SELZENTRY

1 INDICATIONS AND USAGE SELZENTRY is 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 weighing at least 2 kg. Limitations of Use • SELZENTRY is not recommended in patients with dual/mixed- or CXCR4-tropic HIV-1 [see Microbiology ( 12.4 )]. SELZENTRY 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 weighing at least 2 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 SELZENTRY for treatment of HIV-1 infection, test all patients for CCR5 tropism using a highly sensitive tropism assay. ( 2.1 ) • SELZENTRY 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 Medications Dosage of SELZENTRY 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 Weighing at Least 2 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 SELZENTRY Prior to initiation of SELZENTRY for treatment of HIV-1 infection, test all patients for CCR5 tropism using a 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 • SELZENTRY 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. • The 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 1 displays oral dosage of SELZENTRY based on different concomitant medications [see Drug Interactions ( 7.1 )] . Table 1. Recommended Dosage in Adults Concomitant Medications Dosage of SELZENTRY 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. 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 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 2 and Table 3 ) [see Drug Interactions ( 7.1 ), Use in Specific Populations ( 8.4 )] . Be …

3 DOSAGE FORMS AND STRENGTHS Tablets: • 25-mg blue, oval, film-coated tablets debossed with “MVC 25” on one side and plain on the other. • 75-mg blue, oval, film-coated tablets debossed with “MVC 75” on one side and plain on the other. • 150-mg blue, oval, film-coated tablets debossed with “MVC 150” on one side and plain on the other. • 300-mg blue, oval, film-coated tablets debossed with “MVC 300” on one side and plain on the other. Oral Solution: • 20 mg per mL clear, colorless, strawberry-flavored oral solution. • Tablets: 25 mg, 75 mg, 150 mg and 300 mg. ( 3 ) • Oral Solution: 20 mg per mL ( 3 )

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 )

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 ViiV Healthcare at 1-877-844-8872 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 SELZENTRY is primarily based on 840 HIV-1–infected subjects who received at least 1 dose of SELZENTRY 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 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 2 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 2 subjects (0.5%) on SELZENTRY 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 SELZENTRY are included; events that occurred at the same or higher rate on placebo are not displ …

7 DRUG INTERACTIONS • Coadministration with CYP3A inhibitors, including protease inhibitors (except tipranavir/ritonavir), will increase the concentration of SELZENTRY. ( 7.1 ) • Coadministration with CYP3A inducers, including efavirenz, may decrease the concentration of SELZENTRY. ( 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 )] .

8 USE IN SPECIFIC POPULATIONS • Lactation: Women infected with HIV should be instructed not to breastfeed due to the potential for HIV transmission. ( 8.2 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a 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 Summary Limited data on the use of SELZENTRY during pregnancy from the APR and case reports are not sufficient to inform a 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 5 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 a 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. Data Animal 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 6 to 17 and 7 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 5 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 6 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 Summary The 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 a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving SELZENTRY. Data Maraviroc (and related metabolites) was excreted into the milk of lactating rats following a single oral dose of maraviroc (100 mg per kg) on lactation Day 12, with a maximal milk concentration achieved one hour post-administration at a 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 2 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 …

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

11 DESCRIPTION SELZENTRY (maraviroc) is a selective, slowly reversible, small molecule antagonist of the interaction between human CCR5 and HIV-1 gp120. Blocking this interaction prevents CCR5-tropic HIV-1 entry into cells. SELZENTRY 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 #2 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 -{(1 S )-3 - [ exo -3-(3-isopropyl-5-methyl-4 H -1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}cyclohexanecarboxamide. The molecular formula is C 29 H 41 F 2 N 5 O and the structural formula is: Maraviroc is a white to pale-colored powder with a molecular weight of 513.67. It is highly soluble across the physiological pH range (pH 1.0 to 7.5). Maraviroc chemical structure

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 a CYP3A inducer without a CYP3A inhibitor is 600 mg twice daily, this dose is appropriate due to enhanced metabolism. Prolongation of the QT interval was seen in dogs and monkeys at plasma concentrations 6 and 12 times, respectively, those expected in humans at the intended exposure of 300-mg equivalents twice daily. However, no significant QT prolongation was seen in the trials in treatment-experienced subjects with HIV using the recommended doses of maraviroc, or in a 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 a 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 a minimal effect on maraviroc clearance and exposure in a trial in subjects with ESRD [see Clinical Pharmacology ( 12.3 )] .

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 20 o C to 25 o C (68 o F to 77 o F); excursions permitted between 15 o C and 30 o C (59 o F and 86 o F) [see USP Controlled Room Temperature]. SELZENTRY oral solution is a clear, colorless, strawberry-flavored liquid. Each mL of the solution contains 20 mg of maraviroc. It is supplied in a 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 20 o C to 25 o C (68 o F to 77 o F); excursions permitted between 15 o C and 30 o C (59 o F and 86 o F) [see USP Controlled Room Temperature]. Discard any unused oral solution 60 days after first opening the bottle.