SELZENTRY

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).

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

Exposure-Response Relationship in Treatment-Experienced Subjects: The relationship between maraviroc, modeled plasma trough concentration (C_min) (1 to 9 samples per subject taken on up to 7 visits), and virologic response was evaluated in 973 treatment-experienced HIV-1-infected subjects with varied optimized background antiretroviral regimens in Trials A4001027 and A4001028. The C_min, 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 7 illustrates the proportions of subjects with virologic success (%) within each C_min quartile for 150-mg twice-daily and 300-mg twice-daily groups.

Exposure-Response Relationship in Treatment-Naive Subjects: The relationship between maraviroc, modeled plasma trough concentration (C_min) (1 to 12 samples per subject taken on up to 8 visits), and virologic response was evaluated in 294 treatment-naive HIV-1-infected subjects receiving maraviroc 300 mg twice daily in combination with zidovudine/lamivudine in Trial A4001026. Table 8 illustrates the proportion (%) of subjects with virologic success <50 copies/mL at 48 weeks within each C_min quartile for the 300-mg twice-daily dose.

Eighteen of 75 (24%) subjects in Q1 had no measurable maraviroc concentration on at least one occasion versus 1 of 73 and 1 of 74 in Q3 and Q4, respectively.

Effects on Electrocardiogram: A placebo-controlled, randomized, crossover trial 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 (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.

12.3 Pharmacokinetics

Table 9. Mean Maraviroc Pharmacokinetic Parameters

^aThe estimated exposure is lower compared with other trials possibly due to sparse sampling, food effect, compliance, and concomitant medications.

Absorption: Peak maraviroc plasma concentrations are attained 0.5 to 4 hours following single oral doses of 1 to 1,200 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-gp.

Effect of Food on Oral Absorption: Coadministration of a 300‑mg tablet with a high‑fat breakfast reduced maraviroc C_max and AUC by 33% in healthy volunteers. There were no food restrictions in the trials 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 194 L.

Metabolism: Trials 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 to 18 hours. A mass balance/excretion trial 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.

Hepatic Impairment: Maraviroc is primarily metabolized and eliminated by the liver. A trial compared the pharmacokinetics of a single 300‑mg dose of SELZENTRY in subjects with mild (Child‑Pugh Class A, n = 8), and moderate (Child‑Pugh Class B, n = 8) hepatic impairment with pharmacokinetics in healthy subjects (n = 8). The mean C_max and AUC 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 with subjects with normal hepatic function. These changes do not warrant a dose adjustment. Maraviroc concentrations are higher when SELZENTRY 150 mg is administered with a potent CYP3A inhibitor compared with following administration of 300 mg without a CYP3A inhibitor, so patients with moderate hepatic impairment who receive SELZENTRY 150 mg with a potent CYP3A inhibitor should be monitored closely for maraviroc‑associated adverse events. The pharmacokinetics of maraviroc have not been studied in subjects with severe hepatic impairment [see Warnings and Precautions (5.1)].

Renal Impairment: A trial compared the pharmacokinetics of a single 300‑mg dose of SELZENTRY in subjects with severe renal impairment (CLcr <30 mL/min, n = 6) and ESRD (n = 6) to healthy volunteers (n = 6). Geometric mean ratios for maraviroc C_max and AUC_inf were 2.4‑fold and 3.2‑fold higher, respectively, for subjects with severe renal impairment, and 1.7‑fold and 2.0‑fold higher, respectively, for subjects with ESRD as compared with subjects with normal renal function in this trial. Hemodialysis had a minimal effect on maraviroc clearance and exposure in subjects with ESRD. Exposures observed in subjects with severe renal impairment and ESRD were within the range observed in previous 300‑mg single‑dose trials of SELZENTRY in healthy volunteers with normal renal function. However, maraviroc exposures in the subjects with normal renal function in this trial were 50% lower than that observed in previous trials. Based on the results of this trial, no dose adjustment is recommended for patients with renal impairment receiving SELZENTRY without a potent CYP3A inhibitor or inducer. However, if patients with severe renal impairment or ESRD experience any symptoms of postural hypotension while taking SELZENTRY 300 mg twice daily, their dose should be reduced to 150 mg twice daily [see Dosage and Administration (2.2), Warnings and Precautions (5.2)].

In addition, the trial compared the pharmacokinetics of multiple‑dose SELZENTRY in combination with saquinavir/ritonavir 1,000/100 mg twice daily (a potent CYP3A inhibitor combination) for 7 days in subjects with mild renal impairment (CLcr >50 and ≤80 mL/min, n = 6) and moderate renal impairment (CLcr ≥30 and ≤50 mL/min, n = 6) with healthy volunteers with normal renal function (n = 6). Subjects received 150 mg of SELZENTRY at different dose frequencies (healthy volunteers – every 12 hours; mild renal impairment – every 24 hours; moderate renal impairment – every 48 hours). Compared with healthy volunteers (dosed every 12 hours), geometric mean ratios for maraviroc AUC_tau, C_max, and C_min were 50% higher, 20% higher, and 43% lower, respectively, for subjects with mild renal impairment (dosed every 24 hours). Geometric mean ratios for maraviroc AUC_tau, C_max, and C_min were 16% higher, 29% lower, and 85% lower, respectively, for subjects with moderate renal impairment (dosed every 48 hours) compared with healthy volunteers (dosed every 12 hours). Based on the data from this trial, no adjustment in dose is recommended for patients with mild or moderate renal impairment [see Dosage and Administration (2.2)].

Effect of Concomitant Drugs on the Pharmacokinetics of Maraviroc: Maraviroc is a substrate of CYP3A and P-gp and hence its pharmacokinetics are likely to be modulated by inhibitors and inducers of these enzymes/transporters. The CYP3A/P-gp inhibitors ketoconazole, telaprevir, boceprevir, lopinavir/ritonavir, ritonavir, darunavir/ritonavir, saquinavir/ritonavir, and atazanavir ± ritonavir all increased the C_max and AUC of maraviroc (see Table 10). The CYP3A inducers rifampin, etravirine, and efavirenz decreased the C_max and AUC of maraviroc (see Table 10).

Tipranavir/ritonavir (net CYP3A inhibitor/P-gp inducer) did not affect the steady‑state pharmacokinetics of maraviroc (see Table 10). Cotrimoxazole and tenofovir did not affect the pharmacokinetics of maraviroc.

Table 10. Effect of Coadministered Agents on the Pharmacokinetics of Maraviroc

^aCompared with historical data.

^bConducted under fed conditions. The geometric mean C_max of maraviroc is 858 ng/mL when maraviroc is coadministered with telaprevir.

Effect of Maraviroc on the Pharmacokinetics of Concomitant Drugs: Maraviroc is unlikely to inhibit the metabolism of coadministered 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. Maraviroc does not induce CYP1A2 in vitro.

In vitro results suggest that maraviroc could inhibit P-gp in the gut. However, maraviroc did not significantly affect the pharmacokinetics of digoxin in vivo, indicating maraviroc may not significantly inhibit or induce P-gp clinically.

Drug interaction trials were performed with maraviroc and other drugs likely to be coadministered or commonly used as probes for pharmacokinetic interactions (see Table 10).

Coadministration of fosamprenavir 700 mg/ritonavir 100 mg twice daily and maraviroc 300 mg twice daily decreased the C_min and AUC of amprenavir by 36% and 35%, respectively. Coadministration of fosamprenavir 1,400 mg/ritonavir 100 mg once daily and maraviroc 300 mg once daily decreased the C_min and AUC by 15% and 30%, respectively. No dosage adjustment is necessary when SELZENTRY is dosed 150 mg twice daily in combination with fosamprenavir/ritonavir dosed once or twice daily. Fosamprenavir should be given with ritonavir when coadministered with SELZENTRY.

Maraviroc had no significant effect on the pharmacokinetics of boceprevir, telaprevir, zidovudine, or lamivudine. Maraviroc decreased the C_min and AUC of raltegravir by 27% and 37%, respectively, which is not clinically significant. Maraviroc had no clinically relevant effect on the pharmacokinetics of midazolam, the oral contraceptives ethinylestradiol and levonorgestrel, no effect on the urinary 6β-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 and did not cause inhibition of CYP2D6 in vitro until concentrations >100 µM. However, there was 234% increase in debrisoquine MR on treatment compared with baseline at 600 mg once daily, suggesting potential inhibition of CYP2D6 at higher dose.

12.4 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 peripheral blood leukocyte infection. The mean EC₅₀ value (50% effective concentration) for maraviroc against HIV-1 group M isolates (subtypes A to J and circulating recombinant form AE) and group O isolates ranged from 0.1 to 4.5 nM (0.05 to 2.3 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, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir). Maraviroc was not antagonistic with the HIV fusion inhibitor enfuvirtide. Maraviroc was not active against CXCR4-tropic and dual-tropic viruses (EC₅₀ value >10 µM). 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 2 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, ΔQAI (HXB2 positions 315 to 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.

Cross-Resistance in Cell Culture: Maraviroc had antiviral activity against HIV-1 clinical isolates resistant to NNRTIs, NRTIs, PIs, and the fusion inhibitor 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 enfuvirtide and the protease inhibitor saquinavir.

Clinical Resistance: Virologic failure on maraviroc can result from genotypic and phenotypic resistance to maraviroc, through outgrowth of undetected CXCR4-using virus present before maraviroc treatment (see Tropism below), through resistance to background therapy drugs (Table 11), or due to low exposure to maraviroc [see Clinical Pharmacology (12.2)].

Antiretroviral Treatment-Experienced Subjects (Trials A4001027 and A4001028): Week 48 data from treatment-experienced subjects failing maraviroc-containing regimens with CCR5-tropic virus (n = 58) have identified 22 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.

Fifteen of these viruses were sequenced in the gp120 encoding region and multiple amino acid substitutions with unique patterns in the heterogeneous V3 loop region were detected. Changes at either amino acid position 308 or 323 (HXB2 numbering) were seen in the V3 loop in 7 of the subjects with decreased maraviroc susceptibility. Substitutions outside the V3 loop of gp120 may also contribute to reduced susceptibility to maraviroc.

Antiretroviral Treatment-Naive Subjects (Trial A4001026): Treatment-naive subjects receiving SELZENTRY had more virologic failures and more treatment-emergent resistance to the background regimen drugs compared with those receiving efavirenz (Table 11).

^aIncludes subjects failing with CXCR4- or dual/mixed-tropism because these viruses are not intrinsically susceptible to maraviroc.

In an as-treated analysis of treatment-naive subjects at 96 weeks, 32 subjects failed a maraviroc-containing regimen with CCR5-tropic virus and had a tropism result at failure; 7 of these subjects had evidence of maraviroc phenotypic resistance defined as concentration-response curves that did not reach 95% inhibition. One additional subject had a ≥3-fold shift in the EC₅₀ value for maraviroc at the time of failure. A clonal analysis of the V3 loop amino acid envelope sequences was performed from 6 of the 7 subjects. Changes in V3 loop amino acid sequence differed between each of these different subjects, even for those infected with the same virus clade suggesting that that there are multiple diverse pathways to maraviroc resistance. The subjects who failed with CCR5-tropic virus and without a detectable maraviroc shift in susceptibility were not evaluated for genotypic resistance.

Of the 32 maraviroc virologic failures failing with CCR5-tropic virus, 20 (63%) also had genotypic and/or phenotypic resistance to background drugs in the regimen (lamivudine, zidovudine).

Tropism: In both treatment-experienced and treatment-naive subjects, detection of CXCR4-using virus prior to initiation of therapy has been associated with a reduced virologic response to maraviroc.

Antiretroviral Treatment-Experienced Subjects: In the majority of cases, treatment failure on maraviroc was associated with detection of CXCR4-using virus (i.e., CXCR4- or dual/mixed-tropic) which was not detected by the tropism assay prior to treatment. CXCR4-using virus was detected at failure in approximately 55% of subjects who failed treatment on maraviroc by Week 48, as compared with 9% 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, it was determined that 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 coreceptor 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 twice daily at Week 48 with CXCR4-using virus had a lower median increase in CD4+ cell counts from baseline (+41 cells/mm³) than those subjects failing with CCR5-tropic virus (+162 cells/mm³). The median increase in CD4+ cell count in subjects failing in the placebo arm was +7 cells/mm³.

Antiretroviral Treatment-Naive Subjects: In a 96-week trial of antiretroviral treatment-naive subjects, 14% (12/85) who had CCR5-tropic virus at screening with an enhanced sensitivity tropism assay (TROFILE) and failed therapy on maraviroc had CXCR4-using virus at the time of treatment failure. A detailed clonal analysis was conducted in 2 previously antiretroviral treatment-naive subjects enrolled in a Phase 2a monotherapy trial who had CXCR4-using virus detected after 10 days treatment with maraviroc. Consistent with the detailed clonal analysis conducted in treatment-experienced subjects, the CXCR4-using variants appear to emerge from outgrowth of a pre-existing undetected CXCR4-using virus. Screening with an enhanced sensitivity tropism assay reduced the number of maraviroc virologic failures with CXCR4- or dual/mixed-tropic virus at failure to 12 compared with 24 when screening with the original tropism assay. All but one (11/12; 92%) of the maraviroc failures failing with CXCR4 or dual/mixed-tropic virus also had genotypic and phenotypic resistance to the background drug lamivudine at failure and 33% (4 /12) developed zidovudine-associated resistance substitutions.

Subjects who had CCR5-tropic virus at baseline and failed maraviroc therapy with CXCR4-using virus had a median increase in CD4+ cell counts from baseline of +113 cells/mm³ while those subjects failing with CCR5-tropic virus had an increase of +135 cells/mm³. The median increase in CD4+ cell count in subjects failing in the efavirenz arm was + 95 cells/mm³.

13 NONCLINICAL TOXICOLOGY

13.1 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 1,500 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.

14 CLINICAL STUDIES

The clinical efficacy and safety of SELZENTRY are derived from analyses of data from 3 trials in adult subjects infected with CCR5-tropic HIV-1: A4001027 and A4001028 in antiretroviral treatment-experienced adult subjects and A4001026 in treatment-naive subjects. These trials were supported by a 48-week trial in antiretroviral treatment-experienced adult subjects infected with dual/mixed-tropic HIV-1, A4001029.

14.1 Trials in CCR5-Tropic, Treatment-Experienced Subjects

Trials A4001027 and A4001028 were double-blind, randomized, placebo-controlled, multicenter trials in subjects infected with CCR5-tropic HIV-1. Subjects were required to have an HIV-1 RNA 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 NRTI, ≥1 NNRTI, ≥2 PIs, and/or enfuvirtide) or documented resistance to at least 1 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 SELZENTRY 300 mg once daily, SELZENTRY 300 mg twice daily, or placebo. Doses were adjusted based on background therapy as described in Dosing and Administration (2), Table 1.

In the pooled analysis for A4001027 and A4001028, the demographics and baseline characteristics of the treatment groups were comparable (Table 12). Of the 1,043 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.

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

^bResistance mutations based on IAS guidelines.¹

The Week 48 results for the pooled Trials A4001027 and A4001028 are shown in Table 13.

^aOne additional subject died while receiving open-label therapy with SELZENTRY subsequent to discontinuing double-blind placebo due to insufficient response.

After 48 weeks of therapy, the proportions of subjects with HIV-1 RNA <400 copies/mL receiving SELZENTRY compared with placebo were 56% and 22%, respectively. The mean changes in plasma HIV-1 RNA from baseline to Week 48 were –1.84 log₁₀ copies/mL for subjects receiving SELZENTRY + OBT compared with –0.78 log₁₀ copies/mL for subjects receiving OBT only. The mean increase in CD4+ cell count was higher on SELZENTRY twice daily + OBT (124 cells/mm³) than on placebo + OBT (60 cells/mm³).

14.2 Trial in Dual/Mixed-Tropic, Treatment-Experienced Subjects

Trial A4001029 was an exploratory, randomized, double-blind, multicenter trial to determine the safety and efficacy of SELZENTRY in subjects infected with dual/mixed co-receptor tropic HIV-1. The inclusion/exclusion criteria were similar to those for Trials 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. Use of SELZENTRY was not associated with a significant decrease in HIV-1 RNA compared with placebo in these subjects and no adverse effect on CD4+ cell count was noted.

14.3 Trial in Treatment-Naive Subjects

Trial A4001026 is an ongoing, randomized, double-blind, multicenter trial in subjects infected with CCR5-tropic HIV-1 classified by the original TROFILE tropism assay. Subjects were required to have plasma HIV-1 RNA ≥2,000 copies/mL and could not have: 1) previously received any antiretroviral therapy for >14 days, 2) an active or recent opportunistic infection or a suspected primary HIV-1 infection, or 3) phenotypic or genotypic resistance to zidovudine, lamivudine, or efavirenz. Subjects were randomized in a 1:1:1 ratio to SELZENTRY 300 mg once daily, SELZENTRY 300 mg twice daily, or efavirenz 600 mg once daily, each in combination with zidovudine/lamivudine. The efficacy and safety of SELZENTRY are based on the comparison of SELZENTRY twice daily versus efavirenz. In a pre-planned interim analysis at 16 weeks, SELZENTRY 300 mg once daily failed to meet the pre-specified criteria for demonstrating non-inferiority and was discontinued.

The demographic and baseline characteristics of the maraviroc and efavirenz treatment groups were comparable (Table 14). Subjects were stratified by screening HIV-1 RNA levels and by geographic region. The median CD4+ cell counts and mean HIV-1 RNA at baseline were similar for both treatment groups.

The treatment outcomes at 96 weeks for Trial A4001026 are shown in Table 15. Treatment outcomes are based on reanalysis of the screening samples using a more sensitive tropism assay, enhanced sensitivity TROFILE HIV tropism assay, which became available after the Week 48 analysis, approximately 15% of the subjects identified as CCR5-tropic in the original analysis had dual/mixed- or CXCR4-tropic virus. Screening with enhanced sensitivity version of the TROFILE tropism assay reduced the number of maraviroc virologic failures with CXCR4- or dual/mixed-tropic virus at failure to 12 compared with 24 when screening with the original TROFILE HIV tropism assay.

^aThe total number of subjects (Ns) in Table 15 represents the subjects who had a CCR5-tropic virus in the reanalysis of screening samples using the more sensitive tropism assay. This reanalysis reclassified approximately 15% of subjects shown in Table 14 as having dual/mixed- or CXCR4-tropic virus. These numbers are different than those presented in Table 14 because the numbers in Table 14 reflect the subjects with CCR5-tropic virus according to the original tropism assay.

^bWeek 48 results: Virologic responders (<400): 228/311 (73%) in SELZENTRY, 219/303 (72%) in efavirenz;

Virologic responders (<50): 213/311 (69 %) in SELZENTRY, 207/303 (68%) in efavirenz.

^cOther reasons for discontinuation include lost to follow-up, withdrawn, protocol violation, and other.

The median increase from baseline in CD4+ cell counts at Week 96 was 184 cells/mm³ for the arm receiving SELZENTRY compared with 155 cells/mm³ for the efavirenz arm.

15 REFERENCES

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

16 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 “MVC 150” or “MVC 300” on one side and plain on the other.

Bottle packs 150-mg tablets: 60 tablets (NDC 49702-223-18).

Bottle packs 300-mg tablets: 60 tablets (NDC 49702-224-18).

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

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide)

Patients should be informed that liver problems including life-threatening cases have been reported with SELZENTRY. Patients should be informed that if they develop signs or symptoms of hepatitis or allergic reaction following use of SELZENTRY (rash, skin or eyes look yellow, dark urine, vomiting, abdominal pain), they should stop SELZENTRY and seek medical evaluation immediately. Patients should understand that laboratory tests for liver enzymes and bilirubin will be ordered prior to starting SELZENTRY, at other times during treatment, and if they develop severe rash or signs and symptoms of hepatitis or an allergic reaction on treatment [see Warnings and Precautions (5.1), (5.2)].

Patients should be informed that SELZENTRY is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections.

Patients should remain under the care of a physician when using SELZENTRY.

Patients should be advised to avoid doing things that can spread HIV-1 infection to others.

• • Do not share needles or other injection equipment.
• • Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
• • Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
• • Do not breastfeed. We do not know if SELZENTRY can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.

Patients should be advised that it is important to take all their anti‑HIV medicines as prescribed and at the same time(s) each day. SELZENTRY must always be used in combination with other antiretroviral drugs. Patients should not alter the dose or discontinue therapy without consulting their physician. If a dose is missed, patients should take the next dose of SELZENTRY as soon as possible and then take their next scheduled dose at its regular time. If it is less than 6 hours before their next scheduled dose, they should not take the missed dose and should instead wait and take the next dose at the regular time.

Patients should be advised that when their supply of SELZENTRY starts to run low, they should ask their doctor or pharmacist for a refill.

Caution should be used when administering SELZENTRY in patients with a history of postural hypotension or on concomitant medication known to lower blood pressure. Patients should be advised that if they experience dizziness while taking SELZENTRY, they should avoid driving or operating machinery.

SELZENTRY is a registered trademark of the ViiV Healthcare group of companies.

TROFILE is a registered trademark of Monogram Biosciences, Inc.

Manufactured for:

ViiV Healthcare

Research Triangle Park, NC 27709

by:

Pfizer Manufacturing Deutschland GmbH

Freiburg, Germany

©2014, the ViiV Healthcare group of companies. All rights reserved.

SEL:10PI

PHARMACIST‑DETACH HERE AND GIVE MEDICATION GUIDE TO PATIENT

MEDICATION GUIDE

SELZENTRY ^® (sell-ZEN-tree) Tablets

(maraviroc)

Read the Medication Guide that comes with SELZENTRY before you start taking it and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment.

What is the most important information I should know about SELZENTRY?

Serious side effects have occurred with SELZENTRY, including liver problems (liver toxicity). An allergic reaction may happen before liver problems occur. Stop taking SELZENTRY and call your healthcare provider right away if you get any of the following symptoms:

• •an itchy rash on your body (allergic reaction)
• •yellowing of your skin or whites of your eyes (jaundice)
• •dark (tea-colored) urine
• •vomiting
• •upper right stomach area (abdominal) pain

What is SELZENTRY?

SELZENTRY is an anti-HIV medicine called a CCR5 antagonist. HIV-1 (Human Immunodeficiency Virus) is the virus that causes AIDS (Acquired Immune Deficiency Syndrome).

SELZENTRY is used with other anti-HIV medicines in adults with CCR5-tropic HIV-1 infection.

Use of SELZENTRY is not recommended in people with dual/mixed or CXCR4-tropic HIV-1.

• •SELZENTRY will not cure HIV-1 infection.
• •People taking SELZENTRY may still develop infections, including opportunistic infections or other conditions that happen with HIV-1 infection.
• •It is very important that you stay under the care of your healthcare provider during treatment with SELZENTRY.
• •The long-term effects of SELZENTRY are not known at this time.

SELZENTRY has not been studied in children less than 18 years of age.

General information about SELZENTRY

SELZENTRY does not cure HIV-1 infection and you may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. You should remain under the care of a doctor when using SELZENTRY.

Avoid doing things that can spread HIV-1 infection.

• • Do not share needles or other injection equipment.
• • Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
• • Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.

How does SELZENTRY work?

HIV-1 enters cells in your blood by attaching itself to structures on the surface of the cell called receptors. SELZENTRY blocks a specific receptor called CCR5 that CCR5-tropic HIV-1 uses to enter CD4 or T-cells in your blood. Your healthcare provider will do a blood test to see if you have been infected with CCR5-tropic HIV-1 before prescribing SELZENTRY for you.

• •When used with other anti-HIV medicines, SELZENTRY may:
• •reduce the amount of HIV-1 in your blood. This is called “viral load”.
• •increase the number of white blood cells called T (CD4) cells.

SELZENTRY does not work in all people with CCR5-tropic HIV-1 infection.

Who should not take SELZENTRY?

People with severe kidney problems or who are on hemodialysis and are taking certain other medications should not take SELZENTRY. Talk to your healthcare provider before taking this medicine if you have kidney problems.

What should I tell my healthcare provider before taking SELZENTRY?

Before you take SELZENTRY, tell your healthcare provider if you:

• •have liver problems including a history of hepatitis B or C.
• •have heart problems.
• •have kidney problems.
• •have low blood pressure or take medicines to lower blood pressure.
• •have any other medical condition.
• •are pregnant or plan to become pregnant. It is not known if SELZENTRY may harm your unborn baby.
•   Antiretroviral Pregnancy Registry. There is a pregnancy registry for women who take antiviral medicines during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry.

• •are breastfeeding or plan to breastfeed. Do not breastfeed. We do not know if SELZENTRY can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk. Talk with your healthcare provider about the best way to feed your baby.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Certain other medicines may affect the levels of SELZENTRY in your blood. Your healthcare provider may need to change your dose of SELZENTRY when you take it with certain medicines.

The levels of SELZENTRY in your blood may change and your healthcare provider may need to adjust your dose of SELZENTRY when taking any of the following medications together with SELZENTRY:

Do not take products that contain St. John’s wort (Hypericum perforatum). St. John’s wort may lower the levels of SELZENTRY in your blood so that it will not work to treat your CCR5-tropic HIV-1 infection.

Know the medicines you take. Keep a list of your medicines. Show the list to your healthcare provider and pharmacist when you get a new medicine.

How should I take SELZENTRY?

Take SELZENTRY exactly as prescribed by your healthcare provider. SELZENTRY comes in 150-mg and 300-mg tablets. Your healthcare provider will prescribe the dose that is right for you.

• •Take SELZENTRY 2 times a day.
• •Swallow SELZENTRY tablets whole. Do not chew the tablets.
• •Take SELZENTRY tablets with or without food.
• •Always take SELZENTRY with other anti-HIV drugs as prescribed by your healthcare provider.

Do not change your dose or stop taking SELZENTRY or your other anti-HIV medicines without first talking with your healthcare provider.

• •If you take too much SELZENTRY, call your healthcare provider or the poison control center right away.
• •If you forget to take SELZENTRY, take the next dose of SELZENTRY as soon as possible and then take your next scheduled dose at its regular time. If it is less than 6 hours before 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.
• •It is very important to take all your anti-HIV medicines as prescribed. This can help your medicines work better. It also lowers the chance that your medicines will stop working to fight HIV-1 (drug resistance).
• •When your SELZENTRY supply starts to run low, ask your healthcare provider or pharmacist for a refill. This is very important because the amount of virus in your blood may increase and SELZENTRY could stop working if it is stopped for even a short period of time.

What are the possible side effects of SELZENTRY?

There have been serious side effects when SELZENTRY has been given with other anti-HIV drugs including:

• • Liver problems. See “What is the most important information I should know about SELZENTRY?”
• • Serious skin rash and allergic reactions. Severe and potentially life-threatening skin reactions and allergic reactions have been reported in some patients taking SELZENTRY. If you develop a rash with any of the following symptoms, stop using SELZENTRY and contact your doctor right away:
  • •fever
  • •generally ill feeling
  • •muscle aches
  • •blisters or sores in your mouth
  • •blisters or peeling of the skin
  • •redness or swelling of the eyes
  • •swelling of the mouth or face or lips
  • •problems breathing
  • •yellowing of the skin or whites of your eyes
  • •dark or tea colored urine
  • •pain, aching, or tenderness on the right side below the ribs
  • •loss of appetite
  • •nausea/vomiting
• • Heart problems including heart attack.
• • Low blood pressure when standing up (postural hypotension). Low blood pressure when standing up can cause dizziness or fainting. Do not drive a car or operate heavy machinery if you have dizziness while taking SELZENTRY.
• • Changes in your immune system. A condition called Immune Reconstitution Syndrome can happen when you start taking HIV medicines. Your immune system may get stronger and could begin to fight infections that have been hidden in your body such as pneumonia, herpes virus, or tuberculosis. Tell your healthcare provider if you develop new symptoms after starting your HIV medicines.
• • Possible chance of infection or cancer. SELZENTRY affects other immune system cells and therefore may possibly increase your chance for getting other infections or cancer.

The most common side effects of SELZENTRY include colds, cough, fever, rash, and dizziness.

Tell your healthcare provider about any side effect that bothers you or does not go away.

These are not all of the side effects with SELZENTRY. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store SELZENTRY?

• •Store SELZENTRY tablets at room temperature from 59°F to 86°F (15°C to 30°C).
• •Safely throw away medicine that is out of date or that you no longer need.

Keep SELZENTRY and all medicines out of the reach of children.

General information about SELZENTRY

Medicines are sometimes prescribed for conditions that are not mentioned in Medication Guides. Do not use SELZENTRY for a condition for which it was not prescribed. Do not give SELZENTRY to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide summarizes the most important information about SELZENTRY. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for more information about SELZENTRY that is written for health professionals.

For more information, go to www.selzentry.com.

What are the ingredients in SELZENTRY?

Active ingredient: maraviroc

Inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate (anhydrous), sodium starch glycolate, magnesium stearate

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

SELZENTRY is a registered trademark of the ViiV Healthcare group of companies.

The brands listed are the trademarks of their respective owners and are not trademarks of the ViiV Healthcare group of companies. The makers of these brands are not affiliated with and do not endorse the ViiV Healthcare group of companies or its products.

This Medication Guide has been approved by the US Food and Drug Administration.

Manufactured for:

ViiV Healthcare

Research Triangle Park, NC 27709

by:

Pfizer Manufacturing Deutschland GmbH

Freiburg, Germany

©2014, the ViiV Healthcare group of companies. All rights reserved.

March 2014

SEL:5MG

Principal Display Panel

NDC 49702-223-18

Selzentry^®

(maraviroc) tablets

150 mg

60 Tablets

Rx only

ALWAYS DISPENSE WITH MEDICATION GUIDE

Store at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F - 86°F) [see USP Controlled Room Temperature].

Dispense in tight containers (USP).

DOSAGE AND USE

See prescribing information for dosage information.

Each tablet contains 150 mg of maraviroc.

Manufactured for:

ViiV Healthcare

Research Triangle Park, NC 27709

by:

Pfizer Manufacturing Deutschland GmbH

Freiburg, Germany

Made in Belgium

Rev. 9/11

413168