Maraviroc

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

1 INDICATIONS AND USAGE Maraviroc tablets are indicated in combination with other antiretroviral agents for the treatment of only CCR5-tropic human immunodeficiency virus type 1 (HIV-1) infection in adult and pediatric patients 2 years of age and older weighing at least 10 kg. Limitations of Use: • Maraviroc tablets are not recommended in patients with dual/mixed- or CXCR4-tropic HIV-1 [ see Microbiology ( 12.4 ) ]. Maraviroc tablet is a 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 2 years of age and older weighing at least 10 kg. ( 1 ) Limitations of Use: • Not recommended in patients with dual/mixed- or CXCR4-tropic HIV-1. ( 1 )

2 DOSAGE AND ADMINISTRATION • Prior to initiation of maraviroc tablets for treatment of HIV-1 infection, test all patients for CCR5 tropism using a highly sensitive tropism assay. ( 2.1 ) • Maraviroc tablets are taken twice daily by mouth and may be taken with or without food. Maraviroc tablets must be given in combination with other antiretroviral medications. ( 2.2 ) Recommended Dosage in Adult Patients: ( 2.3 ) Concomitant Medications Dosage of Maraviroc tablets When given with potent cytochrome P450 (CYP)3A inhibitors (with or without potent CYP3A inducers) including PIs (except tipranavir/ritonavir) ( 2.3 , 7.1 ) 150 mg twice daily With NRTIs, tipranavir/ritonavir, nevirapine, raltegravir, and other drugs that are not potent CYP3A inhibitors or CYP3A inducers ( 2.3 , 7.1 ) 300 mg twice daily With potent and moderate CYP3A inducers including efavirenz (without a potent CYP3A inhibitor) ( 2.3 , 7.1 ) 600 mg twice daily A more complete list of coadministered drugs is listed in Dosage and Administration. ( 2 ) Recommended Dosage in Pediatric Patients 2 years and older and weighing at Least 10 kg: Administer twice daily. Dosage should be based on body weight (kg) and concomitant medications and should not exceed the recommended adult dose. ( 2.4 ) Recommended Dosage in Patients with Renal Impairment: Dose adjustment may be necessary in adult patients with renal impairment. ( 2.5 ) 2.1 Testing prior to Initiation of Maraviroc Tablets Prior to initiation of maraviroc tablets for treatment of HIV-1 infection, test all patients for CCR5 tropism using a highly sensitive tropism assay. Maraviroc tablets are recommended for patients with only CCR5-tropic HIV-1 infection. Outgrowth of pre-existing low-level CXCR4- or dual/mixed-tropic HIV-1 not detected by tropism testing at screening has been associated with virologic failure on maraviroc tablets [ see Microbiology ( 12.4 ), Clinical Studies ( 14.1 ) ]. Monitor patients for ALT, AST, and bilirubin prior to initiation of maraviroc tablets and at other time points during treatment as clinically indicated [see Warnings and Precautions ( 5.1 )] . 2.2 General Dosing Recommendations • Maraviroc tablets are taken twice daily by mouth and may be taken with or without food. • Maraviroc tablets must be given in combination with other antiretroviral medications. • The recommended dosage of maraviroc tablets differs based on concomitant medications due to drug interactions. 2.3 Recommended Dosage in Adult Patients with Normal Renal Function Table 1 displays oral dosage of maraviroc tablets based on different concomitant medications [ see Drug Interactions ( 7.1 ) ]. Table 1. Recommended Dosage in Adults Concomitant Medications Dosage of Maraviroc Tablets Potent cytochrome P450 (CYP)3A inhibitors (with or without a potent CYP3A inducer) a 150 mg twice daily Noninteracting concomitant medications b 300 mg twice daily Potent and moderate CYP3A inducers (without a potent CYP3A inhibitor) c 600 mg twice daily a Potent CYP3A inhibitors (with or without a potent CYP3A inducer) including: clarithromycin, cobicistat, elvitegravir/ritonavir, itraconazole, ketoconazole, nefazodone, protease inhibitors (except tipranavir/ritonavir), telithromycin. b 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. c Potent and moderate CYP3A inducers (without a potent CYP3A inhibitor) including: carbamazepine, efavirenz, etravirine, phenobarbital, phenytoin, and rifampin. 2.4 Recommended Dosage in Pediatric Patients with Normal Renal Function The recommended dosage of maraviroc tablets should be based on body weight (kg) and should not exceed the recommended adult dose. The recommended dosage also differs based on concomitant medications due to drug interactions (Table 2 and Table 3) [ see Drug Interactions ( 7.1 ), Use in Specific Populations ( 8.4 )]. Before prescribing maraviroc tablets, assess children for the ability to swallow tablets. If a child is unable to reliably swallow maraviroc tablets, the oral solution formulation should be prescribed. The recommended oral dosage of maraviroc tablets in pediatric patients aged 2 years and older weighing at least 10 kg is presented in Table 2. Table 2. Recommended Dosage in Pediatric Patients Aged 2 Years and Older Weighing at Least 10 kg (Tablets) Concomitant Medications Dosage of Maraviroc Tablets Based on Weight 10 kg to <14 kg 14 kg to <20 kg 20 kg to <30 kg 30 kg to <40 kg ≥40 kg Potent CYP3A inhibitors (with or without a CYP3A inducer) a 50 mg twice daily 50 mg twice daily 75 mg twice daily 100 mg twice daily 150 mg twice daily Noninteracting concomitant medications b 150 mg twice daily 200 mg twice daily 200 mg twice daily 300 mg twice daily 300 mg twice daily Potent and moderate CYP3A inducers (without a potent CYP3A inhibitor) c Not recommended

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: • Hepatotoxicity [ see Boxed Warning, Warnings and Precautions ( 5.1 ) ] • Severe Skin and Hypersensitivity Reactions [ see Warnings and Precautions ( 5.2 ) ] • Cardiovascular Events [ see Warnings and Precautions ( 5.3 ) ] • The most common adverse events in treatment-experienced adult subjects (greater than 8% incidence) which occurred at a higher frequency compared with placebo are upper respiratory tract infections, cough, pyrexia, rash, and dizziness. ( 6.1 ) • The most common adverse events in treatment-naive adult subjects (greater than 8% incidence) which occurred at a higher frequency than the comparator arm are upper respiratory tract infections, bronchitis, flatulence, bloating and distention, upper respiratory tract signs and symptoms, and gastrointestinal atonic and hypomotility disorders. ( 6.1 ) • The most common adverse reactions in treatment-experienced pediatric subjects (greater than or equal to 3% incidence) are vomiting, abdominal pain, diarrhea, nausea, and dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hetero Labs Limited at 1-866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a 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 Subjects Treatment-Experienced Subjects: The safety profile of maraviroc is primarily based on 840 HIV-1-infected subjects who received at least 1 dose of maraviroc during two Phase 3 trials. A 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 2 trials in subjects with CCR5-tropic HIV-1 (A4001027 and A4001028). The median duration of therapy with maraviroc for subjects in these trials was 48 weeks, with the total exposure on maraviroc twice daily at 309 patient-years versus 111 patient-years on placebo each administered with optimized background therapy (OBT). The population was 89% male and 84% white, with mean age of 46 years (range: 17 to 75 years). Subjects received dose equivalents of 300 mg maraviroc once or twice daily. The most common adverse events reported with twice-daily therapy with maraviroc with frequency rates higher than placebo, regardless of causality, were upper respiratory tract infections, cough, pyrexia, rash, and dizziness. In these 2 trials, the rate of discontinuation due to adverse events was 5% for subjects who received maraviroc twice daily + OBT as well as those who received placebo + OBT. Most of the adverse events reported were judged to be mild to moderate in severity. The data described below occurred with twice-daily dosing of maraviroc. The total numbers of subjects reporting infections were 233 (55%) and 84 (40%) in the group receiving maraviroc twice daily and the placebo group, respectively. Correcting for the longer duration of exposure on maraviroc compared with placebo, the exposure-adjusted frequency (rate per 100 subject-years) of these events was 133 for both maraviroc twice daily and placebo. Dizziness or postural dizziness occurred in 8% of subjects on either maraviroc or placebo, with 2 subjects (0.5%) on maraviroc permanently discontinuing therapy (1 due to syncope, 1 due to orthostatic hypotension) versus 1 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 a numerically higher rate in subjects treated with maraviroc are included; events that occurred at the same or higher rate on placebo are not displayed. Table 5. Selected Treatment-Emergent Adverse Events (All Causality) ≥2% on Maraviroc (and at a Higher Rate Compared with Placebo) in Trials A4001027 and A4001028 (Pooled Analysis, 48 Weeks) Body System/ Adverse Event Maraviroc Twice Daily a Placebo (n = 426) % Exposure-Adjusted Rate (per 100 pt-yrs) PYE=309 b (n = 209) % Exposure-Adjusted Rate (per 100 pt-yrs) PYE=111 b Eye Disorders Conjunctivitis 2 3 1 3 Ocular infections, inflammations, and associated manifestations 2 3 1 2 Gastrointestinal Disorders Constipation 6 9 3 6 General Disorders and Administration Site Conditions Pyrexia 13 20 9 17 Pain and discomfort 4 5 3 5 Infections and Infestations Upper respiratory tract infection 23 37 13 27 Herpes infection 8 11 4 8 Sinusitis 7 10 3 6 Bronchitis 7 9 5 9 Folliculitis 4 5 2 4 Anogenital warts 2 3 1 3 Influenza 2 3 0.5 1 Otitis media 2 3 0.5 1 Metabolism and Nutrition Disorders Appetite disorders 8 11 7 13 Musculoskeletal and Connective Tissue Disorders Joint-related signs

7 DRUG INTERACTIONS • Coadministration with CYP3A inhibitors, including protease inhibitors (except tipranavir/ritonavir), will increase the concentration of maraviroc. ( 7.1 ) • Coadministration with CYP3A inducers, including efavirenz, may decrease the concentration of maraviroc. ( 7.1 ) • Coadministration with St. John’s 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 a 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, a 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. John's wort ( Hypericum perforatum ) or products containing St. John's wort is not recommended. Coadministration of maraviroc with St. John's wort is expected to substantially decrease maraviroc concentrations and may result in suboptimal levels of maraviroc and lead to loss of virologic response and possible resistance to maraviroc. Additional drug interaction information is available [ see Clinical Pharmacology ( 12.3 ) ].