CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Maraviroc is an HIV-1 antiviral drug see Microbiology 12.4) ]. 12.2 Pharmacodynamics. Exposure-Response Relationship in Treatment-Experienced Adult SubjectsThe relationship between maraviroc, modeled plasma trough concentration (C min) (1 to samples per subject taken on up to 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 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 less than 400 copies per mL at 24 weeks). Table illustrates the proportions of subjects with virologic success (%) within each min quartile for 150-mg twice-daily and 300-mg twice-daily groups. Table 9. Treatment-Experienced Subjects with Virologic Success by Cmin Quartile (Q1 to Q4) 150 mg Twice Daily(with CYP3A Inhibitors)300 mg Twice Daily(without CYP3A Inhibitors)nMedianC min Subjects with Virologic SuccessnMedianC min Subjects with Virologic SuccessPlacebo160-30.635-28.6Q1783352.6221350.0Q2778763.6222968.2Q37816678.2224663.6Q47827974.4229768.2Exposure-Response Relationship in Treatment-Naive Adult SubjectsThe relationship between maraviroc, modeled plasma trough concentration (C min) (1 to 12 samples per subject taken on up to visits), and virologic response was evaluated in 294 treatment-naive HIV-1-infected subjects receiving maraviroc 300 mg twice daily in combination with lamivudine/zidovudine in Trial A4001026. Table 10 illustrates the proportion (%) of subjects with virologic success less than 50 copies per mL at 48 weeks within each min quartile for the 300-mg twice-daily dose. Table 10. Treatment-Naive Subjects with Virologic Success by min Quartile (Q1 to Q4) 300 mg Twice DailynMedian min Subjects with Virologic SuccessQ1752357.3Q2723972.2Q3735674.0Q4748183.8Eighteen of 75 (24%) subjects in Q1 had no measurable maraviroc concentration on at least one occasion versus of 73 and of 74 in Q3 and Q4, respectively.Effects on ElectrocardiogramA placebo-controlled, randomized, crossover trial to evaluate the effect on the QT interval of healthy male and female volunteers was conducted with 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 (3) msec, respectively, and 13 (15) msec for moxifloxacin 400 mg. No subject in any group had an increase in QTc of greater than or equal to 60 msec from baseline. No subject experienced an interval exceeding the potentially clinically relevant threshold of 500 msec.. 12.3 Pharmacokinetics. Table 11. Mean Maraviroc Pharmacokinetic Parameters in AdultsPatient PopulationMaraviroc DosenAUC12(ng.h/mL)Cmax(ng/mL)Cmin(ng/mL)Healthy volunteers (Phase 1)300 mg twice daily642,90888843.1Asymptomatic HIV subjects (Phase 2a)300 mg twice daily82,55061833.6Treatment-experienced HIV subjects (Phase 3) 300 mg twice daily941,51326637.2150 mg twice daily (+ CYP3A inhibitor) 3752,463332101Treatment-naiveHIV subjects (Phase 2b/3) 300 mg twice daily3441,86528760a The estimated exposure is lower compared with other trials possibly due to sparse sampling, food effect, compliance, and concomitant medications. AbsorptionPeak maraviroc plasma concentrations are attained 0.5 to hours following single oral doses of to1,200 mg administered to uninfected volunteers. The pharmacokinetics of oral maraviroc are not dose proportional over the dose range. The absolute bioavailability of 100-mg dose is 23% and is predicted to be 33% at 300 mg. Maraviroc is substrate for the efflux transporter P-gp. Effect of Food on Oral Absorption: Coadministration of 300-mg tablet with high-fat breakfast reduced maraviroc max and AUC by 33% and coadministration of 75 mg of oral solution with high-fat breakfast reduced maraviroc AUC by 73% in healthy adult volunteers. Studies with the tablet formulation demonstrated reduced food effect at higher doses. There were no food restrictions in the adult trials (using the tablet formulation) or in the pediatric trial (using both tablet and oral solution formulations) that demonstrated the efficacy/antiviral activity and safety of maraviroc see Clinical Studies 14.1, 14.2) ]. DistributionMaraviroc 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. Elimination 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 single oral dose of 300 mg 14C]-maraviroc. The most significant circulating metabolite in humans is 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. mass balance/excretion trial was conducted using 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. Specific Populations Patients with Hepatic Impairment: Maraviroc is primarily metabolized and eliminated by the liver. trial compared the pharmacokinetics of single 300-mg dose of maraviroc in subjects with mild (Child-Pugh Class A, = 8) and moderate (Child-Pugh Class B, = 8) hepatic impairment with pharmacokinetics in healthy subjects (n 8). The mean 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 dose adjustment. Maraviroc concentrations are higher when maraviroc 150 mg is administered with potent CYP3A inhibitor compared with following administration of 300 mg without CYP3A inhibitor, so patients with moderate hepatic impairment who receive maraviroc 150 mg with 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) ]. Patients with Renal Impairment: trial compared the pharmacokinetics of single 300-mg dose of maraviroc in adult subjects with severe renal impairment (CrCl less than 30 mL per minute, = 6) and ESRD (n 6) with healthy volunteers (n 6). Geometric mean ratios for maraviroc 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 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 maraviroc in healthy volunteers with normal renal function. However, maraviroc exposures in the subjects with normal renal function in this trial were 50% lower than those observed in previous trials. Based on the results of this trial, no dose adjustment is recommended for patients with renal impairment receiving maraviroc without potent CYP3A inhibitor or inducer. However, if patients with severe renal impairment or ESRD experience any symptoms of postural hypotension while taking maraviroc 300 mg twice daily, their dose should be reduced to 150 mg twice daily see Dosage and Administration 2.3), Warnings and Precautions 5.3) ]. In addition, the trial compared the pharmacokinetics of multiple-dose maraviroc in combination with saquinavir/ritonavir 1,000/100 mg twice daily (a potent CYP3A inhibitor combination) for days in subjects with mild renal impairment (CrCl greater than 50 and less than or equal to 80 mL per minute, = 6) and moderate renal impairment (CrCl greater than or equal to 30 and less than or equal to 50 mL per minute, = 6) with healthy volunteers with normal renal function (n 6). Subjects received 150 mg of maraviroc 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, max and 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, max and 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 2.3) ]. Pediatric Patients:Aged to Less Than 18 Years: The pharmacokinetics of maraviroc were evaluated in CCR5-tropic, HIV-1-infected, treatment-experienced pediatric subjects aged to less than 18 years. In the dose-finding stage of Trial A4001031, doses were administered with food on intensive pharmacokinetic evaluation days and optimized to achieve an average concentration over the dosing interval (C avg) of greater than 100 ng per mL. Throughout the trial, on non-intensive pharmacokinetic evaluation days maraviroc was taken with or without food. The initial dose of maraviroc was based on BSA and concomitant medication category (i.e., presence of CYP3A inhibitors and/or inducers). The conversion of dosing to weight (kg)-band basis in children provides comparable exposures with those observed in the trial at the corresponding BSA. Maraviroc pharmacokinetic parameters in pediatric subjects aged to less than 18 years receiving potent CYP3A inhibitors with or without potent CYP3A inducer were similar to those observed in adults (Table 12).Table 12. Maraviroc Pharmacokinetic Parameters in Treatment-Experienced Pediatric Patients Receiving Maraviroc with Potent CYP3A Inhibitors (with or without Potent CYP3A Inducer)WeightDose ofMaravirocMaraviroc Pharmacokinetic ParameteraGeometric MeanAUC12(ng.h/mL)Cavg(ng/mL)Cmax(ng/mL)Cmin(ng/mL)10 kg to <20 kg50 mg twice daily2,3491963247820 kg to <30 kg75 mg twice daily3,02025239411830 kg to <40 kg100 mg twice daily3,229269430126>=40 kg150 mg twice daily4,044337563152a Model-predicted steady-state pharmacokinetic parameters are presented Aged from Birth to Less Than Weeks: The pharmacokinetics of maraviroc were evaluated in 38 of 47 enrolled HIV-1-exposed neonates (born to HIV-1-infected mothers) aged from birth up to weeks [see Adverse Reactions 6.1)] In the IMPAACT P2007 trial, 13 neonates received weight-based maraviroc dosing as single doses at birth and approximately days, and 25 neonates received maraviroc twice daily up to weeks of age without exposure to potent CYP3A inhibitors and/or inducers. Maraviroc pharmacokinetic parameters in neonates weighing at least kg at birth (Table 13) were similar to those observed in adults. Exposure to maternal efavirenz both in utero (for minimum of weeks immediately prior to delivery) and after birth while breastfeeding did not have meaningful impact on maraviroc pharmacokinetic parameters. Table 13. Maraviroc Pharmacokinetic Parameters in Full-Term Neonates (Birth Up to Weeks of Age) Receiving Maraviroc with Noninteracting Concomitant Medications PharmacokineticSampling TimenMedian Dose(range)Maraviroc Pharmacokinetic Parameter Geometric MeanAUC 12 (ng.h/mL)C avg (ng/mL)C max (ng/mL)C min (ng/mL)Day 11330 mg (20 to 40 mg) single dose 3,510 292380-Week 12525 mg (20 to 30 mg) twice daily 1,21610126223Week 42530 mg (20 to 40 mg) twice daily 1,38511529543a Noninteracting concomitant medications include all medications that are not potent CYP3A inhibitors or inducers. AUCinf calculated for single-dose pharmacokinetics. Clinical pharmacokinetic data with maraviroc in pediatric patients aged older than weeks to less than years are not available and clinical pharmacokinetic data in pediatric patients aged to less than 18 years receiving noninteracting concomitant medications are limited. Based on population pharmacokinetic modeling and simulation, the recommended dosing regimen of maraviroc for this population is predicted to result in similar maraviroc exposures when compared with exposures achieved in adults receiving maraviroc 300 mg twice daily (with noninteracting concomitant medications) [see Dosage and Administration 2.4)]. Geriatric Patients: Pharmacokinetics of maraviroc have not been fully evaluated in the elderly (aged 65 years and older). Based on population pharmacokinetic analyses, age did not have clinically relevant effect on maraviroc exposure in subjects up to age 65 years [see Use in Specific Populations 8.5)]. Race and Gender: Based on population pharmacokinetics and clinical CYP3A5 genotype analyses for race, no dosage adjustment is recommended based on race or gender. Drug Interaction StudiesEffect of Concomitant Drugs on the Pharmacokinetics of Maraviroc:Maraviroc is 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, lopinavir/ritonavir, ritonavir, darunavir/ritonavir, saquinavir/ritonavir, and atazanavir +- ritonavir all increased the max and AUC of maraviroc (Table 14). The CYP3A and/or P-gp inducers rifampin, etravirine, and efavirenz decreased the Cmax and AUC of maraviroc (Table 14). While not studied, potent CYP3A and/or P-gp inducers carbamazepine, phenobarbital, and phenytoin are expected to decrease maraviroc concentrations. Based on in vitro study results, maraviroc is also substrate of OATP1B1 and MRP2; its pharmacokinetics may be modulated by inhibitors of these transporters. Tipranavir/ritonavir (net CYP3A inhibitor/P-gp inducer) did not affect the steady-state pharmacokinetics of maraviroc (Table 14). Cotrimoxazole and tenofovir did not affect the pharmacokinetics of maraviroc.Table 14. Effect of Coadministered Agents on the Pharmacokinetics of MaravirocCoadministered Drug and DosenDose of maravirocRatio (90% CI) of Maraviroc Pharmacokinetic Parameters with/without Coadministered Drug(No Effect 1.00)C min AUC tau max CYP3A and/or P-gp InhibitorsKetoconazole 400 mg q.d. 12100 mg b.i.d.3.75 (3.01, 4.69) 5.00 (3.98, 6.29) 3.38 (2.38, 4.78) Ritonavir 100 mg b.i.d. 8100 mg b.i.d.4.55 (3.37, 6.13) 2.61 (1.92, 3.56) 1.28 (0.79, 2.09) Saquinavir (soft gel capsules) /ritonavir 1,000 mg/100 mg b.i.d.11100 mg b.i.d.11.3 (8.96, 14.1) 9.77 (7.87, 12.14) 4.78 (3.41, 6.71) Lopinavir/ritonavir400 mg/100 mg b.i.d.11300 mg b.i.d.9.24 (7.98, 10.7) 3.95 (3.43, 4.56) 1.97 (1.66, 2.34) Atazanavir 400 mg q.d.12300 mg b.i.d.4.19 (3.65, 4.80) 3.57 (3.30, 3.87) 2.09 (1.72, 2.55) Atazanavir/ritonavir 300 mg/100 mg q.d.12300 mg b.i.d.6.67 (5.78, 7.70) 4.88 (4.40, 5.41) 2.67 (2.32, 3.08) Darunavir/ritonavir600 mg/100 mg b.i.d.12150 mg b.i.d.8.00 (6.35, 10.1) 4.05 (2.94, 5.59) 2.29 (1.46, 3.59) Elvitegravir/ritonavir 150 mg/100 mg q.d.11150 mg b.i.d.4.23 (3.47, 5.16) 2.86 (2.33, 3.51) 2.15 (1.71, 2.69) CYP3A and/or P-gp InducersEfavirenz 600 mg q.d.12100 mg b.i.d.0.55 (0.43, 0.72) 0.55 (0.49, 0.62) 0.49 (0.38, 0.63) Efavirenz 600 mg q.d.12200 mg b.i.d. (+ efavirenz): 100 mg b.i.d. (alone)1.09 (0.89, 1.35) 1.15 (0.98, 1.35) 1.16 (0.87, 1.55) Rifampicin 600 mg q.d.12100 mg b.i.d.0.22 (0.17, 0.28) 0.37 (0.33, 0.41) 0.34 (0.26, 0.43) Rifampicin 600 mg q.d.12200 mg b.i.d. (+ rifampicin): 100 mg b.i.d. (alone)0.66 (0.54, 0.82) 1.04 (0.89, 1.22) 0.97 (0.72, 1.29) Etravirine 200 mg b.i.d.14300 mg b.i.d.0.61 (0.53, 0.71) 0.47 (0.38, 0.58) 0.40 (0.28, 0.57) Nevirapine 200 mg b.i.d. (+ lamivudine 150 mg b.i.d., tenofovir 300 mg q.d.) 8300 mg single dose -1.01 (0.65, 1.55) 1.54 (0.94, 2.51) CYP3A and/or P-gp Inhibitors and InducersLopinavir/ritonavir efavirenz 400 mg/100 mg b.i.d. 600 mg q.d. 11300 mg b.i.d.6.29 (4.72, 8.39) 2.53 (2.24, 2.87) 1.25 (1.01, 1.55) Saquinavir (soft gel capsules) /ritonavir efavirenz 1,000 mg/100 mg b.i.d. 600 mg q.d. 11100 mg b.i.d.8.42 (6.46, 10.97) 5.00 (4.26, 5.87) 2.26 (1.64, 3.11) Darunavir/ritonavir etravirine 600 mg/100 mg b.i.d. 200 mg b.i.d.10150 mg b.i.d.5.27 (4.51, 6.15) 3.10 (2.57, 3.74) 1.77 (1.20, 2.60) Fosamprenavir/ritonavir 700 mg/100 mg b.i.d. 14300 mg b.i.d.4.74 (4.03, 5.57) 2.49 (2.19, 2.82) 1.52 (1.27, 1.82) Fosamprenavir/ritonavir 1,400 mg/100 mg q.d. 14300 mg q.d.1.80 (1.53, 2.13) 2.26 (1.99, 2.58) 1.45 (1.20, 1.74) Tipranavir/ritonavir 500 mg/200 mg b.i.d.12150 mg b.i.d.1.80 (1.55, 2.09) 1.02 (0.85, 1.23) 0.86 (0.61, 1.21) OtherRaltegravir 400 mg b.i.d.17300 mg b.i.d.0.90 (0.85, 0.96) 0.86 (0.80, 0.92) 0.79 (0.67, 0.94) aCompared with historical data. Effect of Maraviroc on the Pharmacokinetics of Concomitant Drugs: Maraviroc is unlikely to inhibit the metabolism of coadministered drugs metabolized by the following cytochrome enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A) or to inhibit the uptake of OATP1B1 or the export of MRP2 because maraviroc did not inhibit activity of those enzymes or transporters at clinically relevant concentrations in vitro. Maraviroc does not induce CYP1A2 in vitro. Additionally, in vitrostudies have shown that maraviroc is not substrate for, and does not inhibit, any of the major renal uptake inhibitors (organic anion transporter [OAT]1, OAT3, organic cation transporter [OCT]2, novel organic cation transporter [OCTN]1, and OCTN2) at clinically relevant concentrations. 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 (Table 14). Coadministration of fosamprenavir 700 mg/ritonavir 100 mg twice daily and maraviroc 300 mg twice daily decreased the 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 min and AUC of amprenavir by 15% and 30%, respectively. No dosage adjustment is necessary when maraviroc tablets are dosed 150 mg twice daily in combination with fosamprenavir/ritonavir dosed once or twice daily. Fosamprenavir should be given with ritonavir when coadministered with maraviroc tablets. Maraviroc had no significant effect on the pharmacokinetics of elvitegravir, zidovudine, or lamivudine. Maraviroc decreased the 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 6-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 greater than 100 uM. 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 doses. 12.4 Microbiology. Mechanism of ActionMaraviroc is member of 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 CultureMaraviroc inhibits the replication of CCR5-tropic laboratory strains and primary isolates of HIV-1 in models of acute peripheral blood leukocyte infection. The mean EC 50 value (50% effective concentration) for maraviroc against HIV-1 group isolates (subtypes to and circulating recombinant form AE) and group isolates ranged from 0.1 to 4.5 nM (0.05 to 2.3 ng per mL) in cell culture. When used with other antiretroviral agents in cell culture, the combination of maraviroc was not antagonistic with non-nucleoside reverse transcriptase inhibitors (NNRTIs: efavirenz and nevirapine), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine), or protease inhibitors (PIs: amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir). Maraviroc was not antagonistic with the HIV-1 gp41 fusion inhibitor enfuvirtide. Maraviroc was not active against CXCR4-tropic and dual-tropic viruses (EC 50 value greater than 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 CCR5-tropic viruses (CCl/85 and RU570). The maraviroc-resistant viruses remained CCR5-tropic with no evidence of change from CCR5-tropic virus to 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 CCl/85. In the RU570 isolate 3-amino acid residue deletion in the V3 loop, QAI (HXB2 positions 315 to 317), was associated with maraviroc resistance. The relevance of the specific gp120 substitutions 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 EC 50 values. Cross-Resistance in Cell Culture: Maraviroc had antiviral activity against HIV-1 clinical isolates resistant to NNRTIs, NRTIs, PIs, and the gp41 fusion inhibitor enfuvirtide in cell culture (EC 50 values ranged from 0.7 to 8.9 nM [0.36 to 4.57 ng per mL]). Maraviroc-resistant viruses that emerged in cell culture remained susceptible to 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 15), or due to low exposure to maraviroc see Clinical Pharmacology 12.2) ]. Antiretroviral Treatment-Experienced Adult 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 of these treatment-failure subjects had greater than or equal to 3-fold shifts in EC 50 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 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 Adult Subjects (Trial A4001026): Treatment-naive subjects receiving maraviroc had more virologic failures and more treatment-emergent resistance to the background regimen drugs compared with those receiving efavirenz (Table 15). Table 15. Development of Resistance to Maraviroc or Efavirenz and Background Drugs in Antiretroviral Treatment-Naive Trial A4001026 for Patients with Only CCR5-Tropic Virus at Screening Using Enhanced Sensitivity TROFILE AssayMaravirocEfavirenzTotal in dataset (as-treated)273241Total virologic failures (as-treated)85 (31%)56 (23%)Evaluable virologic failures with post baseline genotypic and phenotypic data7343Lamivudine resistance39 (53%)13 (30%)Zidovudine resistance2 (3%)0Efavirenz resistance-23 (53%)Phenotypic resistance to maraviroc 19 (26 )-a Includes 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 maraviroc-containing regimen with CCR5-tropic virus and had tropism result at failure; of these subjects had evidence of maraviroc phenotypic resistance defined as concentration-response curves that did not reach 95% inhibition. One additional subject had greater than or equal to 3-fold shift in the EC 50 value for maraviroc at the time of failure. clonal analysis of the V3 loop amino acid envelope sequences was performed from of the 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 there are multiple diverse pathways to maraviroc resistance. The subjects who failed with CCR5-tropic virus and without 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 reduced virologic response to maraviroc. Antiretroviral Treatment-Experienced Subjects (Trials A4001027 and A4001028): 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, detailed clonal analysis was conducted on virus from 20 representative subjects (16 subjects from the maraviroc arms and 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 low level of pre-existing CXCR4-using virus not detected by the tropism assay (which is population-based) prior to treatment rather than from 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 reduced virological response to maraviroc. Furthermore, subjects failing twice-daily maraviroc at Week 48 with CXCR4-using virus had lower median increase in CD4+ cell counts from baseline (+41 cells per mm 3) than those subjects failing with CCR5-tropic virus (+162 cells per mm 3). The median increase in CD4+ cell count in subjects failing in the placebo arm was +7 cells per mm 3. Antiretroviral Treatment-Naive Subjects (Trial A4001026): In 96-week trial of antiretroviral treatment-naive subjects, 14% (12 of 85) who had only 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. detailed clonal analysis was conducted in previously antiretroviral treatment-naive subjects enrolled in 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 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 of 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 of 12) developed zidovudine-associated resistance substitutions. Subjects who had only CCR5-tropic virus at baseline and failed maraviroc therapy with CXCR4-using virus had median increase in CD4+ cell counts from baseline of +113 cells per mm while those subjects failing with CCR5-tropic virus had an increase of +135 cells per mm 3. The median increase in CD4+ cell count in subjects failing in the efavirenz arm was +95 cells per mm 3. Antiretroviral Treatment-Experienced Pediatric Subjects (Trial A4001031): In the Week 48 analysis of Trial A4001031 (n 103), the mechanisms of resistance to maraviroc observed in the treatment-experienced pediatric population were similar to those observed in adult populations: reasons for virologic failure included failing with CXCR4- or dual/mixed-tropic virus, evidence of reduced maraviroc susceptibility as measured by decrease in maximal percentage inhibition (MPI), and emergence of resistance to background drug in the regimen.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed in other sections of the labeling: Hepatotoxicity see Boxed Warning, Warnings and Precautions 5.1) o Severe Skin and Hypersensitivity Reactions see Warnings and Precautions 5.2) o Cardiovascular Events see Warnings and Precautions 5.3) . The most common adverse events in treatment-experienced adult subjects (greater than 8% incidence) which occurred at higher frequency compared with placebo are upper respiratory tract infections, cough, pyrexia, rash, and dizziness. 6.1) The most common adverse events in treatment-naive adult subjects (greater than 8% incidence) which occurred at higher frequency than the comparator arm are upper respiratory tract infections, bronchitis, flatulence, bloating and distention, upper respiratory tract signs and symptoms, and gastrointestinal atonic and hypomotility disorders. 6.1) The most common adverse reactions in treatment-experienced pediatric subjects (greater than or equal to 3% incidence) are vomiting, abdominal pain, diarrhea, nausea, and dizziness. 6.1) To report SUSPECTED ADVERSE REACTIONS, contact Hetero Labs Limited at 1-866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.Clinical Trials Experience in Adult SubjectsTreatment-Experienced Subjects:The safety profile of maraviroc is primarily based on 840 HIV-1-infected subjects who received at least dose of maraviroc during two Phase trials. total of 426 of these subjects received the indicated twice-daily dosing regimen. Assessment of treatment-emergent adverse events is based on the pooled data from trials in subjects with CCR5-tropic HIV-1 (A4001027 and A4001028). The median duration of therapy with maraviroc for subjects in these trials was 48 weeks, with the total exposure on maraviroc twice daily at 309 patient-years versus 111 patient-years on placebo each administered with optimized background therapy (OBT). The population was 89% male and 84% white, with mean age of 46 years (range: 17 to 75 years). Subjects received dose equivalents of 300 mg maraviroc once or twice daily. The most common adverse events reported with twice-daily therapy with maraviroc with frequency rates higher than placebo, regardless of causality, were upper respiratory tract infections, cough, pyrexia, rash, and dizziness. In these trials, the rate of discontinuation due to adverse events was 5% for subjects who received maraviroc twice daily OBT as well as those who received placebo OBT. Most of the adverse events reported were judged to be mild to moderate in severity. The data described below occurred with twice-daily dosing of maraviroc. The total numbers of subjects reporting infections were 233 (55%) and 84 (40%) in the group receiving maraviroc twice daily and the placebo group, respectively. Correcting for the longer duration of exposure on maraviroc compared with placebo, the exposure-adjusted frequency (rate per 100 subject-years) of these events was 133 for both maraviroc twice daily and placebo. Dizziness or postural dizziness occurred in 8% of subjects on either maraviroc or placebo, with subjects (0.5%) on maraviroc permanently discontinuing therapy (1 due to syncope, due to orthostatic hypotension) versus subject on placebo (0.5%) permanently discontinuing therapy due to dizziness. Treatment-emergent adverse events, regardless of causality, from Trials A4001027 and A4001028 are summarized in Table 5. Selected events occurring at greater than or equal to 2% of subjects and at numerically higher rate in subjects treated with maraviroc are included; events that occurred at the same or higher rate on placebo are not displayed. Table 5. Selected Treatment-Emergent Adverse Events (All Causality) >=2% on Maraviroc (and at Higher Rate Compared with Placebo) in Trials A4001027 and A4001028 (Pooled Analysis, 48 Weeks) Body System/Adverse EventMaraviroc Twice Daily Placebo(n 426)%Exposure-Adjusted Rate (per 100 pt-yrs) PYE=309 (n 209)%Exposure-Adjusted Rate (per 100 pt-yrs) PYE=111 Eye DisordersConjunctivitis2313Ocular infections, inflammations, and associated manifestations2312Gastrointestinal DisordersConstipation6936General Disorders and Administration Site ConditionsPyrexia1320917Pain and discomfort4535Infections and InfestationsUpper respiratory tract infection23371327Herpes infection81148Sinusitis71036Bronchitis7959Folliculitis4524Anogenital warts2313Influenza230.51Otitis media230.51Metabolism and Nutrition DisordersAppetite disorders811713Musculoskeletal and Connective Tissue DisordersJoint-related signs and symptoms71035Muscle pains340.51Neoplasms Benign, Malignant, and UnspecifiedSkin neoplasms benign3413Nervous System DisordersDizziness/postural dizziness913817Paresthesias and dysesthesias5736Sensory abnormalities4613Disturbances in consciousness4536Peripheral neuropathies4536Psychiatric DisordersDisturbances in initiating and maintaining sleep811510Depressive disorders4635Anxiety symptoms4537Renal and Urinary DisordersBladder and urethral symptoms5713Urinary tract signs and symptoms3413Respiratory, Thoracic, and Mediastinal DisordersCoughing and associated symptoms1421510Upper respiratory tract signs and symptoms6936Nasal congestion and inflammations4635Breathing abnormalities4525Paranasal sinus disorders340.51Skin and Subcutaneous Tissue DisordersRash1116511Apocrine and eccrine gland disorders5747.5Pruritus4524Lipodystrophies350.51Erythema2312Vascular DisordersVascular hypertensive disorders3424a 300-mg dose equivalent. PYE Patient-years of exposure. Laboratory Abnormalities:Table shows the treatment-emergent Grade to laboratory abnormalities that occurred in greater than 2% of subjects receiving maraviroc.Table 6. Maximum Shift in Laboratory Test Values (without Regard to Baseline) >=2% of Grade to Abnormalities (ACTG Criteria) in Trials A4001027 and A4001028 (Pooled Analysis, 48 Weeks)Laboratory Parameter Preferred TermLimitMaravirocTwice Daily OBT(n 421) %Placebo OBT(n 207) %Aspartate aminotransferase>5.0 ULN4.82.9Alanine aminotransferase>5.0 ULN2.63.4Total bilirubin>2.5 ULN5.55.3Amylase>2.0 ULN5.75.8Lipase>2.0 ULN4.96.3Absolute neutrophil count<750/mm 4.32.4ULN Upper limit of normal. Percentages based on total subjects evaluated for each laboratory parameter. Treatment-Naive Subjects: Treatment-Emergent Adverse Events:Treatment-emergent adverse events, regardless of causality, from Trial A4001026, double-blind, comparative, controlled trial in which 721 treatment-naive subjects received maraviroc 300 mg twice daily (n 360) or efavirenz 600 mg once daily (n 361) in combination with lamivudine/zidovudine (COMBIVIR) for 96 weeks, are summarized in Table 7. Selected events occurring in greater than or equal to 2% of subjects and at numerically higher rate in subjects treated with maraviroc are included; events that occurred at the same or higher rate on efavirenz are not displayed.Table 7. Selected Treatment-Emergent Adverse Events (All Causality) >=2% on maraviroc (and at Higher Rate Compared with Efavirenz) in Trial A4001026 (96 Weeks)Body System/Adverse EventMaraviroc tablets300 mg Twice Daily Lamivudine/Zidovudine(n 360)(%)Efavirenz600 mg Once Daily Lamivudine/Zidovudine(n 361)(%)Blood and Lymphatic System DisordersAnemias NEC85Neutropenias43Ear and Labyrinth DisordersEar disorders NEC32Gastrointestinal DisordersFlatulence, bloating, and distention107Gastrointestinal atonic and hypomotility disorders NEC95Gastrointestinal signs and symptoms NEC32General Disorders and Administration Site ConditionsBody temperature perception31Infections and InfestationsUpper respiratory tract infection3230Bronchitis139Herpes infection76Bacterial infections NEC63Herpes zoster/varicella 54Tinea infections43Lower respiratory tract and lung infections32Neisseria infections 30Viral infections NEC32Musculoskeletal and Connective Tissue DisordersJoint-related signs and symptoms65Nervous System DisordersParasthesias and dyesthesias43Memory loss (excluding dementia)31Renal and Urinary Disorders Bladder and urethral symptoms43Reproductive System and Breast DisordersErection and ejaculation conditions and disorders32Respiratory, Thoracic, and Mediastinal Disorders Upper respiratory tract signs and symptoms95Skin and Subcutaneous DisordersNail and nail bed conditions (excluding infections and infestations)62Lipodystrophies43Acnes32Alopecias21Laboratory Abnormalities:Table 8. Maximum Shift in Laboratory Test Values (without Regard to Baseline) >=2% of Grade to Abnormalities (ACTG Criteria) in Trial A4001026 (96 Weeks)Laboratory Parameter Preferred TermLimitMaraviroc300 mg Twice Daily Lamivudine/Zidovudine (n 353) %Efavirenz600 mg Once Daily +Lamivudine/Zidovudine (n 350) %Aspartate aminotransferase>5.0 ULN4.04.0Alanine aminotransferase>5.0 ULN3.94.0Creatine kinase>10.0 ULN3.94.8Amylase>2.0 ULN4.36.0Absolute neutrophil count<750/mm 5.74.9Hemoglobin<7.0 g/dL2.92.3ULN Upper limit of normal. n Total number of subjects evaluable for laboratory abnormalities. Percentages based on total subjects evaluated for each laboratory parameter. If the same subject in given treatment group had greater than occurrence of the same abnormality, only the most severe is counted. Less Common Adverse Events in Clinical Trials:The following adverse events occurred in less than 2% of subjects treated with maraviroc or at rate similar to the comparator. These events have been included because of their seriousness and either increased frequency on maraviroc or are potential risks due to the mechanism of action. Events attributed to the subjects underlying HIV-1 infection are not listed.Blood and Lymphatic System:Marrow depression and hypoplastic anemia.Cardiac Disorders: Unstable angina, acute cardiac failure, coronary artery disease, coronary artery occlusion, myocardial infarction, myocardial ischemia.Hepatobiliary Disorders:Hepatic cirrhosis, hepatic failure, cholestatic jaundice, portal vein thrombosis, jaundice. Infections and Infestations: Endocarditis, infective myositis, viral meningitis, pneumonia, treponema infections, septic shock, Clostridium difficile colitis, meningitis. Musculoskeletal and Connective Tissue Disorders:Myositis, osteonecrosis, rhabdomyolysis, blood CK increased. Neoplasms Benign, Malignant, and Unspecified (Including Cysts and Polyps):Abdominal neoplasm, anal cancer, basal cell carcinoma, Bowens disease, cholangiocarcinoma, diffuse large B-cell lymphoma, lymphoma, metastases to liver, esophageal carcinoma, nasopharyngeal carcinoma, squamous cell carcinoma, squamous cell carcinoma of skin, tongue neoplasm (malignant stage unspecified), anaplastic large cell lymphomas T- and null-cell types, bile duct neoplasms malignant, endocrine neoplasms malignant and unspecified. Nervous System Disorders:Cerebrovascular accident, convulsions and epilepsy, tremor (excluding congenital), facial palsy, hemianopia, loss of consciousness, visual field defect. Clinical Trials Experience in Pediatric Subjects HIV-1-Infected Pediatric Subjects:Trial A4001031 is an open-label trial in which 103 treatment-experienced, CCR5-tropic, HIV-1-infected pediatric subjects aged to less than 18 years weighing at least 10 kg received maraviroc twice daily in combination with OBT. The dose of maraviroc was based on body surface area (BSA) and on whether the subject was receiving potent CYP3A inhibitors and/or inducers. The median duration of therapy with maraviroc was 131 weeks with 72% of subjects receiving study treatment for greater than 48 weeks and 62% of subjects receiving study treatment for 96 weeks. In these 103 children and adolescents, the safety profile through 96 weeks was similar to that for adults. Most of the adverse reactions reported were mild to moderate; severe (Grade and 4) adverse reactions occurred in 2% of subjects. The most common adverse reactions (all grades) reported with twice-daily therapy with maraviroc were vomiting (12%), abdominal pain (4%), diarrhea (4%), nausea (4%), and dizziness (3%). Three subjects (3%) discontinued due to adverse events. Maraviroc-related gastrointestinal adverse events through 48 weeks (nausea, vomiting, diarrhea, constipation, and abdominal pain/cramps) were observed more commonly in subjects who received the maraviroc oral solution (21%) compared with those who received maraviroc tablets (16%). Subjects were permitted to change formulations after Week 48. 6.2 Postmarketing Experience. The following adverse events have been identified during post-approval use of maraviroc. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Skin and Subcutaneous Tissue DisordersStevens-Johnson syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), toxic epidermal necrolysis (TEN).

BOXED WARNING SECTION.

BOXED WARNING. WARNING: HEPATOTOXICITY Hepatotoxicity has been reported with use of maraviroc tablets. Severe rash or evidence of systemic allergic reaction (e.g., fever, 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 maraviroc tablets should be evaluated immediately [see Warnings and Precautions 5.1)]. WARNING: HEPATOTOXICITYSee full prescribing information for complete boxed warning.o Hepatotoxicity has been reported which may be preceded by severe rash or other features of systemic allergic reaction (e.g., fever, eosinophilia, or elevated IgE). 5.1) Immediately evaluate patients with signs or symptoms of hepatitis or allergic reaction. 5.1).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis Mutagenesis Impairment Of Fertility. CarcinogenesisLong-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 per kg per day and in male and female rats at 900 mg per kg per 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.MutagenesisMaraviroc was not genotoxic in the reverse mutation bacterial test (Ames test in Salmonella and E. coli), chromosome aberration test in human lymphocytes, and mouse bone marrow micronucleus test. Impairment of FertilityMaraviroc 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 SECTION.

14 CLINICAL STUDIES. 14.1 Clinical Studies in Adult Subjects. The clinical efficacy and safety of maraviroc are derived from analyses of data from trials in adult subjects infected with CCR5-tropic HIV-1: Trials A4001027 and A4001028 in antiretroviral treatment-experienced adult subjects and Trial A4001026 in treatment-naive subjects. These trials were supported by 48-week trial in antiretroviral treatment-experienced adult subjects infected with dual/mixed-tropic HIV-1, Trial A4001029.Trials in CCR5-Tropic, Treatment-Experienced SubjectsTrials 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 per mL despite at least months of prior therapy with at least agent from of the antiretroviral drug classes (greater than or equal to NRTI, greater than or equal to NNRTI, greater than or equal to PIs, and/or enfuvirtide) or documented resistance to at least member of each class. All subjects received an optimized background regimen consisting of to antiretroviral agents (excluding low-dose ritonavir) selected on the basis of the subjects prior treatment history and baseline genotypic and phenotypic viral resistance measurements. In addition to the optimized background regimen, subjects were then randomized in 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 Dosage and Administration 2) Table 1. In the pooled analysis for Trials A4001027 and A4001028, the demographics and baseline characteristics of the treatment groups were comparable (Table 16). Of the 1,043 subjects with CCR5-tropism result at screening, 7.6% had dual/mixed-tropism result at the baseline visit to weeks later. This illustrates the background change from CCR5- to dual/mixed-tropism result over time in this treatment-experienced population, prior to change in antiretroviral regimen or administration of CCR5 co-receptor antagonist. Table 16. Demographic and Baseline Characteristics of Subjects in Trials A4001027 and A4001028 MaravirocTwice Daily(n 426)Placebo(n 209)Age (years) Mean (range) 46.3 (21-73)45.7 (29-72)Sex:Male382 (89.7%)185 (88.5%)Female44 (10.3%)24 (11.5%)Race:White363 (85.2%)178 (85.2%)Black51 (12.0%)26 (12.4%)Other12 (2.8%)5 (2.4%)Region:U.S.276 (64.8%)135 (64.6%)Non-U.S.150 (35.2%)74 (35.4%)Subjects with previous enfuvirtide use142 (33.3%)62 (29.7%)Subjects with enfuvirtide as part of OBT182 (42.7%)91 (43.5%)Baseline plasma HIV-1 RNA (log 10 copies/mL) Mean (range) 4.85 (2.96-6.88)4.86 (3.46-7.07)Subjects with screening viral load >=100,000 copies/mL179 (42.0%)84 (40.2%)Baseline CD4+ cell count (cells/mm 3) Median (range) 167 (2-820)171 (1-675)Subjects with baseline CD4+ cell count <=200 cells/mm 3) 250 (58.7%)118 (56.5%)Subjects with Overall Susceptibility Score (OSS): 0 2 >=3 57 (13.4%) 136 (31.9%) 104 (24.4%) 125 (29.3%) 35 (16.7%) 44 (21.1%) 59 (28.2%) 66 (31.6%) Subjects with enfuvirtide resistance substitutions90 (21.2%)45 (21.5%)Median number of resistance-associated: PI substitutions NNRTI substitutions NRTI substitutions 10 6 10 6 OSS Sum of active drugs in OBT based on combined information from genotypic and phenotypic testing. Resistance substitutions based on IAS guidelines. The Week 48 results for the pooled Trials A4001027 and A4001028 are shown in Table 17. Table 17. Outcomes of Randomized Treatment at Week 48 in Trials A4001027 and A4001028OutcomeMaravirocTwice Daily(n 426)Placebo(n 209)MeanDifferenceMean change from Baseline to Week 48 inHIV-1 RNA (log 10 copies/mL) -1.84-0.78-1.05<400 copies/mL at Week 48239 (56%)47 (22%)34%<50 copies/mL at Week 48194 (46%)35 (17%)29%Discontinuations: Insufficient clinical response Adverse events Other 97 (23%) 19 (4%) 27 (6%) 113 (54%) 11 (5%) 18 (9%) - Subjects with treatment-emergent CDC Category events22 (5%)16 (8%)-Deaths (during trial or within 28 days of last dose 9 (2%) 1 (0.5%)-a One additional subject died while receiving open-label therapy with maraviroc subsequent to discontinuing double-blind placebo due to insufficient response. After 48 weeks of therapy, the proportions of subjects with HIV-1 RNA less than 400 copies per mL receiving maraviroc compared with placebo were 56% and 22%, respectively. The mean changes in plasma HIV-1 RNA from baseline to Week 48 were -1.84 log 10 copies per mL for subjects receiving maraviroc OBT compared with -0.78 log 10 copies per mL for subjects receiving OBT only. The mean increase in CD4+ cell count was higher on maraviroc twice daily OBT (124 cells per mm 3) than on placebo OBT (60 cells per mm ). 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 maraviroc 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 1:1:1 ratio to maraviroc once daily, maraviroc twice daily, or placebo. No increased risk of infection or HIV-1 disease progression was observed in the subjects who received maraviroc. Use of maraviroc was not associated with significant decrease in HIV-1 RNA compared with placebo in these subjects and no adverse effect on CD4+ cell count was noted.Trial in Treatment-Naive Subjects Trial A4001026 was 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 greater than or equal to 2,000 copies per mL and could not have: 1) previously received any antiretroviral therapy for greater than 14 days, 2) an active or recent opportunistic infection or suspected primary HIV-1 infection, or 3) phenotypic or genotypic resistance to zidovudine, lamivudine, or efavirenz. Subjects were randomized in 1:1:1 ratio to maraviroc 300 mg once daily, maraviroc 300 mg twice daily, or efavirenz 600 mg once daily, each in combination with lamivudine/zidovudine. The efficacy and safety of maraviroc are based on the comparison of maraviroc twice daily versus efavirenz. In pre-planned interim analysis at 16 weeks, maraviroc 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 18). 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. Table 18. Demographic and Baseline Characteristics of Subjects in Trial A4001026Maraviroc 300 mg Twice Daily Lamivudine/Zidovudine(n 360)Efavirenz 600 mg Once Daily Lamivudine/Zidovudine(n 361)Age (years):Mean36.737.4Range20-6918-77Female, n%104 (29)102 (28)Race, n%: White Black Asian Other 204 (57) 123 (34) (2) 27 (8) 198 (55) 133 (37) (1) 25 (7) Median (range) CD4+ cell count (cells/uL)241 (5-1,422)254 (8-1,053)Median (range) HIV-1 RNA (log 10 copies/mL) 4.9 (3-7)4.9 (3-7)The treatment outcomes at 96 weeks for Trial A4001026 are shown in Table 19. Treatment outcomes are based on reanalysis of the screening samples using 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.Table 19. Trial Outcome (Snapshot) at Week 96 Using Enhanced Sensitivity Assay Outcome at Week 96 Maraviroc300 mg Twice Daily Lamivudine/Zidovudine(n 311)n (%)Efavirenz600 mg Once Daily +Lamivudine/Zidovudine(n 303) (%)Virologic Responders: (HIV-1 RNA <400 copies/mL) 199 (64)195 (64) Virologic Failure:Non-sustained HIV-1 RNA suppression39 (13)22 (7)HIV-1 RNA never suppressed9 (3)1 (<1)Virologic Responders: (HIV-1 RNA <50 copies/mL) 183 (59)190 (63)Virologic Failure:Non-sustained HIV-1 RNA suppression43 (14)25 (8)HIV-1 RNA never suppressed21 (7)3 (1)Discontinuations due to:Adverse events19 (6)47 (16)Death2 (1)2 (1)Other 43 (14)36 (12)a The total number of subjects (311, 303) in Table 19 represents the subjects who had 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 18 as having dual/mixed- or CXCR4-tropic virus. These numbers are different than those presented in Table 18 because the numbers in Table 18 reflect the subjects with CCR5-tropic virus according to the original tropism assay. Week 48 results: Virologic responders (less than 400): 228 of 311 (73%) in maraviroc, 219 of 303 (72%) in efavirenz; Virologic responders (less than 50): 213 of 311 (69%) in maraviroc, 207 of 303 (68%) in efavirenz. Other 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 per mm for the arm receiving maraviroc compared with 155 cells per mm for the efavirenz arm. 14.2 Clinical Studies in Pediatric Subjects. Trial in CCR5-Tropic, Treatment-Experienced SubjectsTrial A4001031 is an open-label, multicenter trial in pediatric subjects aged to less than 18 years infected with only CCR5-tropic HIV-1. Subjects were required to have HIV-1 RNA greater than 1,000 copies per mL at screening. All subjects (n 103) received maraviroc twice daily and OBT. Dosing of maraviroc was based on BSA and doses were adjusted based on whether the subject was receiving potent CYP3A inhibitors and/or inducers. The population was 52% female and 69% black, with mean age of 10 years (range: to 17 years). At baseline, mean plasma HIV-1 RNA was 4.4 log 10 copies per mL (range: 2.4 to 6.2 log 10 copies per mL), mean CD4+ cell count was 551 cells per mm (range: to 1,654 cells per mm 3), and mean CD4+ percent was 21% (range: 0% to 42%). At 48 weeks, 48% of subjects treated with maraviroc and OBT achieved plasma HIV-1 RNA less than 48 copies per mL and 65% of subjects achieved plasma HIV-1 RNA less than 400 copies per mL. The mean CD4+ cell count (percent) increase from baseline to Week 48 was 247 cells per mm (5%).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Maraviroc tablets are contraindicated in patients with severe renal impairment or ESRD (CrCl less than 30 mL per minute) who are concomitantly taking potent CYP3A inhibitors or inducers see Warnings and Precautions 5.3) ]. o Maraviroc tablets are contraindicated in patients with severe renal impairment or end-stage renal disease (ESRD) (CrCl less than 30 mL per minute) who are concomitantly taking potent CYP3A inhibitors or inducers. 4).

DESCRIPTION SECTION.

11 DESCRIPTION. Maraviroc is 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.Maraviroc is available as film-coated tablets for oral administration containing either 150 or 300 mg of maraviroc and the following inactive ingredients: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium starch glycolate. The tablets are coated with, Opadry II White contains lecithin, polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide. Maraviroc is chemically described as 4,4-Difluoro-N-[(1S)-3-[(3-exo)-3-[3-methyl-5- (1-methylethyl)-4H-1,2,4-triazol-4-yl]-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl]-cyclohexane carboxamide. The molecular formula is 29H 41F 2N 5O and the structural formula is: Maraviroc is white to pale colored powder with molecular weight of 513.67. It is freely soluble in methanol and hygroscopic. maraviroctabletstructure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Prior to initiation of maraviroc tablets for treatment of HIV-1 infection, test all patients for CCR5 tropism using highly sensitive tropism assay. 2.1) Maraviroc tablets are taken twice daily by mouth and may be taken with or without food. Maraviroc tablets must be given in combination with other antiretroviral medications. 2.2) Recommended Dosage in Adult Patients: 2.3) Concomitant MedicationsDosage of Maraviroc tabletsWhen given with potent cytochrome P450 (CYP)3A inhibitors (with or without potent CYP3A inducers) including PIs (except tipranavir/ritonavir) 2.3, 7.1) 150 mg twice daily With NRTIs, tipranavir/ritonavir, nevirapine, raltegravir, and other drugs that are not potent CYP3A inhibitors or CYP3A inducers 2.3, 7.1) 300 mg twice daily With potent and moderate CYP3A inducers including efavirenz (without potent CYP3A inhibitor) 2.3, 7.1) 600 mg twice daily more complete list of coadministered drugs is listed in Dosage and Administration. 2) Recommended Dosage in Pediatric Patients years and older and weighing at Least 10 kg: Administer twice daily. Dosage should be based on body weight (kg) and concomitant medications and should not exceed the recommended adult dose. 2.4) Recommended Dosage in Patients with Renal Impairment: Dose adjustment may be necessary in adult patients with renal impairment. 2.5) 2.1 Testing prior to Initiation of Maraviroc Tablets. Prior to initiation of maraviroc tablets for treatment of HIV-1 infection, test all patients for CCR5 tropism using highly sensitive tropism assay. Maraviroc tablets are recommended for patients with only CCR5-tropic HIV-1 infection. Outgrowth of pre-existing low-level CXCR4- or dual/mixed-tropic HIV-1 not detected by tropism testing at screening has been associated with virologic failure on maraviroc tablets see Microbiology 12.4), Clinical Studies 14.1) ]. Monitor patients for ALT, AST, and bilirubin prior to initiation of maraviroc tablets and at other time points during treatment as clinically indicated [see Warnings and Precautions 5.1)] . 2.2 General Dosing Recommendations. Maraviroc tablets are taken twice daily by mouth and may be taken with or without food.o Maraviroc tablets must be given in combination with other antiretroviral medications. The recommended dosage of maraviroc tablets differs based on concomitant medications due to drug interactions. 2.3 Recommended Dosage in Adult Patients with Normal Renal Function. Table displays oral dosage of maraviroc tablets based on different concomitant medications see Drug Interactions 7.1) ]. Table 1. Recommended Dosage in AdultsConcomitant MedicationsDosage of Maraviroc TabletsPotent cytochrome P450 (CYP)3A inhibitors (with or without potent CYP3A inducer) 150 mg twice dailyNoninteracting concomitant medications 300 mg twice dailyPotent and moderate CYP3A inducers (without potent CYP3A inhibitor) 600 mg twice dailyaPotent CYP3A inhibitors (with or without potent CYP3A inducer) including: clarithromycin, cobicistat, elvitegravir/ritonavir, itraconazole, ketoconazole, nefazodone, protease inhibitors (except tipranavir/ritonavir), telithromycin. Noninteracting concomitant medications include all medications that are not potent CYP3A inhibitors or inducers such as: dolutegravir, enfuvirtide, nevirapine, all nucleoside reverse transcriptase inhibitors (NRTIs), raltegravir, and tipranavir/ritonavir. Potent and moderate CYP3A inducers (without potent CYP3A inhibitor) including: carbamazepine, efavirenz, etravirine, phenobarbital, phenytoin, and rifampin. 2.4 Recommended Dosage in Pediatric Patients with Normal Renal Function. The recommended dosage of maraviroc tablets should be based on body weight (kg) and should not exceed the recommended adult dose. The recommended dosage also differs based on concomitant medications due to drug interactions (Table and Table 3) see Drug Interactions 7.1), Use in Specific Populations 8.4)]. Before prescribing maraviroc tablets, assess children for the ability to swallow tablets. If child is unable to reliably swallow maraviroc tablets, the oral solution formulation should be prescribed.The recommended oral dosage of maraviroc tablets in pediatric patients aged years and older weighing at least 10 kg is presented in Table 2.Table 2. Recommended Dosage in Pediatric Patients Aged Years and Older Weighing at Least 10 kg (Tablets)Concomitant MedicationsDosage of Maraviroc Tablets Based on Weight10 kg to<14 kg14 kg to<20 kg20 kg to<30 kg30 kg to<40 kg>=40 kgPotent CYP3A inhibitors (with or without CYP3A inducer) 50 mg twice daily 50 mg twice daily 75 mg twice daily 100 mg twice daily 150 mg twice daily Noninteracting concomitant medications 150 mg twice daily 200 mg twice daily 200 mg twice daily 300 mg twice daily 300 mg twice daily Potent and moderate CYP3A inducers (without potent CYP3A inhibitor) Not recommended a Potent CYP3A inhibitors (with or without CYP3A inducer) including: clarithromycin, cobicistat, elvitegravir/ritonavir, itraconazole, ketoconazole, nefazodone, protease inhibitors (except tipranavir/ritonavir), telithromycin. Noninteracting concomitant medications including all medications that are not potent CYP3A inhibitors or inducers such as: dolutegravir, enfuvirtide, nevirapine, all NRTIs, raltegravir, and tipranavir/ritonavir. Potent and moderate CYP3A inducers (without potent CYP3A inhibitor) including: carbamazepine, efavirenz, etravirine, phenobarbital, phenytoin, and rifampin. Insufficient data are available to recommend use. The recommended oral dosage of maraviroc oral solution in pediatric patients weighing at least 10 kg is presented in Table 3. Table 3. Recommended Dosage in Pediatric Patients Weighing at Least 10 kgConcomitant MedicationsDosage (Volume of Solution) of Maraviroc Tablets Based on Weight10 kg to<14 kg14 kg to<20 kg20 kg to<30 kg30 kg to<40 kg>=40 kgPotent CYP3A inhibitors (with or without CYP3A inducer) 50 mg (2.5 mL) twice daily 50 mg (2.5 mL twice daily 80 mg (4 mL) twice daily 100 mg (5 mL) twice daily 150 mg (7.5 mL) twice daily Noninteracting concomitant medications 150 mg (7.5 mL) twice daily 200 mg (10 mL) twice daily 200 mg (10 mL) twice daily 300 mg (15 mL) twice daily 300 mg (15 mL) twice daily Potent and moderate CYP3A inducers (without potent CYP3A inhibitor) Not recommended a PotentCYP3A inhibitors(with or without CYP3A inducer) including:clarithromycin, cobicistat,elvitegravir/ritonavir, itraconazole,ketoconazole,nefazodone,proteaseinhibitors (excepttipranavir/ritonavir), telithromycin. Insufficient data areavailable to recommend use. Noninteractingconcomitantmedicationsincluding all medicationsthatare not potent CYP3A inhibitorsor inducers such as: dolutegravir, enfuvirtide,nevirapine, all NRTIs,raltegravir, and tipranavir/ritonavir. Potent and moderateCYP3A inducers (without potent CYP3A inhibitor)including: carbamazepine,efavirenz,etravirine, phenobarbital,phenytoin, and rifampin. Administer the oral solution using the included press-in bottle adapter and the appropriate oral dosing syringe: for doses of 2.5 mL, use the 3-mL syringe; for doses greater than 2.5 mL, use the 10-mL syringe.. 2.5 Recommended Dosage in Patients with Renal Impairment. Adult PatientsTable provides dosing recommendations for patients based on renal function and concomitant medications.Table 4. Recommended Dosage in Adults Based on Renal FunctionConcomitant MedicationsDosage of Maraviroc Tablets Based on Renal FunctionNormal(CrCl >80mL/min)Mild(CrCl >50and <=80mL/min)Moderate(CrCl >=30and <=50mL/min)Severe(CrCl <30mL/min)End-StageRenal Diseaseon RegularHemodialysisPotent CYP3A inhibitors (with or without CYP3A inducer) 150 mg twice daily 150 mg twice daily 150 mg twice daily ContraindicatedContraindicatedNoninteracting concomitant medications 300 mg twice daily 300 mg twice daily 300 mg twice daily 300 mg twice daily 300 mg twice daily Potent and moderate CYP3A inducers (without potent CYP3A inhibitor) 600 mg twice daily 600 mg twice daily 600 mg twice daily ContraindicatedContraindicateda Potent CYP3A inhibitors (with or without CYP3A inducer) including: clarithromycin, cobicistat, elvitegravir/ritonavir, itraconazole, ketoconazole, nefazodone, protease inhibitors (except tipranavir/ritonavir), telithromycin. Noninteracting concomitant medications include all medications that are not potent CYP3A inhibitors or inducers such as: dolutegravir, enfuvirtide, nevirapine, all NRTIs, raltegravir, and tipranavir/ritonavir. Dosage of maraviroc tablets should be reduced to 150 mg twice daily if there are any symptoms of postural hypotension see Contraindications 4) Warnings and Precautions 5.3)] d Potent and moderate CYP3A inducers (without potent CYP3A inhibitor) including: carbamazepine, efavirenz, etravirine, phenobarbital, phenytoin, and rifampin. Pediatric PatientsThere are no data to recommend specific doses of maraviroc tablets in pediatric patients with mild or moderate renal impairment see Use in Specific Populations 8.6) ]. Additionally, maraviroc tablets are contraindicated for pediatric patients with severe renal impairment or end-stage renal disease (ESRD) on regular hemodialysis who are receiving potent CYP3A inhibitors or inducers see Contraindications 4) ].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. 150 mg white to off-white colored, oval, biconvex, film coated tablets debossed with on one side and 62 on the other side.o 300 mg white to off-white colored, oval, biconvex, film coated tablets debossed with on one side and 63 on the other side. Tablets: 150 mg and 300 mg 3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Coadministration with CYP3A inhibitors, including protease inhibitors (except tipranavir/ritonavir), will increase the concentration of maraviroc. 7.1) Coadministration with CYP3A inducers, including efavirenz, may decrease the concentration of maraviroc. 7.1) Coadministration with St. Johns wort is not recommended. 7.1). 7.1 Effect of Concomitant Drugs on the Pharmacokinetics of Maraviroc. Maraviroc is metabolized by CYP3A and is also substrate for P-glycoprotein (P-gp), organic anion-transporting polypeptide (OATP)1B1, and multidrug resistance-associated protein (MRP)2. The pharmacokinetics of maraviroc are likely to be modulated by inhibitors and inducers of CYP3A and P-gp and may be modulated by inhibitors of OATP1B1 and MRP2.Therefore, dosage adjustment may be required when maraviroc is coadministered with those drugs see Dosage and Administration 2.3, 2.4) ]. Concomitant use of maraviroc and St. Johns wort Hypericum perforatum) or products containing St. Johns wort is not recommended. Coadministration of maraviroc with St. Johns 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. Additional drug interaction information is available see Clinical Pharmacology 12.3) ].

GERIATRIC USE SECTION.

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

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Maraviroc film-coated tablets are available as follows: 150 mg white to off-white colored, oval, biconvex, film coated tablets debossed with on one side and 62 on the other side. Bottle of 60 tablets (NDC 31722-579-60) 300 mg white to off-white colored, oval, biconvex, film coated tablets debossed with on one side and 63 on the other side. Bottle of 60 tablets (NDC 31722-580-60) Maraviroc film-coated tablets should be stored at 20 to 25C (68 to 77F). [See USP Controlled Room Temperature.].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Maraviroc tablets are indicated in combination with other antiretroviral agents for the treatment of only CCR5-tropic human immunodeficiency virus type (HIV-1) infection in adult and pediatric patients years of age and older weighing at least 10 kg.Limitations of Use: Maraviroc tablets are not recommended in patients with dual/mixed- or CXCR4-tropic HIV-1 see Microbiology 12.4) ]. Maraviroc tablet is CCR5 co-receptor antagonist indicated in combination with other antiretroviral agents for the treatment of only CCR5-tropic HIV-1 infection in adults and pediatric patients years of age and older weighing at least 10 kg. 1) Limitations of Use: Not recommended in patients with dual/mixed- or CXCR4-tropic HIV-1. 1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).HepatotoxicityInform patients that hepatotoxicity, including life-threatening cases, has been reported with maraviroc tablets; therefore, it is important to inform the healthcare professional if patients have underlying hepatitis or or elevations in liver-associated tests prior to treatment. Inform patients to stop maraviroc tablets and seek medical evaluation immediately if they develop signs or symptoms of hepatitis or allergic reaction following use of maraviroc tablets. Advise patients that laboratory tests for liver enzymes and bilirubin will be ordered prior to starting maraviroc tablets, at other times during treatment, and if they develop severe rash or signs and symptoms of hepatitis or an allergic reaction on treatment see Dosage and Administration 2.1), Warnings and Precautions 5.1, 5.2) ]. Cardiovascular EventsWhen administering maraviroc tablets in patients with cardiovascular comorbidities, history of postural hypotension or receiving concomitant medication known to lower blood pressure, advise patients that they may be at increased risk for cardiovascular events. Advise patients to avoid driving or operating machinery if they experience dizziness while taking maraviroc tablets see Warnings and Precautions 5.3) ]. Drug InteractionsAdvise patients to inform their healthcare provider of concomitant HIV medications as dosage of maraviroc tablets may be modified depending on other HIV medications taken with maraviroc tablets. Advise patients that coadministration of maraviroc tablets with St. Johns wort is not recommended as it can lead to loss of virologic response and possible resistance to maraviroc tablets see Dosage and Administration 2.2), Drug Interactions 7.1) ]. Missed DosageInform patients that it is important to take maraviroc tablets in combination with other antiretroviral medications on regular dosing schedule with or without food. Advise patients to avoid missing doses as it can result in development of resistance. Instruct patients that if they miss dose, to take it as soon as they remember. Advise patients not to double their next dose or take more than the prescribed dose see Dosage and Administration 2.2) ]. PregnancyInform patients that there is insufficient data on the safety of maraviroc tablets in pregnancy. Inform patients that there is an antiretroviral pregnancy registry that monitors pregnancy outcomes in women exposed to maraviroc tablets during pregnancy see Use in Specific Populations 8.1) ]. LactationInstruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk see Use in Specific Populations 8.2) ]. The brands listed are trademarks of their respective owners and are not trademarks of the Hetero Labs Limited.Manufactured for: Camber Pharmaceuticals, Inc., Piscataway, NJ 08854 Manufactured by: HETERO TM Hetero Labs Limited Jeedimetla, Hyderabad 500 055, India Issued: 01/2022. maraviroctabletcamberlogo1.

LABOR & DELIVERY SECTION.

8.2 Lactation. Risk SummaryThe Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.There are no data on the presence of maraviroc in human milk, the effects on the breastfed infant, or the effects on milk production. When administered to lactating rats, maraviroc was present in milk see Data). Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) serious adverse reactions in breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving maraviroc. DataMaraviroc (and related metabolites) was excreted into the milk of lactating rats following single oral dose of maraviroc (100 mg per kg) on lactation Day 12, with maximal milk concentration achieved one hour post-administration at milk concentration approximately 2.5 times that of maternal plasma concentrations.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Maraviroc is an HIV-1 antiviral drug see Microbiology 12.4) ].

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis Mutagenesis Impairment Of Fertility. CarcinogenesisLong-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 per kg per day and in male and female rats at 900 mg per kg per 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.MutagenesisMaraviroc was not genotoxic in the reverse mutation bacterial test (Ames test in Salmonella and E. coli), chromosome aberration test in human lymphocytes, and mouse bone marrow micronucleus test. Impairment of FertilityMaraviroc 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.

OVERDOSAGE SECTION.

10 OVERDOSAGE. The highest single dose administered in clinical trials was 1,200 mg. The dose-limiting adverse event was postural hypotension, which was observed at 600 mg. While the recommended dose for maraviroc in patients receiving CYP3A inducer without 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 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 trials in treatment-experienced subjects with HIV using the recommended doses of maraviroc, or in specific pharmacokinetic trial to evaluate the potential of maraviroc to prolong the QT interval see Clinical Pharmacology 12.2) ]. There is no specific antidote for overdose with maraviroc. Treatment of overdose should consist of general supportive measures including keeping the patient in supine position, careful assessment of patient vital signs, blood pressure, and ECG. Administration of activated charcoal may also be used to aid in removal of unabsorbed drug. Hemodialysis had minimal effect on maraviroc clearance and exposure in trial in subjects with ESRD see Clinical Pharmacology 12.3) ].

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL. Maraviroc Tablet 150 mg LabelMaraviroc Tablet 300 mg Label. maraviroctablet150mglabel. maraviroctablet300mglabel.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and efficacy of maraviroc have been established in pediatric patients aged from aged to less than 18 years. The use of maraviroc in pediatric patients was supported by pharmacokinetic and safety data described below and by previous demonstration of efficacy in adult patients see Indications and Usage (1)], Dosage and Administration 2.4) ]. HIV-1-Infected Pediatric Patients Aged to Less Than 18 Years: The safety, pharmacokinetic profile, and antiviral activity of maraviroc were evaluated in treatment-experienced, CCR5- tropic, HIV-1-infected pediatric subjects aged to less than 18 years weighing at least 10 kg in an open-label, multicenter clinical trial, A4001031 see Adverse Reactions 6.1), Clinical Studies 14.2) ]. Pharmacokinetics were evaluated in total of 98 pediatric subjects: 85 subjects received maraviroc and concomitant medications that included potent CYP3A inhibitors with or without potent CYP3A inducers, 10 subjects received maraviroc and noninteracting medications (not containing potent CYP3A inhibitors or potent CYP3A inducers), and three subjects received maraviroc and medications that included potent CYP3A inducers without potent CYP3A inhibitors see Clinical Pharmacology 12.3) ]. There are insufficient data to make dosing recommendations for use of maraviroc in pediatric patients concomitantly receiving potent CYP3A inhibitors and weighing less than 10 kg, or in any pediatric patients concomitantly receiving potent CYP3A inducers without potent CYP3A inhibitor see Dosage and Administration 2.4, 2.5) ]. Maraviroc is not recommended in pediatric patients weighing less than 10 kg.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Exposure-Response Relationship in Treatment-Experienced Adult SubjectsThe relationship between maraviroc, modeled plasma trough concentration (C min) (1 to samples per subject taken on up to 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 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 less than 400 copies per mL at 24 weeks). Table illustrates the proportions of subjects with virologic success (%) within each min quartile for 150-mg twice-daily and 300-mg twice-daily groups. Table 9. Treatment-Experienced Subjects with Virologic Success by Cmin Quartile (Q1 to Q4) 150 mg Twice Daily(with CYP3A Inhibitors)300 mg Twice Daily(without CYP3A Inhibitors)nMedianC min Subjects with Virologic SuccessnMedianC min Subjects with Virologic SuccessPlacebo160-30.635-28.6Q1783352.6221350.0Q2778763.6222968.2Q37816678.2224663.6Q47827974.4229768.2Exposure-Response Relationship in Treatment-Naive Adult SubjectsThe relationship between maraviroc, modeled plasma trough concentration (C min) (1 to 12 samples per subject taken on up to visits), and virologic response was evaluated in 294 treatment-naive HIV-1-infected subjects receiving maraviroc 300 mg twice daily in combination with lamivudine/zidovudine in Trial A4001026. Table 10 illustrates the proportion (%) of subjects with virologic success less than 50 copies per mL at 48 weeks within each min quartile for the 300-mg twice-daily dose. Table 10. Treatment-Naive Subjects with Virologic Success by min Quartile (Q1 to Q4) 300 mg Twice DailynMedian min Subjects with Virologic SuccessQ1752357.3Q2723972.2Q3735674.0Q4748183.8Eighteen of 75 (24%) subjects in Q1 had no measurable maraviroc concentration on at least one occasion versus of 73 and of 74 in Q3 and Q4, respectively.Effects on ElectrocardiogramA placebo-controlled, randomized, crossover trial to evaluate the effect on the QT interval of healthy male and female volunteers was conducted with 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 (3) msec, respectively, and 13 (15) msec for moxifloxacin 400 mg. No subject in any group had an increase in QTc of greater than or equal to 60 msec from baseline. No subject experienced an interval exceeding the potentially clinically relevant threshold of 500 msec.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Table 11. Mean Maraviroc Pharmacokinetic Parameters in AdultsPatient PopulationMaraviroc DosenAUC12(ng.h/mL)Cmax(ng/mL)Cmin(ng/mL)Healthy volunteers (Phase 1)300 mg twice daily642,90888843.1Asymptomatic HIV subjects (Phase 2a)300 mg twice daily82,55061833.6Treatment-experienced HIV subjects (Phase 3) 300 mg twice daily941,51326637.2150 mg twice daily (+ CYP3A inhibitor) 3752,463332101Treatment-naiveHIV subjects (Phase 2b/3) 300 mg twice daily3441,86528760a The estimated exposure is lower compared with other trials possibly due to sparse sampling, food effect, compliance, and concomitant medications. AbsorptionPeak maraviroc plasma concentrations are attained 0.5 to hours following single oral doses of to1,200 mg administered to uninfected volunteers. The pharmacokinetics of oral maraviroc are not dose proportional over the dose range. The absolute bioavailability of 100-mg dose is 23% and is predicted to be 33% at 300 mg. Maraviroc is substrate for the efflux transporter P-gp. Effect of Food on Oral Absorption: Coadministration of 300-mg tablet with high-fat breakfast reduced maraviroc max and AUC by 33% and coadministration of 75 mg of oral solution with high-fat breakfast reduced maraviroc AUC by 73% in healthy adult volunteers. Studies with the tablet formulation demonstrated reduced food effect at higher doses. There were no food restrictions in the adult trials (using the tablet formulation) or in the pediatric trial (using both tablet and oral solution formulations) that demonstrated the efficacy/antiviral activity and safety of maraviroc see Clinical Studies 14.1, 14.2) ]. DistributionMaraviroc 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. Elimination 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 single oral dose of 300 mg 14C]-maraviroc. The most significant circulating metabolite in humans is 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. mass balance/excretion trial was conducted using 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. Specific Populations Patients with Hepatic Impairment: Maraviroc is primarily metabolized and eliminated by the liver. trial compared the pharmacokinetics of single 300-mg dose of maraviroc in subjects with mild (Child-Pugh Class A, = 8) and moderate (Child-Pugh Class B, = 8) hepatic impairment with pharmacokinetics in healthy subjects (n 8). The mean 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 dose adjustment. Maraviroc concentrations are higher when maraviroc 150 mg is administered with potent CYP3A inhibitor compared with following administration of 300 mg without CYP3A inhibitor, so patients with moderate hepatic impairment who receive maraviroc 150 mg with 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) ]. Patients with Renal Impairment: trial compared the pharmacokinetics of single 300-mg dose of maraviroc in adult subjects with severe renal impairment (CrCl less than 30 mL per minute, = 6) and ESRD (n 6) with healthy volunteers (n 6). Geometric mean ratios for maraviroc 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 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 maraviroc in healthy volunteers with normal renal function. However, maraviroc exposures in the subjects with normal renal function in this trial were 50% lower than those observed in previous trials. Based on the results of this trial, no dose adjustment is recommended for patients with renal impairment receiving maraviroc without potent CYP3A inhibitor or inducer. However, if patients with severe renal impairment or ESRD experience any symptoms of postural hypotension while taking maraviroc 300 mg twice daily, their dose should be reduced to 150 mg twice daily see Dosage and Administration 2.3), Warnings and Precautions 5.3) ]. In addition, the trial compared the pharmacokinetics of multiple-dose maraviroc in combination with saquinavir/ritonavir 1,000/100 mg twice daily (a potent CYP3A inhibitor combination) for days in subjects with mild renal impairment (CrCl greater than 50 and less than or equal to 80 mL per minute, = 6) and moderate renal impairment (CrCl greater than or equal to 30 and less than or equal to 50 mL per minute, = 6) with healthy volunteers with normal renal function (n 6). Subjects received 150 mg of maraviroc 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, max and 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, max and 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 2.3) ]. Pediatric Patients:Aged to Less Than 18 Years: The pharmacokinetics of maraviroc were evaluated in CCR5-tropic, HIV-1-infected, treatment-experienced pediatric subjects aged to less than 18 years. In the dose-finding stage of Trial A4001031, doses were administered with food on intensive pharmacokinetic evaluation days and optimized to achieve an average concentration over the dosing interval (C avg) of greater than 100 ng per mL. Throughout the trial, on non-intensive pharmacokinetic evaluation days maraviroc was taken with or without food. The initial dose of maraviroc was based on BSA and concomitant medication category (i.e., presence of CYP3A inhibitors and/or inducers). The conversion of dosing to weight (kg)-band basis in children provides comparable exposures with those observed in the trial at the corresponding BSA. Maraviroc pharmacokinetic parameters in pediatric subjects aged to less than 18 years receiving potent CYP3A inhibitors with or without potent CYP3A inducer were similar to those observed in adults (Table 12).Table 12. Maraviroc Pharmacokinetic Parameters in Treatment-Experienced Pediatric Patients Receiving Maraviroc with Potent CYP3A Inhibitors (with or without Potent CYP3A Inducer)WeightDose ofMaravirocMaraviroc Pharmacokinetic ParameteraGeometric MeanAUC12(ng.h/mL)Cavg(ng/mL)Cmax(ng/mL)Cmin(ng/mL)10 kg to <20 kg50 mg twice daily2,3491963247820 kg to <30 kg75 mg twice daily3,02025239411830 kg to <40 kg100 mg twice daily3,229269430126>=40 kg150 mg twice daily4,044337563152a Model-predicted steady-state pharmacokinetic parameters are presented Aged from Birth to Less Than Weeks: The pharmacokinetics of maraviroc were evaluated in 38 of 47 enrolled HIV-1-exposed neonates (born to HIV-1-infected mothers) aged from birth up to weeks [see Adverse Reactions 6.1)] In the IMPAACT P2007 trial, 13 neonates received weight-based maraviroc dosing as single doses at birth and approximately days, and 25 neonates received maraviroc twice daily up to weeks of age without exposure to potent CYP3A inhibitors and/or inducers. Maraviroc pharmacokinetic parameters in neonates weighing at least kg at birth (Table 13) were similar to those observed in adults. Exposure to maternal efavirenz both in utero (for minimum of weeks immediately prior to delivery) and after birth while breastfeeding did not have meaningful impact on maraviroc pharmacokinetic parameters. Table 13. Maraviroc Pharmacokinetic Parameters in Full-Term Neonates (Birth Up to Weeks of Age) Receiving Maraviroc with Noninteracting Concomitant Medications PharmacokineticSampling TimenMedian Dose(range)Maraviroc Pharmacokinetic Parameter Geometric MeanAUC 12 (ng.h/mL)C avg (ng/mL)C max (ng/mL)C min (ng/mL)Day 11330 mg (20 to 40 mg) single dose 3,510 292380-Week 12525 mg (20 to 30 mg) twice daily 1,21610126223Week 42530 mg (20 to 40 mg) twice daily 1,38511529543a Noninteracting concomitant medications include all medications that are not potent CYP3A inhibitors or inducers. AUCinf calculated for single-dose pharmacokinetics. Clinical pharmacokinetic data with maraviroc in pediatric patients aged older than weeks to less than years are not available and clinical pharmacokinetic data in pediatric patients aged to less than 18 years receiving noninteracting concomitant medications are limited. Based on population pharmacokinetic modeling and simulation, the recommended dosing regimen of maraviroc for this population is predicted to result in similar maraviroc exposures when compared with exposures achieved in adults receiving maraviroc 300 mg twice daily (with noninteracting concomitant medications) [see Dosage and Administration 2.4)]. Geriatric Patients: Pharmacokinetics of maraviroc have not been fully evaluated in the elderly (aged 65 years and older). Based on population pharmacokinetic analyses, age did not have clinically relevant effect on maraviroc exposure in subjects up to age 65 years [see Use in Specific Populations 8.5)]. Race and Gender: Based on population pharmacokinetics and clinical CYP3A5 genotype analyses for race, no dosage adjustment is recommended based on race or gender. Drug Interaction StudiesEffect of Concomitant Drugs on the Pharmacokinetics of Maraviroc:Maraviroc is 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, lopinavir/ritonavir, ritonavir, darunavir/ritonavir, saquinavir/ritonavir, and atazanavir +- ritonavir all increased the max and AUC of maraviroc (Table 14). The CYP3A and/or P-gp inducers rifampin, etravirine, and efavirenz decreased the Cmax and AUC of maraviroc (Table 14). While not studied, potent CYP3A and/or P-gp inducers carbamazepine, phenobarbital, and phenytoin are expected to decrease maraviroc concentrations. Based on in vitro study results, maraviroc is also substrate of OATP1B1 and MRP2; its pharmacokinetics may be modulated by inhibitors of these transporters. Tipranavir/ritonavir (net CYP3A inhibitor/P-gp inducer) did not affect the steady-state pharmacokinetics of maraviroc (Table 14). Cotrimoxazole and tenofovir did not affect the pharmacokinetics of maraviroc.Table 14. Effect of Coadministered Agents on the Pharmacokinetics of MaravirocCoadministered Drug and DosenDose of maravirocRatio (90% CI) of Maraviroc Pharmacokinetic Parameters with/without Coadministered Drug(No Effect 1.00)C min AUC tau max CYP3A and/or P-gp InhibitorsKetoconazole 400 mg q.d. 12100 mg b.i.d.3.75 (3.01, 4.69) 5.00 (3.98, 6.29) 3.38 (2.38, 4.78) Ritonavir 100 mg b.i.d. 8100 mg b.i.d.4.55 (3.37, 6.13) 2.61 (1.92, 3.56) 1.28 (0.79, 2.09) Saquinavir (soft gel capsules) /ritonavir 1,000 mg/100 mg b.i.d.11100 mg b.i.d.11.3 (8.96, 14.1) 9.77 (7.87, 12.14) 4.78 (3.41, 6.71) Lopinavir/ritonavir400 mg/100 mg b.i.d.11300 mg b.i.d.9.24 (7.98, 10.7) 3.95 (3.43, 4.56) 1.97 (1.66, 2.34) Atazanavir 400 mg q.d.12300 mg b.i.d.4.19 (3.65, 4.80) 3.57 (3.30, 3.87) 2.09 (1.72, 2.55) Atazanavir/ritonavir 300 mg/100 mg q.d.12300 mg b.i.d.6.67 (5.78, 7.70) 4.88 (4.40, 5.41) 2.67 (2.32, 3.08) Darunavir/ritonavir600 mg/100 mg b.i.d.12150 mg b.i.d.8.00 (6.35, 10.1) 4.05 (2.94, 5.59) 2.29 (1.46, 3.59) Elvitegravir/ritonavir 150 mg/100 mg q.d.11150 mg b.i.d.4.23 (3.47, 5.16) 2.86 (2.33, 3.51) 2.15 (1.71, 2.69) CYP3A and/or P-gp InducersEfavirenz 600 mg q.d.12100 mg b.i.d.0.55 (0.43, 0.72) 0.55 (0.49, 0.62) 0.49 (0.38, 0.63) Efavirenz 600 mg q.d.12200 mg b.i.d. (+ efavirenz): 100 mg b.i.d. (alone)1.09 (0.89, 1.35) 1.15 (0.98, 1.35) 1.16 (0.87, 1.55) Rifampicin 600 mg q.d.12100 mg b.i.d.0.22 (0.17, 0.28) 0.37 (0.33, 0.41) 0.34 (0.26, 0.43) Rifampicin 600 mg q.d.12200 mg b.i.d. (+ rifampicin): 100 mg b.i.d. (alone)0.66 (0.54, 0.82) 1.04 (0.89, 1.22) 0.97 (0.72, 1.29) Etravirine 200 mg b.i.d.14300 mg b.i.d.0.61 (0.53, 0.71) 0.47 (0.38, 0.58) 0.40 (0.28, 0.57) Nevirapine 200 mg b.i.d. (+ lamivudine 150 mg b.i.d., tenofovir 300 mg q.d.) 8300 mg single dose -1.01 (0.65, 1.55) 1.54 (0.94, 2.51) CYP3A and/or P-gp Inhibitors and InducersLopinavir/ritonavir efavirenz 400 mg/100 mg b.i.d. 600 mg q.d. 11300 mg b.i.d.6.29 (4.72, 8.39) 2.53 (2.24, 2.87) 1.25 (1.01, 1.55) Saquinavir (soft gel capsules) /ritonavir efavirenz 1,000 mg/100 mg b.i.d. 600 mg q.d. 11100 mg b.i.d.8.42 (6.46, 10.97) 5.00 (4.26, 5.87) 2.26 (1.64, 3.11) Darunavir/ritonavir etravirine 600 mg/100 mg b.i.d. 200 mg b.i.d.10150 mg b.i.d.5.27 (4.51, 6.15) 3.10 (2.57, 3.74) 1.77 (1.20, 2.60) Fosamprenavir/ritonavir 700 mg/100 mg b.i.d. 14300 mg b.i.d.4.74 (4.03, 5.57) 2.49 (2.19, 2.82) 1.52 (1.27, 1.82) Fosamprenavir/ritonavir 1,400 mg/100 mg q.d. 14300 mg q.d.1.80 (1.53, 2.13) 2.26 (1.99, 2.58) 1.45 (1.20, 1.74) Tipranavir/ritonavir 500 mg/200 mg b.i.d.12150 mg b.i.d.1.80 (1.55, 2.09) 1.02 (0.85, 1.23) 0.86 (0.61, 1.21) OtherRaltegravir 400 mg b.i.d.17300 mg b.i.d.0.90 (0.85, 0.96) 0.86 (0.80, 0.92) 0.79 (0.67, 0.94) aCompared with historical data. Effect of Maraviroc on the Pharmacokinetics of Concomitant Drugs: Maraviroc is unlikely to inhibit the metabolism of coadministered drugs metabolized by the following cytochrome enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A) or to inhibit the uptake of OATP1B1 or the export of MRP2 because maraviroc did not inhibit activity of those enzymes or transporters at clinically relevant concentrations in vitro. Maraviroc does not induce CYP1A2 in vitro. Additionally, in vitrostudies have shown that maraviroc is not substrate for, and does not inhibit, any of the major renal uptake inhibitors (organic anion transporter [OAT]1, OAT3, organic cation transporter [OCT]2, novel organic cation transporter [OCTN]1, and OCTN2) at clinically relevant concentrations. 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 (Table 14). Coadministration of fosamprenavir 700 mg/ritonavir 100 mg twice daily and maraviroc 300 mg twice daily decreased the 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 min and AUC of amprenavir by 15% and 30%, respectively. No dosage adjustment is necessary when maraviroc tablets are dosed 150 mg twice daily in combination with fosamprenavir/ritonavir dosed once or twice daily. Fosamprenavir should be given with ritonavir when coadministered with maraviroc tablets. Maraviroc had no significant effect on the pharmacokinetics of elvitegravir, zidovudine, or lamivudine. Maraviroc decreased the 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 6-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 greater than 100 uM. 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 doses.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to maraviroc during pregnancy. Physicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.Risk SummaryLimited data on the use of maraviroc during pregnancy from the APR and case reports are not sufficient to inform drug-associated risk of birth defects and miscarriage. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with maraviroc. During organogenesis in the rat and rabbit, systemic exposures (AUC) to maraviroc were approximately 20 times (rats) and times (rabbits) the exposure in humans at the recommended 300-mg twice-daily dose. In the rat pre- and post-natal development study, maternal systemic exposure (AUC) to maraviroc was approximately 14 times the exposure in humans at the recommended 300-mg twice-daily dose see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.DataAnimal Data:Maraviroc was administered orally to pregnant rats (up to 1,000 mg per kg per day) and rabbits (up to 75 mg per kg per day) on gestation Days to 17 and to 19, respectively. No adverse effects on embryo-fetal development were observed at these dose levels, resulting in exposures (AUC) approximately 20 times (rats) and times (rabbits) higher than human exposures at the recommended daily dose. In the rat pre- and post-natal development study, maraviroc was administered orally at up to 1,000 mg per kg per day on gestation Day to lactation/post-partum Day 20, with development of the offspring (including fertility and reproductive performance) unaffected by maternal administration of maraviroc at an exposure (AUC) approximately 14 times higher than human exposure at the recommended daily dose.

REFERENCES SECTION.

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

SPL UNCLASSIFIED SECTION.

2.1 Testing prior to Initiation of Maraviroc Tablets. Prior to initiation of maraviroc tablets for treatment of HIV-1 infection, test all patients for CCR5 tropism using highly sensitive tropism assay. Maraviroc tablets are recommended for patients with only CCR5-tropic HIV-1 infection. Outgrowth of pre-existing low-level CXCR4- or dual/mixed-tropic HIV-1 not detected by tropism testing at screening has been associated with virologic failure on maraviroc tablets see Microbiology 12.4), Clinical Studies 14.1) ]. Monitor patients for ALT, AST, and bilirubin prior to initiation of maraviroc tablets and at other time points during treatment as clinically indicated [see Warnings and Precautions 5.1)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Women infected with HIV should be instructed not to breastfeed due to the potential for HIV transmission. 8.2) 8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to maraviroc during pregnancy. Physicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.Risk SummaryLimited data on the use of maraviroc during pregnancy from the APR and case reports are not sufficient to inform drug-associated risk of birth defects and miscarriage. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with maraviroc. During organogenesis in the rat and rabbit, systemic exposures (AUC) to maraviroc were approximately 20 times (rats) and times (rabbits) the exposure in humans at the recommended 300-mg twice-daily dose. In the rat pre- and post-natal development study, maternal systemic exposure (AUC) to maraviroc was approximately 14 times the exposure in humans at the recommended 300-mg twice-daily dose see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.DataAnimal Data:Maraviroc was administered orally to pregnant rats (up to 1,000 mg per kg per day) and rabbits (up to 75 mg per kg per day) on gestation Days to 17 and to 19, respectively. No adverse effects on embryo-fetal development were observed at these dose levels, resulting in exposures (AUC) approximately 20 times (rats) and times (rabbits) higher than human exposures at the recommended daily dose. In the rat pre- and post-natal development study, maraviroc was administered orally at up to 1,000 mg per kg per day on gestation Day to lactation/post-partum Day 20, with development of the offspring (including fertility and reproductive performance) unaffected by maternal administration of maraviroc at an exposure (AUC) approximately 14 times higher than human exposure at the recommended daily dose.. 8.2 Lactation. Risk SummaryThe Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.There are no data on the presence of maraviroc in human milk, the effects on the breastfed infant, or the effects on milk production. When administered to lactating rats, maraviroc was present in milk see Data). Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) serious adverse reactions in breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving maraviroc. DataMaraviroc (and related metabolites) was excreted into the milk of lactating rats following single oral dose of maraviroc (100 mg per kg) on lactation Day 12, with maximal milk concentration achieved one hour post-administration at milk concentration approximately 2.5 times that of maternal plasma concentrations.. 8.4 Pediatric Use. The safety and efficacy of maraviroc have been established in pediatric patients aged from aged to less than 18 years. The use of maraviroc in pediatric patients was supported by pharmacokinetic and safety data described below and by previous demonstration of efficacy in adult patients see Indications and Usage (1)], Dosage and Administration 2.4) ]. HIV-1-Infected Pediatric Patients Aged to Less Than 18 Years: The safety, pharmacokinetic profile, and antiviral activity of maraviroc were evaluated in treatment-experienced, CCR5- tropic, HIV-1-infected pediatric subjects aged to less than 18 years weighing at least 10 kg in an open-label, multicenter clinical trial, A4001031 see Adverse Reactions 6.1), Clinical Studies 14.2) ]. Pharmacokinetics were evaluated in total of 98 pediatric subjects: 85 subjects received maraviroc and concomitant medications that included potent CYP3A inhibitors with or without potent CYP3A inducers, 10 subjects received maraviroc and noninteracting medications (not containing potent CYP3A inhibitors or potent CYP3A inducers), and three subjects received maraviroc and medications that included potent CYP3A inducers without potent CYP3A inhibitors see Clinical Pharmacology 12.3) ]. There are insufficient data to make dosing recommendations for use of maraviroc in pediatric patients concomitantly receiving potent CYP3A inhibitors and weighing less than 10 kg, or in any pediatric patients concomitantly receiving potent CYP3A inducers without potent CYP3A inhibitor see Dosage and Administration 2.4, 2.5) ]. Maraviroc is not recommended in pediatric patients weighing less than 10 kg.. 8.5 Geriatric Use. There were insufficient numbers of subjects aged 65 and over in the clinical trials to determine whether they respond differently from younger subjects. In general, caution should be exercised when administering maraviroc in elderly patients, also reflecting the greater frequency of decreased hepatic and renal function, of concomitant disease and other drug therapies.. 8.6 Renal Impairment. Recommended doses of maraviroc for adult patients with impaired renal function (CrCl less than or equal to 80 mL per minute) are based on the results of pharmacokinetic trial conducted in healthy adult subjects with various degrees of renal impairment. Maraviroc has not been studied in pediatric patients with renal impairment. There are no data to recommend specific doses of maraviroc in pediatric patients with mild to moderate renal impairment see Use in Specific Populations 8.4) ]. Maraviroc is contraindicated in pediatric patients with severe renal impairment or ESRD on regular hemodialysis who are receiving potent CYP3A inhibitors see Contraindications 4) ]. The pharmacokinetics of maraviroc in adult subjects with mild and moderate renal impairment was similar to that in subjects with normal renal function see Clinical Pharmacology 12.3) ]. limited number of adult subjects with mild and moderate renal impairment in the Phase clinical trials (n 131 and = 12, respectively) received the same dose of maraviroc as that administered to subjects with normal renal function. In these subjects, there was no apparent difference in the adverse event profile for maraviroc compared with subjects with normal renal function. If adult patients with severe renal impairment or ESRD not receiving concomitant potent CYP3A inhibitor or inducer experience any symptoms of postural hypotension while taking maraviroc 300 mg twice daily, the dose should be reduced to 150 mg twice daily. No trials have been performed in subjects with severe renal impairment or ESRD co-treated with potent CYP3A inhibitors or inducers. Hence, no dose of maraviroc can be recommended, and maraviroc is contraindicated for these patients see Dosage and Administration 2.3), Contraindications 4), Warnings and Precautions 5.3), Clinical Pharmacology 12.3) ]. 8.7 Hepatic Impairment. Maraviroc is principally metabolized by the liver; therefore, when administering this drug to patients with hepatic impairment, maraviroc concentrations may be increased. Maraviroc concentrations are higher when maraviroc 150 mg is administered with potent CYP3A inhibitor compared with following administration of 300 mg without CYP3A inhibitor, so patients with moderate hepatic impairment who receive maraviroc 150 mg with potent CYP3A inhibitor should be monitored closely for maraviroc-associated adverse events. Maraviroc has not been studied in subjects with severe hepatic impairment or in pediatric patients with any degree of hepatic impairment see Warnings and Precautions 5.1), Clinical Pharmacology 12.3) ].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hepatotoxicity accompanied by severe rash or systemic allergic reaction, including potentially life-threatening events, has been reported. Hepatic laboratory parameters including ALT, AST, and bilirubin should be obtained prior to starting maraviroc tablets and at other time points during treatment as clinically indicated. If rash or symptoms or signs of hepatitis or allergic reaction develop, hepatic laboratory parameters should be monitored and discontinuation of treatment should be considered. When administering maraviroc tablets to patients with pre-existing liver dysfunction or who are co-infected with hepatitis and/or virus, additional monitoring may be warranted. 5.1) Severe and potentially life-threatening skin and hypersensitivity reactions have been reported in patients taking maraviroc. This includes cases of Stevens-Johnson syndrome, hypersensitivity reaction, and toxic epidermal necrolysis. Immediately discontinue maraviroc and other suspected agents if signs or symptoms of severe skin or hypersensitivity reactions develop and monitor clinical status, including liver aminotransferases, closely. 5.2) More cardiovascular events, including myocardial ischemia and/or infarction, were observed in treatment-experienced subjects who received maraviroc. Additional monitoring may be warranted. 5.3) If patients with severe renal impairment or ESRD receiving maraviroc (without concomitant CYP3A inducers or inhibitors) experience postural hypotension, the dose of maraviroc should be reduced from 300 mg twice daily to 150 mg twice daily. 5.3) 5.1 Hepatotoxicity. Hepatotoxicity with allergic features including life-threatening events has been reported in clinical trials and postmarketing. Severe rash or evidence of systemic allergic reaction including drug-related rash with fever, eosinophilia, elevated IgE, or other systemic symptoms have been reported in conjunction with hepatotoxicity see Warnings and Precautions 5.2) ]. These events occurred approximately month after starting treatment. Among reported cases of hepatitis, some were observed in the absence of allergic features or with no pre-existing hepatic disease. Appropriate laboratory testing including ALT, AST, and bilirubin should be conducted prior to initiating therapy with maraviroc and at other time points during treatment as clinically indicated. Hepatic laboratory parameters should be obtained in any patient who develops rash, or signs or symptoms of hepatitis, or allergic reaction. Discontinuation of maraviroc should be considered in any patient with signs or symptoms of hepatitis, or with increased liver transaminases combined with rash or other systemic symptoms. When administering maraviroc to patients with pre-existing liver dysfunction or who are co-infected with hepatitis and/or virus, additional monitoring may be warranted. The safety and efficacy of maraviroc have not been specifically studied in patients with significant underlying liver disorders. 5.2 Severe Skin and Hypersensitivity Reactions. Severe, potentially life-threatening skin and hypersensitivity reactions have been reported in patients taking maraviroc, in most cases concomitantly with other drugs associated with these reactions. These include cases of Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) see Adverse Reactions (6.3)]. The cases were characterized by features including rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure. Discontinue maraviroc and other suspected agents immediately if signs or symptoms of severe skin or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, malaise, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, lip swelling, eosinophilia). Delay in stopping treatment with maraviroc or other suspect drugs after the onset of rash may result in life-threatening reaction. Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated. 5.3 Cardiovascular Events. Eleven subjects (1.3%) who received maraviroc had cardiovascular events, including myocardial ischemia and/or infarction, during the Phase trials in treatment-experienced subjects (total exposure 609 patient-years [300 on maraviroc once daily 309 on maraviroc twice daily]), while no subjects who received placebo had such events (total exposure 111 patient-years). These subjects generally had cardiac disease or cardiac risk factors prior to use of maraviroc, and the relative contribution of maraviroc to these events is not known.In the Phase 2b/3 trial in treatment-naive adult subjects, subjects (0.8%) who received maraviroc had events related to ischemic heart disease and subjects (1.4%) who received efavirenz had such events (total exposure 506 and 508 patient-years for maraviroc and efavirenz, respectively). When maraviroc was administered to healthy volunteers at doses higher than the recommended dose, symptomatic postural hypotension was seen at greater frequency than in placebo. However, when maraviroc was given at the recommended dose in HIV-1-infected adult subjects in Phase trials, postural hypotension was seen at rate similar to placebo (approximately 0.5%). Patients with cardiovascular comorbidities, risk factors for postural hypotension, or receiving concomitant medication known to lower blood pressure, could be at increased risk of cardiovascular adverse events triggered by postural hypotension. Additional monitoring may be warranted. Postural Hypotension in Patients with Renal ImpairmentAn increased risk of postural hypotension may occur in patients with severe renal insufficiency or in those with ESRD due to increased maraviroc exposure in some patients. Maraviroc should be used in patients with severe renal impairment or ESRD only if they are not receiving concomitant potent CYP3A inhibitor or inducer. However, the use of maraviroc in these patients should only be considered when no alternative treatment options are available. If adult patients with severe renal impairment or ESRD experience any symptoms of postural hypotension while taking 300 mg twice daily, the dose should be reduced to 150 mg twice daily see Dosage and Administration 2.5) ]. 5.4 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 systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as infection with Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], tuberculosis, or reactivation of Herpes simplex and Herpes zoster), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves disease, polymyositis, and Guillain-Barre syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.. 5.5 Potential Risk of Infection. Maraviroc 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 infections, were comparable in the treatment groups during the Phase adult treatment-experienced trials of maraviroc. While there was higher rate of certain upper respiratory tract infections reported in the treatment arm receiving maraviroc compared with placebo (23% versus 13%), there was lower rate of pneumonia (2% versus 5%) reported in subjects receiving maraviroc. higher incidence of Herpes virus infections (11 per 100 patient-years) was also reported in the treatment arm receiving maraviroc when adjusted for exposure compared with placebo (8 per 100 patient-years). In the Phase 2b/3 trial in treatment-naive adult subjects, the incidence of AIDS-defining Category events when adjusted for exposure was 1.8 for maraviroc compared with 2.4 for efavirenz per 100 patient-years of exposure. Patients should be monitored closely for evidence of infections while receiving maraviroc. 5.6 Potential Risk of Malignancy. While no increase in malignancy has been observed with maraviroc, due to this drugs mechanism of action, it could affect immune surveillance and lead to an increased risk of malignancy. The exposure-adjusted rate for malignancies per 100 patient-years of exposure in adult treatment-experienced trials was 4.6 for maraviroc compared with 9.3 on placebo. In treatment-naive adult subjects, the rates were 1.0 and 2.4 per 100 patient-years of exposure for maraviroc and efavirenz, respectively. Long-term follow-up is needed to more fully assess this risk.