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 (Cmin) (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 Cmin, baseline viral load, baseline CD4+ cell count, and overall sensitivity score (OSS) were found to be important predictors of virologic success (defined as viral load less than 400 copies per mL at 24 weeks). Table illustrates the proportions of subjects with virologic success (%) within each Cmin quartile for 150-mg twice-daily and 300-mg twice-daily groups.Table 9. Treatment-Experienced Subjects with Virologic Success by Cmin Quartile (Q1-Q4)150 mg Twice Daily(with CYP3A Inhibitors)300 mg Twice Daily(without CYP3A Inhibitors)nMedian Cmin Subjects with Virologic SuccessnMedian Cmin 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 (Cmin) (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 Cmin quartile for the 300-mg twice-daily dose.Table 10. Treatment-Naive Subjects with Virologic Success by Cmin Quartile (Q1-Q4)300 mg Twice Daily nMedian Cmin 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 Adultsa The estimated exposure is lower compared with other trials possibly due to sparse sampling, food effect, compliance, and concomitant medications.Patient 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)a 300 mg twice daily941,51326637.2 150 mg twice daily(+ CYP3A inhibitor)3752,463332101Treatment-naive HIV subjects (Phase 2b/3)a 300 mg twice daily3441,86528760AbsorptionPeak maraviroc plasma concentrations are attained 0.5 to hours following single oral doses of to 1,200 mg administered to uninfected volunteers. The pharmacokinetics of oral maraviroc are not dose proportional over the dose range. The absolute bioavailability of 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 Cmax 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. EliminationMetabolism: 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 PopulationsPatients with Hepatic Impairment: Maraviroc is primarily metabolized and eliminated by the liver. trial compared the pharmacokinetics of single 300-mg dose of SELZENTRY 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 Cmax 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 SELZENTRY 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 SELZENTRY 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 SELZENTRY 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 Cmax and AUCinf 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 SELZENTRY in healthy volunteers with normal renal function. However, maraviroc exposures in the subjects with normal renal function in this trial were 50% lower than those observed in previous trials. Based on the results of this trial, no dose adjustment is recommended for patients with renal impairment receiving SELZENTRY without potent CYP3A inhibitor or inducer. However, if patients with severe renal impairment or ESRD experience any symptoms of postural hypotension while taking SELZENTRY 300 mg twice daily, their dose should be reduced to 150 mg twice daily [see Dosage and Administration (2.3), Warnings and Precautions (5.3)].In addition, the trial compared the pharmacokinetics of multiple-dose SELZENTRY in combination with saquinavir/ritonavir 1,000/100 mg twice daily (a potent CYP3A inhibitor combination) for 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 SELZENTRY at different dose frequencies (healthy volunteers every 12 hours; mild renal impairment every 24 hours; moderate renal impairment every 48 hours). Compared with healthy volunteers (dosed every 12 hours), geometric mean ratios for maraviroc AUCtau, Cmax, and Cmin were 50% higher, 20% higher, and 43% lower, respectively, for subjects with mild renal impairment (dosed every 24 hours). Geometric mean ratios for maraviroc AUCtau, Cmax, and Cmin 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 (Cavg) 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 SELZENTRY with Potent CYP3A Inhibitors (with or without Potent CYP3A Inducer)a Model-predicted steady-state pharmacokinetic parameters are presented.WeightDose of SELZENTRYMaraviroc Pharmacokinetic Parametera Geometric MeanAUC12 (ng.h/mL)Cavg (ng/mL)Cmax (ng/mL)Cmin (ng/mL)10 kg to <20 kg50 mgtwice daily2,3491963247820 kg to <30 kg75 mgtwice daily3,02025239411830 kg to <40 kg100 mgtwice daily3,229269430126>=40 kg150 mgtwice daily4,044337563152Aged 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 SELZENTRY with Noninteracting Concomitant Medicationsa Noninteracting concomitant medications include all medications that are not potent CYP3A inhibitors or inducers. AUCinf calculated for single-dose pharmacokinetics.Pharmacokinetic Sampling TimenMedian Dose (range)Maraviroc Pharmacokinetic ParameterGeometric MeanAUC12 (ng.h/mL)Cavg (ng/mL)Cmax (ng/mL)Cmin (ng/mL)Day 11330 mg (20 to 40 mg)single dose3,510b 292380-Week 12525 mg(20 to 30 mg)twice daily1,21610126223Week 42530 mg(20 to 40 mg)twice daily1,38511529543Clinical 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 SELZENTRY for this population is predicted to result in similar maraviroc exposures when compared with exposures achieved in adults receiving SELZENTRY 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 Cmax 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 Maraviroca Compared with historical data.Coadministered Drugand DosenDose of SELZENTRYRatio (90% CI) of Maraviroc Pharmacokinetic Parameters with/without Coadministered Drug(No Effect 1.00)Cmin AUCtau Cmax CYP3A and/or P-gp InhibitorsKetoconazole400 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)Ritonavir100 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) /ritonavir1,000 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)Atazanavir400 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/ritonavir300 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)Efavirenz600 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)Rifampicin600 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)Rifampicin600 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)Etravirine200 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)Nevirapinea 200 mg b.i.d. (+ lamivudine 150 mg b.i.d., tenofovir 300 mg q.d.)8300 mgsingle 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/ritonavir700 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/ritonavir1,400 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/ritonavir500 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)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 vitro studies 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 Cmin 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 Cmin and AUC of amprenavir by 15% and 30%, respectively. No dosage adjustment is necessary when SELZENTRY is dosed 150 mg twice daily in combination with fosamprenavir/ritonavir dosed once or twice daily. Fosamprenavir should be given with ritonavir when coadministered with SELZENTRY.Maraviroc had no significant effect on the pharmacokinetics of elvitegravir, zidovudine, or lamivudine. Maraviroc decreased the Cmin 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 microM. 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 EC50 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 (EC50 value greater than 10 microM). 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 EC50 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 (EC50 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), 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 EC50 values for maraviroc at the time of failure.Fifteen of these viruses were sequenced in the gp120 encoding region and multiple amino acid substitutions with unique patterns in the heterogeneous V3 loop region were detected. Changes at either amino acid position 308 or 323 (HXB2 numbering) were seen in the V3 loop in 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 SELZENTRY 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 Assaya Includes subjects failing with CXCR4- or dual/mixed-tropism because these viruses are not intrinsically susceptible to maraviroc.MaravirocEfavirenzTotal in dataset (as-treated)273241Total virologic failures (as-treated)85 (31%)56 (23%)Evaluable virologic failures with post baseline genotypic and phenotypic data7343 Lamivudine resistance39 (53%)13 (30%) Zidovudine resistance2 (3%)0 Efavirenz resistance-23 (53%) Phenotypic resistance to maraviroca 19 (26%)-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 EC50 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 mm3) than those subjects failing with CCR5-tropic virus (+162 cells per mm3). The median increase in CD4+ cell count in subjects failing in the placebo arm was +7 cells per mm3.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 mm3 while those subjects failing with CCR5-tropic virus had an increase of +135 cells per mm3. The median increase in CD4+ cell count in subjects failing in the efavirenz arm was +95 cells per mm3.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:oHepatotoxicity [see Boxed Warning, Warnings and Precautions (5.1)]oSevere Skin and Hypersensitivity Reactions [see Warnings and Precautions (5.2)]oCardiovascular Events [see Warnings and Precautions (5.3)]. oHepatotoxicity [see Boxed Warning, Warnings and Precautions (5.1)]. oSevere Skin and Hypersensitivity Reactions [see Warnings and Precautions (5.2)]. oCardiovascular Events [see Warnings and Precautions (5.3)]. oThe 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)oThe 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)oThe 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 ViiV Healthcare at 1-877-844-8872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. oThe 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). oThe 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). oThe 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). 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 SELZENTRY is primarily based on 840 HIV-1-infected subjects who received at least dose of SELZENTRY 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 SELZENTRY for subjects in these trials was 48 weeks, with the total exposure on SELZENTRY 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 SELZENTRY 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 SELZENTRY 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 SELZENTRY.The total numbers of subjects reporting infections were 233 (55%) and 84 (40%) in the group receiving SELZENTRY twice daily and the placebo group, respectively. Correcting for the longer duration of exposure on SELZENTRY compared with placebo, the exposure-adjusted frequency (rate per 100 subject-years) of these events was 133 for both SELZENTRY twice daily and placebo.Dizziness or postural dizziness occurred in 8% of subjects on either SELZENTRY or placebo, with subjects (0.5%) on SELZENTRY 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 SELZENTRY 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 SELZENTRY (and at Higher Rate Compared with Placebo) in Trials A4001027 and A4001028 (Pooled Analysis, 48 Weeks)a 300-mg dose equivalent. PYE Patient-years of exposure.SELZENTRYTwice Dailya PlaceboBody System/Adverse Event(n 426)%Exposure-Adjusted Rate(per 100 pt-yrs)PYE 309b (n 209)%Exposure-Adjusted Rate(per 100 pt-yrs)PYE 111b Eye DisordersConjunctivitis 2313Ocular infections, inflammations, and associated manifestations2312Gastrointestinal Disorders Constipation6936General Disorders and Administration Site ConditionsPyrexia 1320917Pain and discomfort 4535Infections and Infestations Upper respiratory tract infection23371327Herpes infection81148Sinusitis71036Bronchitis7959Folliculitis4524Anogenital warts 2313Influenza 230.51Otitis 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 dizziness 913817Paresthesias 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 symptoms 1421510Upper respiratory tract signs and symptoms6936Nasal congestion and inflammations 4635Breathing abnormalities4525Paranasal sinus disorders 340.51Skin and Subcutaneous Tissue DisordersRash 1116511Apocrine and eccrine gland disorders5747.5Pruritus 4524Lipodystrophies 350.51Erythema2312Vascular DisordersVascular hypertensive disorders3424Laboratory Abnormalities: Table shows the treatment-emergent Grade 3-4 laboratory abnormalities that occurred in greater than 2% of subjects receiving SELZENTRY. Table 6. Maximum Shift in Laboratory Test Values (without Regard to Baseline) >=2% of Grade 3-4 Abnormalities (ACTG Criteria) in Trials A4001027 and A4001028 (Pooled Analysis, 48 Weeks)ULN Upper limit of normal; OBT Optimized background therapy. Percentages based on total subjects evaluated for each laboratory parameter.Laboratory Parameter Preferred TermLimitSELZENTRYTwice Daily OBT(n 421)a %Placebo OBT(n 207)a %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/mm3 4.32.4Treatment-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 SELZENTRY 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 SELZENTRY 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 SELZENTRY (and at Higher Rate Compared with Efavirenz) in Trial A4001026 (96 Weeks)Body System/Adverse EventSELZENTRY 300 mg Twice Daily +Lamivudine/Zidovudine(n 360)%Efavirenz 600 mg Once Daily +Lamivudine/Zidovudine(n 361)%Blood and Lymphatic System DisordersAnemias NEC85Neutropenias43Ear and Labyrinth DisordersEar disorders NEC32Gastrointestinal Disorders Flatulence, bloating, and distention107Gastrointestinal atonic and hypomotility disorders NEC95Gastrointestinal signs and symptoms NEC32General Disorders and Administration Site ConditionsBody temperature perception 31Infections and Infestations Upper respiratory tract infection3230Bronchitis139Herpes infection76Bacterial infections NEC63Herpes zoster/varicella54Tinea infections43Lower respiratory tract and lung infections32Neisseria infections30Viral infections NEC32Musculoskeletal and Connective Tissue DisordersJoint-related signs and symptoms65Nervous System DisordersParesthesias and dysesthesias 43Memory loss (excluding dementia)31Renal and Urinary DisordersBladder and urethral symptoms43Reproductive System and Breast DisordersErection and ejaculation conditions and disorders32Respiratory, Thoracic, and Mediastinal DisordersUpper 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 3-4 Abnormalities (ACTG Criteria) in Trial A4001026 (96 Weeks)ULN 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.Laboratory Parameter Preferred TermLimitSELZENTRY300 mg Twice Daily +Lamivudine/Zidovudine(n 353)a %Efavirenz600 mg Once Daily+Lamivudine/Zidovudine(n 350)a %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/mm3 5.74.9Hemoglobin<7.0 g/dL2.92.3Less Common Adverse Events in Clinical Trials: The following adverse events occurred in less than 2% of subjects treated with SELZENTRY or at rate similar to the comparator. These events have been included because of their seriousness and either increased frequency on SELZENTRY 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 creatine kinase 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 SubjectsHIV-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 SELZENTRY twice daily in combination with OBT. The dose of SELZENTRY 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 SELZENTRY 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 SELZENTRY 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 SELZENTRY oral solution (21%) compared with those who received SELZENTRY tablets (16%). Subjects were permitted to change formulations after Week 48.HIV-1-Exposed Neonates: The IMPAACT P2007 trial was an open-label trial in which 47 full-term HIV-1-exposed neonates (born to HIV-1-infected mothers) received at least one dose of SELZENTRY in combination with other antiretrovirals, mostly zidovudine and/or nevirapine [see Clinical Pharmacology (12.3)]. Cohort received single doses of SELZENTRY: the first within days of birth and the second at to 14 days of age. Cohort received SELZENTRY twice daily for weeks beginning within days of birth and continued through Week 6. Both cohorts received SELZENTRY with or without exposure to maternal efavirenz (in utero only in Cohort 1, and both in utero and after birth while breastfeeding in Cohort 2). The population was 51% male and 81% black. All infants were followed for safety through 16 weeks, with total of 37 infants evaluable for safety. There were no additional adverse reactions observed in neonates compared with those seen in adults. All adverse reactions reported were mild to moderate. The most common adverse reaction (all grades) reported with SELZENTRY was hemoglobin decreased (14%). One subject (3%) discontinued due to an adverse event (Grade staphylococcal sepsis).. 6.2 Postmarketing Experience. The following adverse events have been identified during postapproval use of SELZENTRY. 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.

WARNING: HEPATOTOXICITY. Hepatotoxicity has been reported with use of SELZENTRY. 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 SELZENTRY should be evaluated immediately [see Warnings and Precautions (5.1)].. WARNING: HEPATOTOXICITYSee full prescribing information for complete boxed warning.oHepatotoxicity 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)oImmediately evaluate patients with signs or symptoms of hepatitis or allergic reaction. (5.1). oHepatotoxicity 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). oImmediately 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 SELZENTRY 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 SELZENTRY 300 mg once daily, SELZENTRY 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 A4001028NNRTI Non-nucleoside reverse transcriptase inhibitors; NRTI nucleoside reverse transcriptase inhibitors; OBT optimized background therapy; PI protease inhibitor. OSS Sum of active drugs in OBT based on combined information from genotypic and phenotypic testing. Resistance substitutions based on IAS guidelines.1 SELZENTRYTwice 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 (log10 copies/mL) Mean (range)4.85 (2.96-6.88)4.86 (3.46-7.07)Subjects with screening viral load >100,000 copies/mL179 (42.0%)84 (40.2%)Baseline CD4+ cell count (cells/mm3) Median (range)167 (2-820)171 (1-675)Subjects with baseline CD4+ cell count <=200 cells/mm3)250 (58.7%)118 (56.5%)Subjects with Overall Susceptibility Score (OSS):a 057 (13.4%)35 (16.7%) 1136 (31.9%)44 (21.1%) 2104 (24.4%)59 (28.2%) >=3125 (29.3%)66 (31.6%)Subjects with enfuvirtide resistance substitutions90 (21.2%)45 (21.5%)Median number of resistance-associated:b PI substitutions1010 NNRTI substitutions11 NRTI substitutions66The 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 A4001028a One additional subject died while receiving open-label therapy with SELZENTRY subsequent to discontinuing double-blind placebo due to insufficient response.OutcomeSELZENTRYTwice Daily(n 426)Placebo(n 209)Mean DifferenceMean change from Baseline to Week 48 in HIV-1 RNA (log10 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 response97 (23%)113 (54%)- Adverse events19 (4%)11 (5%)- Other27 (6%)18 (9%)-Subjects with treatment-emergent CDC Category events 22 (5%)16 (8%)-Deaths (during trial or within 28 days of last dose)9 (2%)a (0.5%)-After 48 weeks of therapy, the proportions of subjects with HIV-1 RNA less than 400 copies per mL receiving SELZENTRY compared with placebo were 56% and 22%, respectively. The mean changes in plasma HIV-1 RNA from baseline to Week 48 were -1.84 log10 copies per mL for subjects receiving SELZENTRY OBT compared with -0.78 log10 copies per mL for subjects receiving OBT only. The mean increase in CD4+ cell count was higher on SELZENTRY twice daily OBT (124 cells per mm3) than on placebo OBT (60 cells per mm3).Trial in Dual/Mixed-Tropic, Treatment-Experienced SubjectsTrial A4001029 was an exploratory, randomized, double-blind, multicenter trial to determine the safety and efficacy of SELZENTRY in subjects infected with dual/mixed co-receptor tropic HIV-1. The inclusion/exclusion criteria were similar to those for Trials A4001027 and A4001028 above and the subjects were randomized in 1:1:1 ratio to SELZENTRY once daily, SELZENTRY twice daily, or placebo. No increased risk of infection or HIV-1 disease progression was observed in the subjects who received SELZENTRY. Use of SELZENTRY 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 SubjectsTrial 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 SELZENTRY 300 mg once daily, SELZENTRY 300 mg twice daily, or efavirenz 600 mg once daily, each in combination with lamivudine/zidovudine. The efficacy and safety of SELZENTRY are based on the comparison of SELZENTRY twice daily versus efavirenz. In pre-planned interim analysis at 16 weeks, SELZENTRY 300 mg once daily failed to meet the pre-specified criteria for demonstrating non-inferiority and was discontinued.The demographic and baseline characteristics of the maraviroc and efavirenz treatment groups were comparable (Table 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 A4001026SELZENTRY 300 mg Twice Daily Lamivudine/Zidovudine(n 360)Efavirenz 600 mg Once Daily Lamivudine/Zidovudine(n 361)Age (years): Mean36.737.4 Range20-6918-77Female, n%104 (29)102 (28)Race, n%: White204 (57)198 (55) Black123 (34)133 (37) Asian6 (2)5 (1) Other27 (8)25 (7)Median (range) CD4+ cell count (cells/microL)241 (5-1,422)254 (8-1,053)Median (range) HIV-1 RNA (log10 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 Assaya 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 SELZENTRY, 219 of 303 (72%) in efavirenz; Virologic responders (less than 50): 213 of 311 (69%) in SELZENTRY, 207 of 303 (68%) in efavirenz. Other reasons for discontinuation include lost to follow-up, withdrawn, protocol violation, and other.Outcome at Week 96b SELZENTRY 300 mg Twice Daily Lamivudine/Zidovudine(n 311)n (%)Efavirenz 600 mg Once Daily +Lamivudine/Zidovudine(n 303)n (%)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 suppressed (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) Otherc 43 (14)36 (12)The median increase from baseline in CD4+ cell counts at Week 96 was 184 cells per mm3 for the arm receiving SELZENTRY compared with 155 cells per mm3 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 SELZENTRY twice daily and OBT. Dosing of SELZENTRY 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 log10 copies per mL (range: 2.4 to 6.2 log10 copies per mL), mean CD4+ cell count was 551 cells per mm3 (range: to 1,654 cells per mm3), and mean CD4+ percent was 21% (range: 0% to 42%).At 48 weeks, 48% of subjects treated with SELZENTRY 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 mm3 (5%).

CONTRAINDICATIONS SECTION.

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

DESCRIPTION SECTION.

11 DESCRIPTION. SELZENTRY (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.SELZENTRY film-coated tablets for oral administration contain 25, 75, 150, or 300 mg of maraviroc and the following inactive ingredients: dibasic calcium phosphate (anhydrous), magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The film coat (Opadry II Blue [85G20583]) contains FD&C blue aluminum lake, soya lecithin, polyethylene glycol (macrogol 3350), polyvinyl alcohol, talc, and titanium dioxide.SELZENTRY oral solution contains 20 mg per mL of maraviroc and the following inactive ingredients: citric acid (anhydrous), purified water, sodium benzoate, sodium citrate dihydrate, strawberry flavoring (501440T), and sucralose.Maraviroc is chemically described as 4,4-difluoro-N-(1S)-3-[exo-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropylcyclohexanecarboxamide.The molecular formula is C29H41F2N5O and the structural formula is:Maraviroc is white to pale-colored powder with molecular weight of 513.67. It is highly soluble across the physiological pH range (pH 1.0 to 7.5).. Maraviroc chemical structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oPrior to initiation of SELZENTRY for treatment of HIV-1 infection, test all patients for CCR5 tropism using highly sensitive tropism assay. (2.1)oSELZENTRY tablets and oral solution are taken twice daily by mouth and may be taken with or without food. SELZENTRY must be given in combination with other antiretroviral medications. (2.2)Recommended Dosage in Adult Patients: (2.3)Concomitant MedicationsDosage of SELZENTRYWhen given with potent cytochrome P450 (CYP)3A inhibitors (with or without potent CYP3A inducers) including PIs (except tipranavir/ritonavir) (2.3, 7.1)150 mgtwice dailyWith NRTIs, tipranavir/ritonavir, nevirapine, raltegravir, and other drugs that are not potent CYP3A inhibitors or CYP3A inducers (2.3, 7.1)300 mgtwice dailyWith potent and moderate CYP3A inducers including efavirenz (without potent CYP3A inhibitor) (2.3, 7.1)600 mgtwice dailyA more complete list of coadministered drugs is listed in Dosage and Administration. (2)Recommended Dosage in Pediatric Patients Weighing at Least 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). oPrior to initiation of SELZENTRY for treatment of HIV-1 infection, test all patients for CCR5 tropism using highly sensitive tropism assay. (2.1). oSELZENTRY tablets and oral solution are taken twice daily by mouth and may be taken with or without food. SELZENTRY must be given in combination with other antiretroviral medications. (2.2). 2.1 Testing prior to Initiation of SELZENTRY Prior to initiation of SELZENTRY for treatment of HIV-1 infection, test all patients for CCR5 tropism using highly sensitive tropism assay. SELZENTRY is 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 SELZENTRY [see Microbiology (12.4), Clinical Studies (14.1)].Monitor patients for alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin prior to initiation of SELZENTRY and at other time points during treatment as clinically indicated [see Warnings and Precautions (5.1)]. 2.2 General Dosing Recommendations. oSELZENTRY tablets and oral solution are taken twice daily by mouth and may be taken with or without food.oSELZENTRY must be given in combination with other antiretroviral medications.oThe recommended dosage of SELZENTRY differs based on concomitant medications due to drug interactions.. oSELZENTRY tablets and oral solution are taken twice daily by mouth and may be taken with or without food.. oSELZENTRY must be given in combination with other antiretroviral medications.. oThe recommended dosage of SELZENTRY 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 SELZENTRY based on different concomitant medications [see Drug Interactions (7.1)].Table 1. Recommended Dosage in AdultsConcomitant MedicationsDosage of SELZENTRYa Potent 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.Potent cytochrome P450 (CYP)3A inhibitors (with or without potent CYP3A inducer)a 150 mg twice dailyNoninteracting concomitant medicationsb 300 mg twice dailyPotent and moderate CYP3A inducers (without potent CYP3A inhibitor)c 600 mg twice daily. 2.4 Recommended Dosage in Pediatric Patients with Normal Renal Function The recommended dosage of SELZENTRY 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 SELZENTRY tablets, assess children for the ability to swallow tablets. If child is unable to reliably swallow SELZENTRY tablets, the oral solution formulation should be prescribed. The recommended oral dosage of SELZENTRY 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)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.Concomitant MedicationsDosage of SELZENTRY 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)a 50 mgtwice daily50 mgtwice daily75 mgtwice daily100 mgtwice daily150 mgtwice dailyNoninteracting concomitant medicationsb 150 mg twice daily200 mgtwice daily200 mgtwice daily300 mgtwice daily300 mgtwice dailyPotent and moderate CYP3A inducers (without potent CYP3A inhibitor)c Not recommendedd The recommended oral dosage of SELZENTRY oral solution in pediatric patients weighing at least kg is presented in Table 3.Table 3. Recommended Dosage in Pediatric Patients Weighing at Least kg (Oral Solution)a Potent CYP3A inhibitors (with or without CYP3A inducer) including: clarithromycin, cobicistat, elvitegravir/ritonavir, itraconazole, ketoconazole, nefazodone, protease inhibitors (except tipranavir/ritonavir), telithromycin. Insufficient data are available to recommend use. 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.Concomitant MedicationsDosage (Volume of Solution) of SELZENTRYBased on Weight2 kg to<4 kg4 kg to<6 kg6 kg to<10 kg10 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)a Not recommendedb 50 mg(2.5 mL)twice daily50 mg(2.5 mL)twice daily80 mg(4 mL)twice daily100 mg(5 mL)twice daily150 mg(7.5 mL)twice dailyNoninteracting concomitant medicationsc 30 mg(1.5 mL)twice daily40 mg(2 mL)twice daily100 mg(5 mL)twice daily150 mg(7.5 mL)twice daily200 mg(10 mL)twice daily200 mg(10 mL)twice daily300 mg(15 mL)twice daily300 mg(15 mL)twice dailyPotent and moderate CYP3A inducers (without potent CYP3A inhibitor)d Not recommendedb Administer the oral solution using the included press-in bottle adapter and the appropriate oral dosing syringe: for doses of 2.5 mL or less, use the 3-mL syringe; for doses greater than 2.5 mL, use the 10-mL syringe. Care should be taken when measuring neonate doses due to the small volumes of oral solution required.. 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 FunctionCrCl Creatinine clearance. 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 SELZENTRY should be reduced to 150 mg twice daily if there are any symptoms of postural hypotension [see Contraindications (4), Warnings and Precautions (5.3)]. Potent and moderate CYP3A inducers (without potent CYP3A inhibitor) including: carbamazepine, efavirenz, etravirine, phenobarbital, phenytoin, and rifampin.Concomitant MedicationsDosage of SELZENTRY Based on Renal FunctionNormal(CrCl >80 mL/min)Mild(CrCl >50 and <=80 mL/min)Moderate(CrCl >=30 and <=50 mL/min)Severe(CrCl <30 mL/min)End-Stage Renal Disease on Regular HemodialysisPotent CYP3A inhibitors (with or without CYP3A inducer)a 150 mg twice daily150 mg twice daily150 mg twice dailyContra-indicatedContra-indicatedNoninteracting concomitant medicationsb 300 mg twice daily300 mg twice daily300 mg twice daily300 mg twice daily300 mg twice dailyc Potent and moderate CYP3A inducers (without potent CYP3A inhibitor)d 600 mg twice daily600 mg twice daily600 mg twice dailyContra-indicatedContra-indicatedPediatric PatientsThere are no data to recommend specific doses of SELZENTRY in pediatric patients with mild or moderate renal impairment [see Use in Specific Populations (8.6)]. Additionally, SELZENTRY is 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. Tablets:o25-mg blue, oval, film-coated tablets debossed with MVC 25 on one side and plain on the other.o75-mg blue, oval, film-coated tablets debossed with MVC 75 on one side and plain on the other.o150-mg blue, oval, film-coated tablets debossed with MVC 150 on one side and plain on the other.o300-mg blue, oval, film-coated tablets debossed with MVC 300 on one side and plain on the other.Oral Solution:o20 mg per mL clear, colorless, strawberry-flavored oral solution.. o25-mg blue, oval, film-coated tablets debossed with MVC 25 on one side and plain on the other.. o75-mg blue, oval, film-coated tablets debossed with MVC 75 on one side and plain on the other.. o150-mg blue, oval, film-coated tablets debossed with MVC 150 on one side and plain on the other.. o300-mg blue, oval, film-coated tablets debossed with MVC 300 on one side and plain on the other.. o20 mg per mL clear, colorless, strawberry-flavored oral solution.. oTablets: 25 mg, 75 mg, 150 mg and 300 mg. (3)oOral Solution: 20 mg per mL (3). oTablets: 25 mg, 75 mg, 150 mg and 300 mg. (3). oOral Solution: 20 mg per mL (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. oCoadministration with CYP3A inhibitors, including protease inhibitors (except tipranavir/ritonavir), will increase the concentration of SELZENTRY. (7.1)oCoadministration with CYP3A inducers, including efavirenz, may decrease the concentration of SELZENTRY. (7.1)oCoadministration with St. Johns wort is not recommended. (7.1). oCoadministration with CYP3A inhibitors, including protease inhibitors (except tipranavir/ritonavir), will increase the concentration of SELZENTRY. (7.1). oCoadministration with CYP3A inducers, including efavirenz, may decrease the concentration of SELZENTRY. (7.1). oCoadministration 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 SELZENTRY 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. SELZENTRY film-coated tablets are available as follows:25-mg, 75-mg, 150-mg, and 300-mg tablets are blue, biconvex, oval, film-coated tablets debossed with MVC 25, MVC 75, MVC 150, or MVC 300, respectively, on one side and plain on the other.25-mg tablets: Bottle of 120 tablets (NDC 49702-233-08).75-mg tablets: Bottle of 120 tablets (NDC 49702-235-08).150-mg tablets: Bottle of 60 tablets (NDC 49702-223-18).300-mg tablets: Bottle of 60 tablets (NDC 49702-224-18).SELZENTRY film-coated tablets should be stored at 20oC to 25oC (68oF to 77oF); excursions permitted between 15oC and 30oC (59oF and 86oF) [see USP Controlled Room Temperature].SELZENTRY oral solution is clear, colorless, strawberry-flavored liquid. Each mL of the solution contains 20 mg of maraviroc. It is supplied in Convenience Combination Kit (NDC 49702-260-55) as follows:Bottle of 230 mL (NDC 49702-237-48). Each plastic bottle is packaged with one press-in bottle adapter, one 10-mL oral dosing syringe with 0.5-mL gradations, and one 3-mL oral dosing syringe with 0.5-mL gradations. The press-in bottle adapter and oral dosing syringes are not made with natural rubber latex. This product does not require reconstitution.SELZENTRY oral solution should be stored at 20oC to 25oC (68oF to 77oF); excursions permitted between 15oC and 30oC (59oF and 86oF) [see USP Controlled Room Temperature]. Discard any unused oral solution 60 days after first opening the bottle.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. SELZENTRY is 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 weighing at least kg.Limitations of UseoSELZENTRY is not recommended in patients with dual/mixed- or CXCR4-tropic HIV-1 [see Microbiology (12.4)].. oSELZENTRY is not recommended in patients with dual/mixed- or CXCR4-tropic HIV-1 [see Microbiology (12.4)].. SELZENTRY 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 weighing at least kg. (1)Limitations of Use:oNot recommended in patients with dual/mixed- or CXCR4-tropic HIV-1. (1). oNot 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 and Instructions for Use).HepatotoxicityInform patients that hepatotoxicity, including life-threatening cases, has been reported with SELZENTRY; 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 SELZENTRY and seek medical evaluation immediately if they develop signs or symptoms of hepatitis or allergic reaction following use of SELZENTRY. Advise patients that laboratory tests for liver enzymes and bilirubin will be ordered prior to starting SELZENTRY, at other times during treatment, and if they develop severe rash or signs and symptoms of hepatitis or an allergic reaction on treatment [see Dosage and Administration (2.1), Warnings and Precautions (5.1, 5.2)].Cardiovascular EventsWhen administering SELZENTRY 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 SELZENTRY [see Warnings and Precautions (5.3)].Drug InteractionsAdvise patients to inform their healthcare provider of concomitant HIV medications as dosage of SELZENTRY may be modified depending on other HIV medications taken with SELZENTRY. Advise patients that coadministration of SELZENTRY with St. Johns wort is not recommended as it can lead to loss of virologic response and possible resistance to SELZENTRY [see Dosage and Administration (2.2), Drug Interactions (7.1)].Missed DosageInform patients that it is important to take SELZENTRY 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)].Pregnancy Inform patients that there is insufficient data on the safety of SELZENTRY in pregnancy. Inform patients that there is an antiretroviral pregnancy registry that monitors pregnancy outcomes in women exposed to SELZENTRY 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)]. SELZENTRY and COMBIVIR are trademarks owned by or licensed to the ViiV Healthcare group of companies.TROFILE is trademark owned by or licensed to Monogram BioSciences, Inc., and is not owned by or licensed to the ViiV Healthcare group of companies. The maker of this brand is not affiliated with and does not endorse the ViiV Healthcare group of companies or its products.Manufactured for:ViiV HealthcareDurham, NC 27701(C)2022 ViiV Healthcare group of companies or its licensor. SEL:16PIPHARMACIST-DETACH HERE AND GIVE MEDICATION GUIDE TO PATIENT.

INSTRUCTIONS FOR USE SECTION.

INSTRUCTIONS FOR USESELZENTRY (sell-ZEN-tree)(maraviroc)oral solutionRead this Instructions for Use before you start taking SELZENTRY oral solution and each time you get refill. There may be new information. This leaflet does not take the place of talking to your healthcare provider about your medical condition or treatment.Important information about measuring SELZENTRY oral solution:Always use the correct oral syringe that comes with your SELZENTRY oral solution to measure your prescribed dose. Ask your healthcare provider or pharmacist to show you which syringe to use and how to measure your prescribed dose if you are not sure.Each carton of SELZENTRY oral solution contains:oOne 3-mL oral syringe (for doses of 2.5 mL or less)oOne 10-mL oral syringe (for doses more than 2.5 mL)o1 press-in bottle adaptero1 bottle of SELZENTRY oral solutionBefore each use: Wash your hands with soap and water. Place the texts from the carton on clean flat surface.Step 1. Open the bottle of SELZENTRY oral solution. Open the bottle by pushing down firmly on the child-resistant cap and turning it counter-clockwise. See Figure A.Do not throw away the child-resistant cap.Figure A. Opening the bottleStep 2. First time use only: Insert the press-in bottle adapter.Remove the press-in bottle adapter and oral syringe from the plastic overwrap. With the bottle on flat surface, push the ribbed end of the press-in bottle adapter all the way into the neck of the bottle while holding the bottle firmly. See Figure B.Note: Do not remove the press-in bottle adapter from the bottle after it is inserted.Figure B. Inserting the press-in bottle adapterStep 3. Choose the oral syringe you need and find your prescribed dose on the oral syringe.Check the dose in milliliters (mL) as prescribed by your healthcare provider. Choose the right syringe for your childs dose: use the 3-mL (small) syringe for doses of 2.5 mL or less, or the 10-mL (large) syringe for doses more than 2.5 mL. Then find this marking on the oral syringe. See Figure C. Figure C. Choose the oral syringe you need and find your prescribed dose.Step 4. Remove air from oral syringe.Push the oral syringe plunger to the bottom of the barrel of the syringe (toward its tip) to remove excess air. See Figure D.Figure D. Removing air from oral syringe.Step 5. Insert the oral syringe. Insert the oral syringe into the upright bottle through the opening of the press-in bottle adapter until it is firmly in place. See Figure E.Figure E. Inserting the oral syringeStep 6. Withdraw the prescribed dose of SELZENTRY from the bottle.With the oral syringe in place, turn the bottle upside down. Pull back the plunger of the oral syringe until the top of the plunger is even with the markings on the oral syringe for your prescribed dose. See Figure F.If you see air bubbles in the oral syringe, fully push the plunger in to empty the oral solution back into the bottle. Then withdraw your prescribed dose of oral solution.Figure F. Withdrawing the oral solutionStep 7. Removing the oral syringe.Turn the bottle upright and place the bottle on flat surface. Remove the oral syringe from the bottle adapter and bottle by pulling straight up on the barrel of the oral syringe. See Figure G.Figure G. Removing the oral syringeStep 8. Check the dose withdrawn.Check that the correct dose was drawn up into the oral syringe. See Figure H.If the dose is not correct, re-insert the oral syringe tip firmly into the bottle adapter. Fully push in the plunger so that the oral solution flows back into the bottle. Repeat Steps and 7.Figure H. Checking the dose withdrawn.Step 9. Take the dose of SELZENTRY. See Figure I.Place the tip of the oral syringe against the inside of the childs cheek.Slowly push the plunger all the way down to give all the medicine in the oral syringe. Make sure the child has time to swallow the medicine.Note: If the prescribed dose is more than 10 mL, you will need to divide the dose. Follow the instructions given to you by your healthcare provider or pharmacist about how to divide the dose and repeat Steps through 9.Figure I. Taking the dose of SELZENTRYStep 10. Close the bottle.Close the bottle tightly by turning the child-resistant cap clockwise, leaving the press-in bottle adapter in place. See Figure J.Figure J. Closing the bottleStep 11. Clean the oral syringe.Rinse the oral syringe with tap water after each use.Remove the plunger from the barrel by pulling the plunger and the barrel away from each other. See Figure K.Rinse the plunger and barrel with water. See Figure L. Allow parts to air dry completely.Figure K. Removing the plunger from the barrelFigure L. Rinsing the plunger and barrelStep 12. Put the oral syringe back together.When the barrel and plunger are dry, put the oral syringe back together by inserting the plunger into the barrel. See Figure M. Store the oral syringe with the SELZENTRY oral solution.Do not throw away the oral syringe.Figure M. Putting the oral syringe back togetherHow should store SELZENTRYStore SELZENTRY oral solution at room temperature between 68F to 77F (20C to 25C). oThrow away any unused oral solution 60 days after first opening the bottle.Ask your healthcare provider or pharmacist how to dispose of unused oral solution.Keep SELZENTRY and all medicines out of the reach of children.Manufactured for:ViiV HealthcareDurham, NC 27701SELZENTRY is trademark owned by or licensed to the ViiV Healthcare group of companies.(C)2022 ViiV Healthcare group of companies or its licensor.SEL:4IFUThis Instructions for Use has been approved by the U.S. Food and Drug Administration.Revised: 9/2022. oOne 3-mL oral syringe (for doses of 2.5 mL or less). oOne 10-mL oral syringe (for doses more than 2.5 mL). o1 press-in bottle adapter. o1 bottle of SELZENTRY oral solution. oThrow away any unused oral solution 60 days after first opening the bottle.. carton contents. Figure A. Figure B. Figure C. Figure D. Figure E. Figure F. Figure G. Figure H. Figure Ia. Figure Ib. Figure J. Figure K. Figure L. Figure M.

LACTATION 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 SELZENTRY.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)].

MICROBIOLOGY SECTION.

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 EC50 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 (EC50 value greater than 10 microM). 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 EC50 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 (EC50 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), 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 EC50 values for maraviroc at the time of failure.Fifteen of these viruses were sequenced in the gp120 encoding region and multiple amino acid substitutions with unique patterns in the heterogeneous V3 loop region were detected. Changes at either amino acid position 308 or 323 (HXB2 numbering) were seen in the V3 loop in 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 SELZENTRY 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 Assaya Includes subjects failing with CXCR4- or dual/mixed-tropism because these viruses are not intrinsically susceptible to maraviroc.MaravirocEfavirenzTotal in dataset (as-treated)273241Total virologic failures (as-treated)85 (31%)56 (23%)Evaluable virologic failures with post baseline genotypic and phenotypic data7343 Lamivudine resistance39 (53%)13 (30%) Zidovudine resistance2 (3%)0 Efavirenz resistance-23 (53%) Phenotypic resistance to maraviroca 19 (26%)-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 EC50 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 mm3) than those subjects failing with CCR5-tropic virus (+162 cells per mm3). The median increase in CD4+ cell count in subjects failing in the placebo arm was +7 cells per mm3.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 mm3 while those subjects failing with CCR5-tropic virus had an increase of +135 cells per mm3. The median increase in CD4+ cell count in subjects failing in the efavirenz arm was +95 cells per mm3.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.

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 SELZENTRY 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 electrocardiogram.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.

maraviroc tablet, film coated. Label Image.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and efficacy of SELZENTRY have been established in pediatric patients aged from birth to less than 18 years. The use of SELZENTRY 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 SELZENTRY 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 SELZENTRY and concomitant medications that included potent CYP3A inhibitors with or without potent CYP3A inducers, 10 subjects received SELZENTRY and noninteracting medications (not containing potent CYP3A inhibitors or potent CYP3A inducers), and three subjects received SELZENTRY and medications that included potent CYP3A inducers without potent CYP3A inhibitors [see Clinical Pharmacology (12.3)].HIV-1-Infected Pediatric Patients Aged Older Than Weeks to Less Than Years: No clinical trials have been conducted in children aged older than weeks to less than years. Dosing recommendations for SELZENTRY in this population when concomitantly receiving noninteracting medications are based on population pharmacokinetic modeling and simulation only [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)]. HIV-1-Infected Neonates Aged from Birth to Weeks: The recommendation of SELZENTRY for the treatment of HIV-1 infection in this pediatric population is based on safety and pharmacokinetic data obtained from clinical trial IMPAACT P2007. In IMPAACT P2007, the safety and pharmacokinetic profiles of SELZENTRY were evaluated in full-term HIV-1-exposed neonates (born to HIV-1-infected mothers) aged from birth through weeks [see Adverse Reactions (6.1)]. Pharmacokinetics were evaluated in 38 of 47 enrolled neonates who received SELZENTRY as single dose (n 13) or multiple doses (n 25) up to weeks of age concomitantly with other antiretrovirals (mostly zidovudine and/or nevirapine) with or without maternal exposure to efavirenz. HIV-1 status was assessed by nucleic acid test at birth, Week 6, and Week 16; all 47 enrolled neonates were HIV-1 negative at completion of the study [see Clinical Pharmacology (12.3)].There are insufficient data to make dosing recommendations for use of SELZENTRY 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)]. SELZENTRY is not recommended in pre-term neonates or in pediatric patients weighing less than kg.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Exposure-Response Relationship in Treatment-Experienced Adult SubjectsThe relationship between maraviroc, modeled plasma trough concentration (Cmin) (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 Cmin, baseline viral load, baseline CD4+ cell count, and overall sensitivity score (OSS) were found to be important predictors of virologic success (defined as viral load less than 400 copies per mL at 24 weeks). Table illustrates the proportions of subjects with virologic success (%) within each Cmin quartile for 150-mg twice-daily and 300-mg twice-daily groups.Table 9. Treatment-Experienced Subjects with Virologic Success by Cmin Quartile (Q1-Q4)150 mg Twice Daily(with CYP3A Inhibitors)300 mg Twice Daily(without CYP3A Inhibitors)nMedian Cmin Subjects with Virologic SuccessnMedian Cmin 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 (Cmin) (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 Cmin quartile for the 300-mg twice-daily dose.Table 10. Treatment-Naive Subjects with Virologic Success by Cmin Quartile (Q1-Q4)300 mg Twice Daily nMedian Cmin 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 Adultsa The estimated exposure is lower compared with other trials possibly due to sparse sampling, food effect, compliance, and concomitant medications.Patient 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)a 300 mg twice daily941,51326637.2 150 mg twice daily(+ CYP3A inhibitor)3752,463332101Treatment-naive HIV subjects (Phase 2b/3)a 300 mg twice daily3441,86528760AbsorptionPeak maraviroc plasma concentrations are attained 0.5 to hours following single oral doses of to 1,200 mg administered to uninfected volunteers. The pharmacokinetics of oral maraviroc are not dose proportional over the dose range. The absolute bioavailability of 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 Cmax 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. EliminationMetabolism: 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 PopulationsPatients with Hepatic Impairment: Maraviroc is primarily metabolized and eliminated by the liver. trial compared the pharmacokinetics of single 300-mg dose of SELZENTRY 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 Cmax 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 SELZENTRY 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 SELZENTRY 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 SELZENTRY 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 Cmax and AUCinf 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 SELZENTRY in healthy volunteers with normal renal function. However, maraviroc exposures in the subjects with normal renal function in this trial were 50% lower than those observed in previous trials. Based on the results of this trial, no dose adjustment is recommended for patients with renal impairment receiving SELZENTRY without potent CYP3A inhibitor or inducer. However, if patients with severe renal impairment or ESRD experience any symptoms of postural hypotension while taking SELZENTRY 300 mg twice daily, their dose should be reduced to 150 mg twice daily [see Dosage and Administration (2.3), Warnings and Precautions (5.3)].In addition, the trial compared the pharmacokinetics of multiple-dose SELZENTRY in combination with saquinavir/ritonavir 1,000/100 mg twice daily (a potent CYP3A inhibitor combination) for 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 SELZENTRY at different dose frequencies (healthy volunteers every 12 hours; mild renal impairment every 24 hours; moderate renal impairment every 48 hours). Compared with healthy volunteers (dosed every 12 hours), geometric mean ratios for maraviroc AUCtau, Cmax, and Cmin were 50% higher, 20% higher, and 43% lower, respectively, for subjects with mild renal impairment (dosed every 24 hours). Geometric mean ratios for maraviroc AUCtau, Cmax, and Cmin 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 (Cavg) 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 SELZENTRY with Potent CYP3A Inhibitors (with or without Potent CYP3A Inducer)a Model-predicted steady-state pharmacokinetic parameters are presented.WeightDose of SELZENTRYMaraviroc Pharmacokinetic Parametera Geometric MeanAUC12 (ng.h/mL)Cavg (ng/mL)Cmax (ng/mL)Cmin (ng/mL)10 kg to <20 kg50 mgtwice daily2,3491963247820 kg to <30 kg75 mgtwice daily3,02025239411830 kg to <40 kg100 mgtwice daily3,229269430126>=40 kg150 mgtwice daily4,044337563152Aged 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 SELZENTRY with Noninteracting Concomitant Medicationsa Noninteracting concomitant medications include all medications that are not potent CYP3A inhibitors or inducers. AUCinf calculated for single-dose pharmacokinetics.Pharmacokinetic Sampling TimenMedian Dose (range)Maraviroc Pharmacokinetic ParameterGeometric MeanAUC12 (ng.h/mL)Cavg (ng/mL)Cmax (ng/mL)Cmin (ng/mL)Day 11330 mg (20 to 40 mg)single dose3,510b 292380-Week 12525 mg(20 to 30 mg)twice daily1,21610126223Week 42530 mg(20 to 40 mg)twice daily1,38511529543Clinical 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 SELZENTRY for this population is predicted to result in similar maraviroc exposures when compared with exposures achieved in adults receiving SELZENTRY 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 Cmax 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 Maraviroca Compared with historical data.Coadministered Drugand DosenDose of SELZENTRYRatio (90% CI) of Maraviroc Pharmacokinetic Parameters with/without Coadministered Drug(No Effect 1.00)Cmin AUCtau Cmax CYP3A and/or P-gp InhibitorsKetoconazole400 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)Ritonavir100 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) /ritonavir1,000 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)Atazanavir400 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/ritonavir300 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)Efavirenz600 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)Rifampicin600 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)Rifampicin600 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)Etravirine200 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)Nevirapinea 200 mg b.i.d. (+ lamivudine 150 mg b.i.d., tenofovir 300 mg q.d.)8300 mgsingle 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/ritonavir700 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/ritonavir1,400 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/ritonavir500 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)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 vitro studies 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 Cmin 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 Cmin and AUC of amprenavir by 15% and 30%, respectively. No dosage adjustment is necessary when SELZENTRY is dosed 150 mg twice daily in combination with fosamprenavir/ritonavir dosed once or twice daily. Fosamprenavir should be given with ritonavir when coadministered with SELZENTRY.Maraviroc had no significant effect on the pharmacokinetics of elvitegravir, zidovudine, or lamivudine. Maraviroc decreased the Cmin 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 microM. 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 SELZENTRY 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 SELZENTRY 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 Figures. https://www.iasusa.org/resources/hiv-drug-resistance-mutations. 1.IAS-USA Drug Resistance Mutations Figures. https://www.iasusa.org/resources/hiv-drug-resistance-mutations.

SPL MEDGUIDE SECTION.

MEDICATION GUIDESELZENTRY (sell-ZEN-tree)(maraviroc)tabletsSELZENTRY (sell-ZEN-tree)(maraviroc)oral solutionWhat is the most important information should know about SELZENTRYSELZENTRY can cause serious side effects including serious liver problems (liver toxicity). Some people who take SELZENTRY can develop severe rash or an allergic reaction before liver problems happen and may be life-threatening. Stop taking SELZENTRY and call your healthcare provider right away if you get any of the following signs or symptoms of liver problems: oan itchy rash on your body (allergic reaction)oyour skin or the white part of your eyes turns yellow (jaundice)odark or tea-colored urineovomitingopain, aching, or tenderness on the right side of your stomach areaYour healthcare provider will do blood tests to check your liver before you begin treatment with SELZENTRY and as needed during treatment with SELZENTRY.What is SELZENTRYSELZENTRY is prescription Human Immunodeficiency Virus-1 (HIV-1) medicine given with other HIV-1 medicines to treat CCR5-tropic HIV-1 infection in adults and children weighing at least 4.4 lb (2 kg). HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS).Use of SELZENTRY is not recommended in people with dual/mixed- or CXCR4-tropic HIV-1.SELZENTRY should not be used in premature newborns or children weighing less than 4.4 pounds (2 kg).Do not take SELZENTRY if you have severe kidney problems or are on hemodialysis and are also taking certain other medications.Before you take SELZENTRY, tell your healthcare provider about all of your medical conditions, including if you:ohave or have had liver problems including hepatitis or virus infection.ohave heart problems.ohave kidney problems.ohave low blood pressure or take medicines to lower blood pressure.oare pregnant or plan to become pregnant. It is not known if SELZENTRY may harm your unborn baby. Pregnancy Registry. There is pregnancy registry for women who take SELZENTRY during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry.oare breastfeeding or plan to breastfeed. Do not breastfeed if you take SELZENTRY. You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby. Talk to your healthcare provider about the best way to feed your baby.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. oSome medicines may interact with SELZENTRY. Keep list of your medicines to show your healthcare provider and pharmacist.oYou can ask your healthcare provider or pharmacist for list of medicines that interact with SELZENTRY. Do not start taking new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take SELZENTRY with other medicines. Your healthcare provider may need to change your dose of SELZENTRY when you take it with certain medicines. You should not take SELZENTRY if you also take St. Johns wort (Hypericum perforatum). How should take SELZENTRYoTake SELZENTRY exactly as your healthcare provider tells you. oDo not change your dose or stop taking SELZENTRY without first talking with your healthcare provider. oIf you miss dose of SELZENTRY, take it as soon as you remember. Do not take doses at the same time. If you are not sure about your dosing, call your healthcare provider.oStay under the care of healthcare provider during treatment with SELZENTRY.oSwallow SELZENTRY tablets whole. Do not chew the tablets.oSELZENTRY may be taken with or without food.oYour healthcare provider will prescribe dose of SELZENTRY based on your childs body weight and other medicines they are taking.oTell your healthcare provider if your child has trouble swallowing tablets. SELZENTRY comes as tablets or as liquid (oral solution).oSELZENTRY oral solution should be given with the supplied press-in bottle adapter and oral dosing syringe. See the Instructions for Use that comes with SELZENTRY oral solution for information about the right way to take dose.oDo not run out of SELZENTRY. The virus in your blood may increase and the virus in your blood may become harder to treat. When your supply starts to run low, get more from your healthcare provider or pharmacy.oIf you take too much SELZENTRY, call your healthcare provider or go to the nearest hospital emergency room right away.What are the possible side effects of SELZENTRYSELZENTRY can cause serious side effects including: oSee What is the most important information should know about SELZENTRYoSevere skin rash and allergic reactions. Severe and potentially life-threatening skin reactions and allergic reactions have been reported in some people taking SELZENTRY. If you develop rash with any of the following symptoms, stop using SELZENTRY and contact your healthcare provider right away:ofeverogenerally ill feelingomuscle achesoblisters or sores in your mouthoblisters or peeling of the skinoredness or swelling of the eyesoswelling of the mouth or face or lipsoproblems breathingoyellowing of the skin or whites of your eyesodark or tea-colored urineopain, aching, or tenderness on the right side below the ribsoloss of appetiteonausea/vomitingoHeart problems including heart attack.oLow blood pressure when standing up (postural hypotension) that can cause dizziness or fainting. You should avoid driving or operating heavy machinery if you have dizziness during treatment with SELZENTRY.oChanges in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for long time. Tell your healthcare provider right away if you develop new symptoms during treatment with SELZENTRY.oPossible chance of infection or cancer. SELZENTRY affects other immune system cells and therefore may possibly increase your chance for getting other infections or cancer. The most common side effects of SELZENTRY in adults include colds and cold-like symptoms, cough, fever, rash, bloating and gas, indigestion, constipation, and dizziness.The most common side effects of SELZENTRY in children include vomiting, abdominal pain, diarrhea, nausea, and dizziness.The most common side effect of SELZENTRY in newborns is decreased hemoglobin (protein inside red blood cells).These are not all the possible side effects of SELZENTRY. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store SELZENTRYoStore SELZENTRY tablets and oral solution at room temperature between 68F to 77F (20C to 25C).oThrow away any unused oral solution 60 days after first opening the bottle.Keep SELZENTRY and all medicines out of the reach of children.General information about the safe and effective use of SELZENTRYMedicines are sometimes prescribed for purposes other than those mentioned in Medication Guide. Do not use SELZENTRY for condition for which it was not prescribed. Do not give SELZENTRY to other people, even if they have the same symptoms that you have. It may harm them.You can ask your pharmacist or healthcare provider for the information about SELZENTRY that is written for health professionals.What are the ingredients in SELZENTRYActive ingredient: maravirocInactive ingredients:Tablets: Dibasic calcium phosphate (anhydrous), magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. Tablet film-coating contains: FD&C blue aluminum lake, soya lecithin, polyethylene glycol (macrogol 3350), polyvinyl alcohol, talc, and titanium dioxide.Oral Solution: Citric acid, purified water, sodium benzoate, sodium citrate dihydrate, strawberry flavoring (501440T), and sucralose.Manufactured for:ViiV HealthcareDurham, NC 27701SELZENTRY is trademark owned by or licensed to the ViiV Healthcare group of companies.(C)2022 ViiV Healthcare group of companies or its licensor. SEL:10MGFor more information go to www.selzentry.com.This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: 9/2022. oan itchy rash on your body (allergic reaction). oyour skin or the white part of your eyes turns yellow (jaundice). odark or tea-colored urine. ovomiting. opain, aching, or tenderness on the right side of your stomach area. ohave or have had liver problems including hepatitis or virus infection.. ohave heart problems.. ohave kidney problems.. ohave low blood pressure or take medicines to lower blood pressure.. oare pregnant or plan to become pregnant. It is not known if SELZENTRY may harm your unborn baby. Pregnancy Registry. There is pregnancy registry for women who take SELZENTRY during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry.. oare breastfeeding or plan to breastfeed. Do not breastfeed if you take SELZENTRY. You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby. Talk to your healthcare provider about the best way to feed your baby.. oSome medicines may interact with SELZENTRY. Keep list of your medicines to show your healthcare provider and pharmacist.. oYou can ask your healthcare provider or pharmacist for list of medicines that interact with SELZENTRY. oTake SELZENTRY exactly as your healthcare provider tells you. oDo not change your dose or stop taking SELZENTRY without first talking with your healthcare provider. oIf you miss dose of SELZENTRY, take it as soon as you remember. Do not take doses at the same time. If you are not sure about your dosing, call your healthcare provider.. oStay under the care of healthcare provider during treatment with SELZENTRY.. oSwallow SELZENTRY tablets whole. Do not chew the tablets.. oSELZENTRY may be taken with or without food.. oYour healthcare provider will prescribe dose of SELZENTRY based on your childs body weight and other medicines they are taking.. oTell your healthcare provider if your child has trouble swallowing tablets. SELZENTRY comes as tablets or as liquid (oral solution).. oSELZENTRY oral solution should be given with the supplied press-in bottle adapter and oral dosing syringe. See the Instructions for Use that comes with SELZENTRY oral solution for information about the right way to take dose.. oDo not run out of SELZENTRY. The virus in your blood may increase and the virus in your blood may become harder to treat. When your supply starts to run low, get more from your healthcare provider or pharmacy.. oIf you take too much SELZENTRY, call your healthcare provider or go to the nearest hospital emergency room right away.. oSee What is the most important information should know about SELZENTRY. oSevere skin rash and allergic reactions. Severe and potentially life-threatening skin reactions and allergic reactions have been reported in some people taking SELZENTRY. If you develop rash with any of the following symptoms, stop using SELZENTRY and contact your healthcare provider right away:. ofever. ogenerally ill feeling. omuscle aches. oblisters or sores in your mouth. oblisters or peeling of the skin. oredness or swelling of the eyes. oswelling of the mouth or face or lips. oproblems breathing. oyellowing of the skin or whites of your eyes. odark or tea-colored urine. opain, aching, or tenderness on the right side below the ribs. oloss of appetite. onausea/vomiting. oHeart problems including heart attack.. oLow blood pressure when standing up (postural hypotension) that can cause dizziness or fainting. You should avoid driving or operating heavy machinery if you have dizziness during treatment with SELZENTRY.. oChanges in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for long time. Tell your healthcare provider right away if you develop new symptoms during treatment with SELZENTRY.. oPossible chance of infection or cancer. SELZENTRY affects other immune system cells and therefore may possibly increase your chance for getting other infections or cancer. oStore SELZENTRY tablets and oral solution at room temperature between 68F to 77F (20C to 25C).. oThrow away any unused oral solution 60 days after first opening the bottle.

SPL UNCLASSIFIED SECTION.

2.1 Testing prior to Initiation of SELZENTRY Prior to initiation of SELZENTRY for treatment of HIV-1 infection, test all patients for CCR5 tropism using highly sensitive tropism assay. SELZENTRY is 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 SELZENTRY [see Microbiology (12.4), Clinical Studies (14.1)].Monitor patients for alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin prior to initiation of SELZENTRY 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. oLactation: Women infected with HIV should be instructed not to breastfeed due to the potential for HIV transmission. (8.2). oLactation: 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 SELZENTRY 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 SELZENTRY 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 SELZENTRY.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 SELZENTRY have been established in pediatric patients aged from birth to less than 18 years. The use of SELZENTRY 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 SELZENTRY 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 SELZENTRY and concomitant medications that included potent CYP3A inhibitors with or without potent CYP3A inducers, 10 subjects received SELZENTRY and noninteracting medications (not containing potent CYP3A inhibitors or potent CYP3A inducers), and three subjects received SELZENTRY and medications that included potent CYP3A inducers without potent CYP3A inhibitors [see Clinical Pharmacology (12.3)].HIV-1-Infected Pediatric Patients Aged Older Than Weeks to Less Than Years: No clinical trials have been conducted in children aged older than weeks to less than years. Dosing recommendations for SELZENTRY in this population when concomitantly receiving noninteracting medications are based on population pharmacokinetic modeling and simulation only [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)]. HIV-1-Infected Neonates Aged from Birth to Weeks: The recommendation of SELZENTRY for the treatment of HIV-1 infection in this pediatric population is based on safety and pharmacokinetic data obtained from clinical trial IMPAACT P2007. In IMPAACT P2007, the safety and pharmacokinetic profiles of SELZENTRY were evaluated in full-term HIV-1-exposed neonates (born to HIV-1-infected mothers) aged from birth through weeks [see Adverse Reactions (6.1)]. Pharmacokinetics were evaluated in 38 of 47 enrolled neonates who received SELZENTRY as single dose (n 13) or multiple doses (n 25) up to weeks of age concomitantly with other antiretrovirals (mostly zidovudine and/or nevirapine) with or without maternal exposure to efavirenz. HIV-1 status was assessed by nucleic acid test at birth, Week 6, and Week 16; all 47 enrolled neonates were HIV-1 negative at completion of the study [see Clinical Pharmacology (12.3)].There are insufficient data to make dosing recommendations for use of SELZENTRY 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)]. SELZENTRY is not recommended in pre-term neonates or in pediatric patients weighing less than 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 SELZENTRY 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 SELZENTRY 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 SELZENTRY in pediatric patients with mild to moderate renal impairment [see Use in Specific Populations (8.4)]. SELZENTRY 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 SELZENTRY 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 SELZENTRY 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 SELZENTRY can be recommended, and SELZENTRY 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 SELZENTRY 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 SELZENTRY 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. oHepatotoxicity accompanied by severe rash or systemic allergic reaction, including potentially life-threatening events, has been reported. Hepatic laboratory parameters including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin should be obtained prior to starting SELZENTRY 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 SELZENTRY to patients with pre-existing liver dysfunction or who are co-infected with hepatitis and/or virus, additional monitoring may be warranted. (5.1)oSevere and potentially life-threatening skin and hypersensitivity reactions have been reported in patients taking SELZENTRY. This includes cases of Stevens-Johnson syndrome, hypersensitivity reaction, and toxic epidermal necrolysis. Immediately discontinue SELZENTRY 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)oMore cardiovascular events, including myocardial ischemia and/or infarction, were observed in treatment-experienced subjects who received SELZENTRY. Additional monitoring may be warranted. (5.3)oIf patients with severe renal impairment or ESRD receiving SELZENTRY (without concomitant CYP3A inducers or inhibitors) experience postural hypotension, the dose of SELZENTRY should be reduced from 300 mg twice daily to 150 mg twice daily. (5.3). oHepatotoxicity accompanied by severe rash or systemic allergic reaction, including potentially life-threatening events, has been reported. Hepatic laboratory parameters including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin should be obtained prior to starting SELZENTRY 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 SELZENTRY to patients with pre-existing liver dysfunction or who are co-infected with hepatitis and/or virus, additional monitoring may be warranted. (5.1). oSevere and potentially life-threatening skin and hypersensitivity reactions have been reported in patients taking SELZENTRY. This includes cases of Stevens-Johnson syndrome, hypersensitivity reaction, and toxic epidermal necrolysis. Immediately discontinue SELZENTRY 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). oMore cardiovascular events, including myocardial ischemia and/or infarction, were observed in treatment-experienced subjects who received SELZENTRY. Additional monitoring may be warranted. (5.3). oIf patients with severe renal impairment or ESRD receiving SELZENTRY (without concomitant CYP3A inducers or inhibitors) experience postural hypotension, the dose of SELZENTRY 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 SELZENTRY 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 SELZENTRY should be considered in any patient with signs or symptoms of hepatitis, or with increased liver transaminases combined with rash or other systemic symptoms.When administering SELZENTRY 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 SELZENTRY 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 SELZENTRY, 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 (6.2)]. The cases were characterized by features including rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure. Discontinue SELZENTRY 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 SELZENTRY 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 SELZENTRY had cardiovascular events, including myocardial ischemia and/or infarction, during the Phase trials in treatment-experienced subjects (total exposure 609 patient-years [300 on SELZENTRY once daily 309 on SELZENTRY 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 SELZENTRY, and the relative contribution of SELZENTRY to these events is not known.In the Phase 2b/3 trial in treatment-naive adult subjects, subjects (0.8%) who received SELZENTRY 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 SELZENTRY and efavirenz, respectively).When SELZENTRY 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 SELZENTRY 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. SELZENTRY 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 SELZENTRY 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 SELZENTRY. 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. SELZENTRY antagonizes the CCR5 co-receptor located on some immune cells, and therefore could potentially increase the risk of developing infections. The overall incidence and severity of infection, as well as AIDS-defining category infections, were comparable in the treatment groups during the Phase adult treatment-experienced trials of SELZENTRY. While there was higher rate of certain upper respiratory tract infections reported in the treatment arm receiving SELZENTRY compared with placebo (23% versus 13%), there was lower rate of pneumonia (2% versus 5%) reported in subjects receiving SELZENTRY. higher incidence of Herpes virus infections (11 per 100 patient-years) was also reported in the treatment arm receiving SELZENTRY 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 SELZENTRY compared with 2.4 for efavirenz per 100 patient-years of exposure.Patients should be monitored closely for evidence of infections while receiving SELZENTRY.. 5.6 Potential Risk of Malignancy. While no increase in malignancy has been observed with SELZENTRY, 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 SELZENTRY 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 SELZENTRY and efavirenz, respectively.Long-term follow-up is needed to more fully assess this risk.