FULL PRESCRIBING INFORMATION *

DOSAGE AND ADMINISTRATION

DOSAGE FORMS AND STRENGTHS

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

1. Hepatotoxicity

2. Cardiovascular Events

3. Immune Reconstitution Syndrome

4. Potential Risk of Infection

5. Potential Risk of Malignancy

Hepatotoxicity

Cardiovascular Events

Immune Reconstitution Syndrome

Potential Risk of Infection

Potential Risk of Malignancy

DRUG INTERACTIONS

1. Effect of Concomitant Drugs on the Pharmacokinetics of Maraviroc

Effect of Concomitant Drugs on the Pharmacokinetics of Maraviroc

USE IN SPECIFIC POPULATIONS

1. Pregnancy

Nursing MothersPediatric UseGeriatric UseRenal ImpairmentHepatic ImpairmentGenderRace

Pregnancy

Nursing Mothers

Pediatric Use

Geriatric Use

Renal Impairment

Hepatic Impairment

Gender

Race

OVERDOSAGE

DESCRIPTION

CLINICAL PHARMACOLOGY

1. Mechanism of Action

2. Pharmacodynamics

3. Pharmacokinetics

4. Microbiology

5. Pharmacogenomics

Mechanism of Action

Pharmacodynamics

Pharmacokinetics

Microbiology

Pharmacogenomics

NONCLINICAL TOXICOLOGY

1. Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis, Mutagenesis, Impairment of Fertility

CLINICAL STUDIES

1. Studies in CCR5-tropic, Treatment-experienced Patients

2. Study in Dual/Mixed-tropic, Treatment-experienced Patients

Studies in CCR5-tropic, Treatment-experienced Patients

Study in Dual/Mixed-tropic, Treatment-experienced Patients

REFERENCES

HOW SUPPLIED/STORAGE AND HANDLING

PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from the Full Prescribing Information are not listed

FULL PRESCRIBING INFORMATION

WARNING: HEPATOTOXICITY

Hepatotoxicity has been reported with SELZENTRY use. Evidence of a systemic allergic reaction (e.g., pruritic rash, eosinophilia or elevated IgE) prior to the development of

hepatotoxicity may occur. Patients with signs or symptoms of hepatitis or allergic reaction

following use of SELZENTRY should be evaluated immediately [see Warnings and Precautions (5.1)].

DOSAGE AND ADMINISTRATION

The recommended dose of SELZENTRY differs based on concomitant medications due to drug interactions (see Table 1). SELZENTRY can be taken with or without food. SELZENTRY must be given in combination with other antiretroviral medications. Table 1 gives the recommended dose adjustments [see Drug Interactions (7.1)].

Table 1 Recommended Dosing Regimen

• protease inhibitors (except tipranavir/ritonavir)

• delavirdine

• ketoconazole, itraconazole, clarithromycin,

• other strong CYP3A inhibitors (e.g., nefazadone, telithromycin)

Concomitant Medications SELZENTRY Dose

• efavirenz

• rifampin

• carbamazepine, phenobarbital, and phenytoin

DOSAGE FORMS AND STRENGTHS

• 150 mg blue, oval film coated tablets debossed with "Pfizer" on one side and "MVC 150" on the other

• 300 mg blue, oval film coated tablets debossed with "Pfizer" on one side and "MVC 300" on the other

CONTRAINDICATIONS

None

WARNINGS AND PRECAUTIONS

Hepatotoxicity

A case of possible SELZENTRY-induced hepatotoxicity with allergic features has been reported in a study of healthy volunteers. In addition, an increase in hepatic adverse events with SELZENTRY 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 [see Adverse Reactions (6)]. Discontinuation of SELZENTRY should be considered in any patient with signs or symptoms of hepatitis, or with increased liver transaminases combined with rash or other systemic symptoms. The safety and efficacy of SELZENTRY have not been specifically studied in patients with significant underlying liver disorders. In studies of treatment-experienced HIV-infected subjects, approximately 6% of subjects were co-infected with hepatitis B and approximately 6% were co- infected with hepatitis C. Due to the small number of co-infected subjects studied, no conclusions can be drawn regarding whether they are at an increased risk for hepatic adverse events with SELZENTRY administration. However, caution should be used when administering SELZENTRY to patients with pre-existing liver dysfunction or who are co-infected with viral hepatitis B or C.

Cardiovascular Events

Use with caution in patients at increased risk for cardiovascular events. Eleven subjects (1.3%) who received SELZENTRY had cardiovascular events including myocardial ischemia and/or infarction during the Phase 3 studies (total exposure 267 patient-years), while no subjects who received placebo had such events (total exposure 99 patient-years). These subjects generally had cardiac disease or cardiac risk factors prior to SELZENTRY use, and the relative contribution of SELZENTRY to these events is not known. When SELZENTRY was administered to healthy volunteers at doses higher than the recommended dose, symptomatic postural hypotension was seen at a greater frequency than in placebo. However, when SELZENTRY was given at the recommended dose in HIV subjects in Phase 3 studies, postural hypotension was seen at a rate similar to placebo (approximately 0.5%). Caution should be used when administering SELZENTRY in patients with a history of postural hypotension or on concomitant medication known to lower blood pressure.

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including maraviroc. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as infection with Mycobacterium avium, cytomegalovirus, Pneumocystis jirovecii, Mycobacterium tuberculosis, or reactivation of Herpes simplex and Herpes zoster), which may necessitate further evaluation and treatment.

Potential Risk of Infection

SELZENTRY antagonizes the CCR5 co-receptor located on some immune cells, and therefore could potentially increase the risk of developing infections. The overall incidence and severity of infection, as well as AIDS-defining category C infections, was comparable in the treatment groups during the Phase 3 studies of SELZENTRY. While there was a higher rate of certain upper respiratory tract infections reported in the SELZENTRY arm compared to placebo (20.0% versus 11.5%), there was a lower rate of pneumonia (2.1 % vs 4.8%) reported in patients receiving SELZENTRY. A higher incidence of Herpes virus infections (11.4 per 100 patient- years) was also reported in the SELZENTRY arm when adjusted for exposure compared to placebo (8.2 per 100 patient-years). Patients should be monitored closely for evidence of infections while receiving SELZENTRY.

Potential Risk of Malignancy

While no increase in malignancy has been observed with SELZENTRY, due to this drug's mechanism of action it could affect immune surveillance and lead to an increased risk of malignancy. Long-term follow-up is needed to more fully assess this risk.

DRUG INTERACTIONS

Effect of Concomitant Drugs on the Pharmacokinetics of Maraviroc

Maraviroc is a substrate of CYP3A and Pgp and hence its pharmacokinetics are likely to be modulated by inhibitors and inducers of these enzymes/transporters. Therefore, a dose adjustment may be required when maraviroc is coadministered with those drugs [see Dosage and Administration (2)]. 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. For additional drug interaction information see Clinical Pharmacology (12.3).

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category B

The incidence of fetal variations and malformations was not increased in embryofetal toxicity studies performed with maraviroc in rats at exposures (AUC) approximately 20-fold higher and in rabbits at approximately 5-fold higher than human exposures at the recommended daily dose (up to 1000 mg/kg/day in rats and 75 mg/kg/day in rabbits). During the pre-and post-natal development studies in the offspring, development of the offspring, including fertility and reproductive performance, was not affected by the maternal administration of maraviroc. However, there are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, SELZENTRY should be used during pregnancy only if clearly needed.

Antiretroviral Pregnancy Registry

To monitor maternal-fetal outcomes of pregnant women exposed to SELZENTRY and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV infection. Because of the potential for both HIV

Studies in lactating rats indicate that maraviroc is extensively secreted into rat milk. It is not known whether maraviroc is secreted into human milk.

transmission and serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving SELZENTRY.

PEDIATRIC USE

The pharmacokinetics, safety and efficacy of maraviroc in patients <16 years of age have not been established. Therefore, maraviroc should not be used in this patient population.

Geriatric Use

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 SELZENTRY 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 approximately 25% of total clearance of maraviroc. Maraviroc concentrations may be increased in patients with renal impairment, especially when CYP3A inhibitors are coadministered. Patients with a creatinine clearance of less than 50 mL/min who receive maraviroc and a CYP3A inhibitor may be at an increased risk of adverse effects related to increased maraviroc concentrations, such as dizziness and postural hypotension. Thus, patients with a creatinine clearance of less than 50 mL/min should receive maraviroc and a CYP3A inhibitor only if the potential benefit is felt to outweigh the risk, and they should be monitored for adverse effects.

Hepatic Impairment

The pharmacokinetics of maraviroc have not been sufficiently studied in patients with hepatic impairment. Because maraviroc is metabolized by the liver, concentrations are likely to be increased in these patients [see Warnings and Precautions (5.1)].

Gender

Population pharmacokinetic analysis of pooled Phase 1/2a data indicated gender (female: n=96, 23.2% of the total population) does not affect maraviroc concentrations. Dosage adjustment based on gender is not necessary.

Race

Population pharmacokinetic analysis of pooled Phase 1/2a data indicated exposure was 26.5% higher in Asians (N=95) as compared to non-Asians (n=318). However, a study designed to evaluate pharmacokinetic differences between Caucasians (n=12) and Singaporeans (n=12) showed no difference between these two populations. Only 14 Black subjects were included in the population pharmacokinetic analysis. No dosage adjustment based on race is needed.

OVERDOSAGE

The highest dose administered in clinical studies was 1200 mg. The dose limiting adverse event was postural hypotension, which was observed at 600 mg. While the recommended dose for SELZENTRY in patients receiving a CYP3A inducer without a CYP3A inhibitor is 600 mg twice daily, this dose is appropriate due to enhanced metabolism. 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 intended exposure of 300 mg equivalents twice daily. However, no significant QT prolongation was seen in the studies in treatment-experienced patients with HIV using the recommended doses of maraviroc or in a specific pharmacokinetic study to evaluate the potential of maraviroc to prolong the QT interval [see Clinical Pharmacology (12.3)] 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. If indicated, elimination of unabsorbed active maraviroc should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed drug. Since maraviroc is moderately protein bound, dialysis may be beneficial in removal of this medicine.

DESCRIPTION

SELZENTRY (maraviroc) is a selective, slowly reversible, small molecule antagonist of the interaction between human CCR5 and HIV-1 gp120. Blocking this interaction prevents CCR5- tropic HIV-1 entry into cells. SELZENTRY is available as film-coated tablets for oral administration containing either 150 or 300 mg of maraviroc and the following inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate (anhydrous), sodium starch glycolate, and magnesium stearate. The film-coat [Opadry(r) II Blue (85G20583)] contains FD&C blue #2 aluminum lake, soya lecithin, polyethylene glycol (macrogol 3350), polyvinyl alcohol, talc and titanium dioxide. Maraviroc is chemically described as 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. The molecular formula is C29H41F2N5O and the structural formula is:

F F

O

NH

N

H 3 C

N

N

N

CH 3 Maraviroc is a white to pale colored powder with a molecular weight of 513.67. It is highly soluble across the physiological pH range (pH 1.0 to 7.5).

CLINICAL PHARMACOLOGY

Mechanism of Action

Maraviroc is an antiviral drug. [see Clinical Pharmacology (12.4)].

Pharmacodynamics

Exposure Response Relationship

The relationship between maraviroc mean predicted plasma trough concentration (Cmin) (1-9 samples per patient taken on up to 7 visits) and virologic response was evaluated in 973 treatment-experienced HIV-1-infected subjects in studies A4001027 and A4001028. The Cmin, baseline viral load, baseline CD4+ cell count and overall sensitivity score (OSS) were found to be important predictors of virologic success (defined as viral load < 400 copies/mL at 24 weeks). Table 4 illustrates the proportion of patients with virologic success (%) within each Cmin quartile for 150 mg twice daily and 300 mg twice daily groups.

Table 4 Patients with Virologic Success by Cmin Quartile

150 mg BID (with CYP3A inhibitors) 300 mg BID (without CYP3A inhibitors)

n

Median C

min

% patients with virologic

success n Median Cmin

% patients with virologic success

Placebo 160 - 30.6 35 - 28.6

Q1 78 33 52.6 22 13 50.0

Q2 77 87 63.6 22 29 68.2

Q3 78 166 78.2 22 46 63.6

Q4 78 279 74.4 22 97 68.2

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 three single oral doses of maraviroc and moxifloxacin. The placebo-adjusted mean maximum (upper 1-sided 95% CI) increases in QTc from baseline after 100, 300 and 900 mg of maraviroc were -2 (0), -1 (1), and 1 (3) msec, respectively, and 13 (15) 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.

Pharmacokinetics

Table 5 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 300mg 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 Studies (14)]. Therefore, maraviroc can be taken with or without food at the recommended dose [See Dosage and Administration (2)].

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.

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 CYP3A 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. 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.

Excretion

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 300mg 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.

Effect of Concomitant Drugs on the Pharmacokinetics of Maraviroc

Maraviroc is a substrate of CYP3A and Pgp and hence its pharmacokinetics are likely to be modulated by inhibitors and inducers of these enzymes/transporters. The CYP3A/Pgp inhibitors ketoconazole, lopinavir/ritonavir, ritonavir, saquinavir and atazanavir all increased the Cmax and AUC of maraviroc [see Table 6]. The CYP3A inducers rifampin and efavirenz decreased the Cmax and AUC of maraviroc [see Table 6]. Tipranavir/ritonavir (net CYP3A inhibitor/Pgp inducer) did not affect the steady state pharmacokinetics of maraviroc. Co-trimoxazole and tenofovir did not affect the pharmacokinetics of maraviroc (see Table 6).

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

Table 6: Effect of Co-administered Agents on the Pharmacokinetics of Maraviroc

Co-administered drug and dose

N Maraviroc Dose

Ratio (90% CI) of maraviroc pharmacokinetic parameters with/without co-administered drug

(no effect = 1.00)

Effect of Maraviroc on the Pharmacokinetics of Concomitant Drugs

Maraviroc is unlikely to inhibit the metabolism of co-administered drugs metabolized by the following cytochrome P enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A) because maraviroc did not inhibit activity of those enzymes at clinically relevant concentrations in vitro. Drug interaction studies were performed with maraviroc and other drugs likely to be co- administered or commonly used as probes for pharmacokinetic interactions [see Table 6]. Maraviroc had no effect on the pharmacokinetics of zidovudine or lamivudine. Maraviroc had no clinically relevant effect on the pharmacokinetics of midazolam, the oral contraceptives ethinylestradiol and levonorgestrel, no effect on the urinary 6b-hydroxycortisol/cortisol ratio, suggesting no induction of CYP3A in vivo. Maraviroc had no effect on the debrisoquine metabolic ratio (MR) at 300 mg twice daily or less in vivo. However, there was 234% increase in debrisoquine MR on treatment compared to baseline at 600 mg once daily, suggesting potential inhibition of CYP2D6 at higher dose.

MICROBIOLOGY

Mechanism of Action

Maraviroc is a member of a therapeutic class called CCR5 co-receptor antagonists. Maraviroc selectively binds to the human chemokine receptor CCR5 present on the cell membrane, preventing the interaction of HIV-1 gp120 and CCR5 necessary for CCR5-tropic HIV-1 to enter cells. CXCR4-tropic and dual-tropic HIV-1 entry is not inhibited by maraviroc.

Antiviral Activity in Cell Culture

Maraviroc inhibits the replication of CCR5-tropic laboratory strains and primary isolates of HIV-1 in models of acute T-cell infection. The mean EC50 value (50% effective concentration) for maraviroc against HIV-1 group M isolates (clades A to J) and group O isolates ranged from 0.1 to 1.25 nM (0.05 to 0.64 ng/mL) in cell culture. When used with other antiretroviral agents in cell culture, the combination of maraviroc was not antagonistic with NNRTIs (delavirdine, efavirenz and nevirapine), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine and zidovudine), or protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir). Maraviroc was additive/synergistic with the HIV fusion inhibitor enfuvirtide. Maraviroc was not active against CXCR4-tropic and dual-tropic viruses (EC50 value >10 uM). The antiviral activity of maraviroc against HIV-2 has not been evaluated.

Resistance in Cell Culture

HIV-1 variants with reduced susceptibility to maraviroc have been selected in cell culture, following serial passage of two CCR5-tropic viruses (CC1/85 and RU570). The maraviroc- resistant viruses remained CCR5-tropic with no evidence of a change 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 (HXB2 numbering) were shown to be necessary for the maraviroc-resistant phenotype in the HIV-1 isolate CC1/85. In the RU570 isolate a 3-amino acid residue deletion in the V3 loop, [? ]QAI (HXB2 positions 315-317), was associated with maraviroc-resistance. The relevance of the specific gp120 mutations observed in maraviroc-resistant isolates selected in cell culture to clinical maraviroc resistance is not known. Maraviroc-resistant viruses were characterized phenotypically by concentration response curves that did not reach 100% inhibition in phenotypic drug assays, rather than increases in EC50 values.

Clinical Resistance

The resistance profile in treatment-naive and treatment-experienced subjects has not been fully characterized. Virologic failure on maraviroc can result from genotypic and phenotypic resistance to maraviroc or through outgrowth of undetected CXCR4-using virus present before maraviroc treatment (see Tropism below). Preliminary data from a subset of treatment- experienced subjects failing maraviroc-containing regimens with CCR5-tropic virus (n=12) have identified 5 viruses that had decreased susceptibility to maraviroc characterized in phenotypic drug assays by concentration response curves that did not reach 100% inhibition. Additionally, CCR5-tropic virus from 2 of these treatment failure subjects had 3-fold shifts in EC50 values for maraviroc at the time of failure. Each of these viruses had multiple amino acid substitutions with unique patterns in the heterogeneous V3 loop region of gp120. Changes at either amino acid position 308 or 323 (HXB2 numbering) were seen in the V3 loop in all five of the subjects with decreased maraviroc susceptibility. The contribution of mutations outside the V3 loop of gp120 to maraviroc resistance has not been investigated.

Cross-resistance in Cell Culture

Maraviroc had antiviral activity against HIV-1 clinical isolates resistant to NRTIs, NNRTIs, PIs and enfuvirtide in cell culture (EC50 values ranged from 0.7 to 8.9 nM (0.36 to 4.57 ng/mL)). Maraviroc-resistant viruses that emerged in cell culture remained susceptible to the fusion inhibitor enfuvirtide and the protease inhibitor saquinavir.

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.

Pharmacogenomics

The impact of CCR5 promoter and coding sequence polymorphisms on the efficacy of maraviroc is being evaluated.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term oral carcinogenicity studies of maraviroc were carried out in rasH2 transgenic mice (6 months) and in rats for up to 96 weeks (females) and 104 weeks (males). No drug-related increases in tumor incidence were found in mice at 1500 mg/kg/day and in male and female rats at 900 mg/kg/day. The highest exposures in rats were approximately 11 times those observed in humans at the therapeutic dose of 300 mg twice daily for the treatment of HIV-1 infection.

Mutagenesis

Maraviroc was not genotoxic in the reverse mutation bacterial test (Ames test in Salmonella and E. coli), a chromosome aberration test in human lymphocytes and rat bone marrow micronucleus test.

Impairment of Fertility

Maraviroc did not impair mating or fertility of male or female rats and did not affect sperm of treated male rats at approximately 20-fold higher exposures (AUC) than in humans given the recommended 300 mg twice daily dose.

CLINICAL STUDIES

The clinical efficacy and safety of SELZENTRY is derived from analyses of 24-week data from two ongoing studies, A4001027 (MOTIVATE-1) and A4001028 (MOTIVATE-2), in antiretroviral treatment-experienced adult subjects infected with CCR5-tropic HIV-1. These studies are supported by a 24-week study in antiretroviral treatment-experienced adult subjects infected with dual/mixed-tropic HIV-1, A4001029.

Studies in CCR5-tropic, Treatment-Experienced Subjects

Studies A4001027 and A4001028 are ongoing, double-blind, randomized, placebo- controlled, multicenter studies in subjects infected with CCR5-tropic HIV-1. Subjects 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 one agent from three of the four 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 one member of each class. All subjects 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, subjects 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 as described in Dosing and Administration, Table 1. In the pooled analysis for A4001027 and A4001028, the demographics and baseline characteristics of the treatment groups were comparable (Table 7). Of the 1043 subjects with a CCR5 tropism result at screening, 7.6% had a dual/mixed tropism result at the baseline visit 4 to 6 weeks later. This illustrates the background change from CCR5 to dual/mixed tropism result over time in this treatment-experienced population, prior to a change in antiretroviral regimen or administration of a CCR5 co-receptor antagonist.

Table 7

Demographic and Baseline Characteristics of Subjects in Studies A4001027 and A4001028

Age (years)

SELZENTRY BID

N = 426

Placebo N = 209

Sex

Mean (Range) 46.3 (21-73) 45.7 (29-72)

Male 382 (89.7%) 185 (88.5%)

Race

Region

Female 44 (10.3%) 24 (11.5%)

White 363 (85.2%) 178 (85.2%)

Black 51 (12.0%) 26 (12.4%)

Other 12 (2.8%) 5 (2.4%)

U.S. 276 (64.8%) 135 (64.6%)

Non-U.S. 150 (35.2%) 74 (35.4%)

Subjects with Previous Enfuvirtide Use 182 (42.7%) 91 (43.5%) Baseline Plasma HIV-1 RNA (log10 copies/mL)

Mean (Range) 4.85 (2.96-6.88) 4.86 (3.46-7.07)

Subjects with Screening

Viral Load >100,000 copies/mL 179 (42.0%) 84 (40.2%)

Baseline CD4+ Cell Count (cells/mm3)

Median (Range) 167 (2-820) 171 (1-675)

Subjects with Baseline

CD4+ Cell Count <=200 cells/mm3) 250 (58.7%) 118 (56.7%)

Subjects with Overall Susceptibility Score (OSS):a

(13.4%)

(31.9%)

(24.4%)

>=3 125 (29.3%)

(16.7%)

(21.1%)

(28.2%)

(31.6%)

Subjects with enfuvirtide resistance mutations 90 (21.2%) 45 (21.5%)

Median Number of Resistance-Associated:b

PI mutations NNRTI mutations NRTI mutations

a

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

b Resistance mutations based on IAS guidelines1 The week 24 results for the pooled Studies A4001027 and A4001028 are shown in Table 8.

Table 8

Outcomes of Randomized Treatment at Week 24 Studies A4001027 and A4001028

Outcome

Mean change from Baseline to Week 24 in

SELZENTRY BID N=426

PLACEBO

N=

209 Mean Difference

HIV-1 RNA (log10 copies/mL) -1.96 -0.99 0.97

<400 copies/mL at Week 24 259 (60.8%) 58 (27.8%) 33.0%

<50 copies/mL at Week 24 193 (45.3%) 48 (23.0%) 22.3%

Virologic Responders b

Discontinuations

(69.2%) 75 (35.9%) 33.4%

Insufficient Clinical Response Adverse Events

Other

(21.4%)

(3.8%)

(6.1%)

(50.7%)

(3.8%)

(8.6%)

Patients with treatment-emergent CDC

Cat

egory C events 18 (4.2%) 14 (6.7%)

Deaths (during study or within 28 days of

last dose) 5 (1.2%) 1 (0.5%)

b Reduction in HIV-1 RNA >=1 log10 or HIV-1 RNA <400 copies/mL at Week 24. After 24 weeks of therapy, the proportion of subjects with HIV-1 RNA <400 copies/mL receiving maraviroc compared to placebo was 61% and 28%, respectively. The mean changes in plasma HIV-1 RNA from baseline to week 24 was -1.96 log10 copies/mL for subjects receiving maraviroc + OBT compared to -0.99 log10 copies/mL for subjects receiving OBT only. The mean increase in CD4+ counts was higher on maraviroc twice daily + OBT (106.3 cells/mm3) than on placebo + OBT (57.4 cells/mm3 ).

Study in Dual/Mixed-tropic, Treatment-Experienced Subjects

Study A4001029 was an exploratory, randomized, double blind, multicenter trial to determine the safety and efficacy of maraviroc in subjects infected with dual/mixed co-receptor tropic HIV- 1. The inclusion/exclusion criteria were similar to those for Studies A4001027 and A4001028 above and the subjects were randomized in a 1:1:1 ratio to SELZENTRY once daily, SELZENTRY twice daily, or placebo. No increased risk of infection or HIV disease progression was observed in the subjects who received SELZENTRY. SELZENTRY use was not associated with a significant decrease in HIV-1 RNA compared to placebo in these subjects and no adverse effect on CD4 count was noted.

REFERENCES

1IAS-USA Drug Resistance Mutations Figures http://www.iasusa.org/pub/topics/2006/issue3/125.pdf

HOW SUPPLIED/STORAGE AND HANDLING

SELZENTRY film-coated tablets are available as follows: 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. Bottle packs 150 mg tablets

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60 tablets (NDC 0069-0807-60)

Bottle packs 300 mg tablets

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60 tablets (NDC 0069-0808-60)

SELZENTRY film-coated tablets should be stored at 25oC (77oF); excursions permitted between 15o and 30oC (59o-86oF) [see USP Controlled Room Temperature]. Shelf life is 24 months.