment is needed. However, if you are concerned that you may have taken too much CELSENTRI, tell your doctor or contact your regional Poison Control Centre immediately.

Missed Dose:

If you forget to take CELSENTRI, take the next dose of CELSENTRI as soon as possible and then take your next scheduled dose at its regular time. If, however, it is almost time for your next dose, do not take the missed dose. Wait and take the next dose at the regular time. Do not take a double dose to make up for a missed dose.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Like all medicines, CELSENTRI can cause side effects, although not everybody gets them.

The most common side effects include: cough, fever, upper respiratory tract infections, rash, muscle-related symptoms (such as muscle pain, aches or soreness), abdominal pain, dizziness, constipation, itching, and difficulty sleeping.

Other side effects may include:

• Heart problems including heart attack;

• Low blood pressure when standing up (postural hypotension) can cause dizziness or fainting;

• Celsentri affects other immune system cells and may increase your chances of getting other infections.

• A condition called Immune Reconstitution Syndrome can occur when you start taking HIV medications. Your immune system may get stronger and could begin to fight other infections that have been hidden in your body such as pneumonia, herpes virus or tuberculosis. Tell your doctor if you develop new symptoms after starting your HIV medications.

Tell your doctor promptly about these or other symptoms. If the condition persists or worsens, seek medical attention.

If you experience dizziness while taking CELSENTRI, do not drive or operate heavy machinery.

SERIOUS SIDE EFFECTS AND WHAT TO DO ABOUT THEM

For any unexpected effects while taking CELSENTRI, contact your doctor or pharmacist.

HOW TO STORE IT

Store between 15degC and 30degC, in the original package. Do not take CELSENTRI after the expiry date shown on the package. Keep out of the reach of children. This medicine has been prescribed for your medical problem. Do not give it to anyone else. Discuss all your questions about your health with your doctor. If you have questions about CELSENTRI ask your doctor, nurse or pharmacist.

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada through the

Canada Vigilance Program collects information on serious and unexpected side effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Canada Vigilance:

Online: www.healthcanada.gc.ca/medeffect

By toll-free telephone: 1-866-234-2345 By toll-free fax: 1-866-678-6789

Postage Paid Mail:

Canada Vigilance Program Health Canada

AL 0701C

Ottawa, Ontario K1A 0K9

NOTE:

Should you require information related to the management of the side effect, please contact your health care provider before notifying Canada Vigilance. The Canada Vigilance Program does not provide medical advice.

MORE INFORMATION

This document plus the full product monograph, prepared for health professionals can be found at:

http://www.pfizer.ca or by contacting the sponsor, Pfizer Canada Inc., at 1-800-463-6001 (Medical Information).

This leaflet was prepared by Pfizer Canada Inc. Last revised: November 18, 2008

(c) Pfizer Canada Inc., 2008