MARAVIROC: 1,177 Adverse Event Reports & Safety Profile

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

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 )

AND ADMINISTRATION

• Prior to initiation of Maraviroc 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 must be given in combination with other antiretroviral medications. ( 2.2 )

Recommended

Dosage in Adult Patients: ( 2.3 )

Concomitant Medications

Dosage of Maraviroc 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 Prior to initiation of Maraviroc for treatment of HIV-1 infection, test all patients for CCR5 tropism using a highly sensitive tropism assay. Maraviroc 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 Maraviroc <span class="opacity-50 text-xs">[see Microbiology (12.4) , Clinical Studies (14.1) ]</span>. Monitor patients for alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin prior to initiation of Maraviroc and at other time points during treatment as clinically indicated <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span>.

2.2 General Dosing Recommendations Maraviroc tablets are taken twice daily by mouth and may be taken with or without food. Maraviroc must be given in combination with other antiretroviral medications. The recommended dosage of Maraviroc 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 based on different concomitant medications <span class="opacity-50 text-xs">[see Drug Interactions (7.1) ]</span>.

Table

1.

Recommended

Dosage in Adults Concomitant Medications Dosage of Maraviroc Potent cytochrome P450 (CYP)3A inhibitors (with or without a potent CYP3A inducer) Potent CYP3A inhibitors (with or without a potent CYP3A inducer) including: clarithromycin, cobicistat, elvitegravir/ritonavir, itraconazole, ketoconazole, nefazodone, protease inhibitors (except tipranavir/ritonavir), telithromycin. 150 mg twice daily Noninteracting concomitant medications 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. 300 mg twice daily Potent and moderate CYP3A inducers (without a potent CYP3A inhibitor) Potent and moderate CYP3A inducers (without a potent CYP3A inhibitor) including: carbamazepine, efavirenz, etravirine, phenobarbital, phenytoin, and rifampin. 600 mg twice daily

2.4 Recommended Dosage in Pediatric Patients with Normal Renal Function The recommended dosage of Maraviroc 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) <span class="opacity-50 text-xs">[see Drug Interactions (7.1) , Use in Specific Populations (8.4) ]</span>. 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 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) Potent CYP3A inhibitors (with or without a CYP3A inducer) including: clarithromycin, cobicistat, elvitegravir/ritonavir, itraconazole, ketoconazole, nefazodone, protease inhibitors (except tipranavir/ritonavir), telithromycin. 50 mg twice daily 50 mg twice daily 75 mg twice daily 100 mg twice daily 150 mg twice daily Noninteracting concomitant medications 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. 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) Potent and moderate CYP3A inducers (without a potent CYP3A inhibitor) including: carbamazepine, efavirenz, etravirine, phenobarbital, phenytoin, and rifampin. Not recommended Insufficient data are available to recommend use. The recommended oral dosage of maraviroc oral solution in pediatric patients weighing at least 10 kg is presented in Table 3.

Table

3.

Recommended

Dosage in Pediatric Patients Weighing at Least 10 kg (Oral Solution)

Concomitant Medications

Dosage (Volume of Solution) of Maraviroc 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) Potent CYP3A inhibitors (with or without a CYP3A inducer) including: clarithromycin, cobicistat, elvitegravir/ritonavir, itraconazole, ketoconazole, nefazodone, protease inhibitors (except tipranavir/ritonavir), telithromycin. 50 mg (2.5 mL) twice daily 50 mg (2.5 mL) twice daily 80 mg (4 mL) twice daily 100 mg (5 mL) twice daily 150 mg (7.5 mL) twice daily Noninteracting concomitant medications 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. 150 mg (7.5 mL) twice daily 200 mg (10 mL) twice daily 200 mg (10 mL) twice daily 300 mg (15 mL) twice daily 300 mg (15 mL) twice daily Potent and moderate CYP3A inducers (without a potent CYP3A inhibitor) Potent and moderate CYP3A inducers (without a potent CYP3A inhibitor) including: carbamazepine, efavirenz, etravirine, phenobarbital, phenytoin, and rifampin. Not recommended Insufficient data are available to recommend use. Administer the oral solution using the appropriate oral dosing syringe: for doses greater than 2.5 mL, use the 10-mL syringe.

2.5 Recommended Dosage in Patients with Renal Impairment Adult Patients Table 4 provides dosing recommendations for patients based on renal function and concomitant medications.

Table

4.

Recommended

Dosage in Adults Based on Renal Function Concomitant Medications Dosage of Maraviroc Based on Renal Function Normal (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 Hemodialysis Potent CYP3A inhibitors (with or without a CYP3A inducer) Potent CYP3A inhibitors (with or without a CYP3A inducer) including: clarithromycin, cobicistat, elvitegravir/ritonavir, itraconazole, ketoconazole, nefazodone, protease inhibitors (except tipranavir/ritonavir), telithromycin. 150 mg twice daily 150 mg twice daily 150 mg twice daily Contraindicated Contraindicated Noninteracting concomitant medications 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. 300 mg twice daily 300 mg twice daily 300 mg twice daily 300 mg twice daily 300 mg twice daily Dosage of Maraviroc 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 a potent CYP3A inhibitor) Potent and moderate CYP3A inducers (without a potent CYP3A inhibitor) including: carbamazepine, efavirenz, etravirine, phenobarbital, phenytoin, and rifampin. 600 mg twice daily 600 mg twice daily 600 mg twice daily Contraindicated Contraindicated CrCl = Creatinine Clearance.

Pediatric Patients

There are no data to recommend specific doses of Maraviroc in pediatric patients with mild or moderate renal impairment [see Use in Specific Populations (8.6) ] . Additionally, Maraviroc 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) ].

2.1 Testing prior to Initiation of Maraviroc Prior to initiation of Maraviroc for treatment of HIV-1 infection, test all patients for CCR5 tropism using a highly sensitive tropism assay. Maraviroc 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 Maraviroc <span class="opacity-50 text-xs">[see Microbiology (12.4) , Clinical Studies (14.1) ]</span>. Monitor patients for alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin prior to initiation of Maraviroc and at other time points during treatment as clinically indicated <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span>.

2.2 General Dosing Recommendations Maraviroc tablets are taken twice daily by mouth and may be taken with or without food. Maraviroc must be given in combination with other antiretroviral medications. The recommended dosage of Maraviroc 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 based on different concomitant medications <span class="opacity-50 text-xs">[see Drug Interactions (7.1) ]</span>.

Table

1.

Recommended

Dosage in Adults Concomitant Medications Dosage of Maraviroc Potent cytochrome P450 (CYP)3A inhibitors (with or without a potent CYP3A inducer) Potent CYP3A inhibitors (with or without a potent CYP3A inducer) including: clarithromycin, cobicistat, elvitegravir/ritonavir, itraconazole, ketoconazole, nefazodone, protease inhibitors (except tipranavir/ritonavir), telithromycin. 150 mg twice daily Noninteracting concomitant medications 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. 300 mg twice daily Potent and moderate CYP3A inducers (without a potent CYP3A inhibitor) Potent and moderate CYP3A inducers (without a potent CYP3A inhibitor) including: carbamazepine, efavirenz, etravirine, phenobarbital, phenytoin, and rifampin. 600 mg twice daily

2.4 Recommended Dosage in Pediatric Patients with Normal Renal Function The recommended dosage of Maraviroc 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) <span class="opacity-50 text-xs">[see Drug Interactions (7.1) , Use in Specific Populations (8.4) ]</span>. 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 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) Potent CYP3A inhibitors (with or without a CYP3A inducer) including: clarithromycin, cobicistat, elvitegravir/ritonavir, itraconazole, ketoconazole, nefazodone, protease inhibitors (except tipranavir/ritonavir), telithromycin. 50 mg twice daily 50 mg twice daily 75 mg twice daily 100 mg twice daily 150 mg twice daily Noninteracting concomitant medications 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. 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) Potent and moderate CYP3A inducers (without a potent CYP3A inhibitor) including: carbamazepine, efavirenz, etravirine, phenobarbital, phenytoin, and rifampin. Not recommended Insufficient data are available to recommend use. The recommended oral dosage of maraviroc oral solution in pediatric patients weighing at least 10 kg is presented in Table 3.

Table

3.

Recommended

Dosage in Pediatric Patients Weighing at Least 10 kg (Oral Solution)

Concomitant Medications

Dosage (Volume of Solution) of Maraviroc 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) Potent CYP3A inhibitors (with or without a CYP3A inducer) including: clarithromycin, cobicistat, elvitegravir/ritonavir, itraconazole, ketoconazole, nefazodone, protease inhibitors (except tipranavir/ritonavir), telithromycin. 50 mg (2.5 mL) twice daily 50 mg (2.5 mL) twice daily 80 mg (4 mL) twice daily 100 mg (5 mL) twice daily 150 mg (7.5 mL) twice daily Noninteracting concomitant medications 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. 150 mg (7.5 mL) twice daily 200 mg (10 mL) twice daily 200 mg (10 mL) twice daily 300 mg (15 mL) twice daily 300 mg (15 mL) twice daily Potent and moderate CYP3A inducers (without a potent CYP3A inhibitor) Potent and moderate CYP3A inducers (without a potent CYP3A inhibitor) including: carbamazepine, efavirenz, etravirine, phenobarbital, phenytoin, and rifampin. Not recommended Insufficient data are available to recommend use. Administer the oral solution using the appropriate oral dosing syringe: for doses greater than 2.5 mL, use the 10-mL syringe.

2.5 Recommended Dosage in Patients with Renal Impairment Adult Patients Table 4 provides dosing recommendations for patients based on renal function and concomitant medications.

Table

4.

Recommended

Dosage in Adults Based on Renal Function Concomitant Medications Dosage of Maraviroc Based on Renal Function Normal (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 Hemodialysis Potent CYP3A inhibitors (with or without a CYP3A inducer) Potent CYP3A inhibitors (with or without a CYP3A inducer) including: clarithromycin, cobicistat, elvitegravir/ritonavir, itraconazole, ketoconazole, nefazodone, protease inhibitors (except tipranavir/ritonavir), telithromycin. 150 mg twice daily 150 mg twice daily 150 mg twice daily Contraindicated Contraindicated Noninteracting concomitant medications 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. 300 mg twice daily 300 mg twice daily 300 mg twice daily 300 mg twice daily 300 mg twice daily Dosage of Maraviroc 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 a potent CYP3A inhibitor) Potent and moderate CYP3A inducers (without a potent CYP3A inhibitor) including: carbamazepine, efavirenz, etravirine, phenobarbital, phenytoin, and rifampin. 600 mg twice daily 600 mg twice daily 600 mg twice daily Contraindicated Contraindicated CrCl = Creatinine Clearance.

Pediatric Patients

There are no data to recommend specific doses of Maraviroc in pediatric patients with mild or moderate renal impairment [see Use in Specific Populations (8.6) ] . Additionally, Maraviroc 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) ].

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 )

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 displayed.

Table

5.

Selected

Treatment-Emergent Adverse Events (All Causality) ≥2% on SELZENTRY (and at a Higher Rate Compared with Placebo) in Trials A4001027 and A4001028 (Pooled Analysis, 48 Weeks) a 300-mg dose equivalent. b PYE = Patient-years of exposure.

Selzentry

Twice Daily a Placebo Body System/ Adverse Event (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 and symptoms 7 10 3 5 Muscle pains 3 4 0.5 1 Neoplasms Benign, Malignant, and Unspecified Skin neoplasms benign 3 4 1 3 Nervous System Disorders Dizziness/postural dizziness 9 13 8 17 Paresthesias and dysesthesias 5 7 3 6 Sensory abnormalities 4 6 1 3 Disturbances in consciousness 4 5 3 6 Peripheral neuropathies 4 5 3 6 Psychiatric Disorders Disturbances in initiating and maintaining sleep 8 11 5 10 Depressive disorders 4 6 3 5 Anxiety symptoms 4 5 3 7 Renal and Urinary Disorders Bladder and urethral symptoms 5 7 1 3 Urinary tract signs and symptoms 3 4 1 3 Respiratory, Thoracic, and Mediastinal Disorders Coughing and associated symptoms 14 21 5 10 Upper respiratory tract signs and symptoms 6 9 3 6 Nasal congestion and inflammations 4 6 3 5 Breathing abnormalities 4 5 2 5 Paranasal sinus disorders 3 4 0.5 1 Skin and Subcutaneous Tissue Disorders Rash 11 16 5 11 Apocrine and eccrine gland disorders 5 7 4

7.5 Pruritus 4 5 2 4 Lipodystrophies 3 5 0.5 1 Erythema 2 3 1 2 Vascular Disorders Vascular hypertensive disorders 3 4 2 4 Laboratory Abnormalities: Table 6 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. a Percentages based on total subjects evaluated for each laboratory parameter.

Laboratory Parameter Preferred Term

Limit SELZENTRY Twice Daily + OBT (n = 421) a % Placebo + OBT (n = 207) a % Aspartate aminotransferase >5.0 x ULN 4.8

2.9 Alanine aminotransferase &gt;5.0 x ULN 2.6

3.4 Total bilirubin &gt;2.5 x ULN 5.5

5.3 Amylase &gt;2.0 x ULN 5.7

5.8 Lipase &gt;2.0 x ULN 4.9

6.3 Absolute neutrophil count &lt;750/mm 3 4.3

2.4 Treatment ‑ Naive Subjects: Treatment - Emergent Adverse Events: Treatment-emergent adverse events, regardless of causality, from Trial A4001026, a 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 a 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 a Higher Rate Compared with Efavirenz) in Trial A4001026 (96 Weeks)

Body

System/ Adverse Event SELZENTRY 300 mg Twice Daily + Lamivudine/Zidovudine (n = 360) % Efavirenz 600 mg Once Daily + Lamivudine/Zidovudine (n = 361) % Blood and Lymphatic System Disorders Anemias NEC 8 5 Neutropenias 4 3 Ear and Labyrinth Disorders Ear disorders NEC 3 2 Gastrointestinal Disorders Flatulence, bloating, and distention 10 7 Gastrointestinal atonic and hypomotility disorders NEC 9 5 Gastrointestinal signs and symptoms NEC 3 2 General Disorders and Administration Site Conditions Body temperature perception 3 1 Infections and Infestations Upper respiratory tract infection 32 30 Bronchitis 13 9 Herpes infection 7 6 Bacterial infections NEC 6 3 Herpes zoster /varicella 5 4 Tinea infections 4 3 Lower respiratory tract and lung infections 3 2 Neisseria infections 3 0 Viral infections NEC 3 2 Musculoskeletal and Connective Tissue Disorders Joint-related signs and symptoms 6 5 Nervous System Disorders Paresthesias and dysesthesias 4 3 Memory loss (excluding dementia) 3 1 Renal and Urinary Disorders Bladder and urethral symptoms 4 3 Reproductive System and Breast Disorders Erection and ejaculation conditions and disorders 3 2 Respiratory, Thoracic, and Mediastinal Disorders Upper respiratory tract signs and symptoms 9 5 Skin and Subcutaneous Disorders Nail and nail bed conditions (excluding infections and infestations) 6 2 Lipodystrophies 4 3 Acnes 3 2 Alopecias 2 1 Laboratory 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. a n = Total number of subjects evaluable for laboratory abnormalities. Percentages based on total subjects evaluated for each laboratory parameter. If the same subject in a given treatment group had greater than 1 occurrence of the same abnormality, only the most severe is counted.

Laboratory Parameter Preferred Term

Limit SELZENTRY 300 mg Twice Daily + Lamivudine/Zidovudine (n = 353) a % Efavirenz 600 mg Once Daily+ Lamivudine/Zidovudine (n = 350) a % Aspartate aminotransferase >5.0 x ULN 4.0

4.0 Alanine aminotransferase &gt;5.0 x ULN 3.9

4.0 Creatine kinase &gt;10.0 x ULN 3.9

4.8 Amylase &gt;2.0 x ULN 4.3

6.0 Absolute neutrophil count &lt;750/mm 3 5.7

4.9 Hemoglobin &lt;7.0 g/dL 2.9

2.3 Less Common Adverse Events in Clinical Trials: The following adverse events occurred in less than 2% of subjects treated with SELZENTRY or at a 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, Bowen’s disease, cholangiocarcinoma, diffuse large B-cell lymphoma, lymphoma, metastases to liver, esophageal carcinoma, nasopharyngeal carcinoma, squamous cell carcinoma, squamous cell carcinoma of skin, tongue neoplasm (malignant stage unspecified), anaplastic large cell lymphomas T- and null-cell types, bile duct neoplasms malignant, endocrine neoplasms malignant and unspecified.

Nervous System

Disorders: Cerebrovascular accident, convulsions and epilepsy, tremor (excluding congenital), facial palsy, hemianopia, loss of consciousness, visual field defect.

Clinical Trials

Experience in Pediatric Subjects HIV-1–Infected Pediatric Subjects: Trial A4001031 is an open-label trial in which 103 treatment-experienced, CCR5-tropic, HIV-1–infected pediatric subjects aged 2 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 3 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

1 received 2 single doses of SELZENTRY: the first within 3 days of birth and the second at 7 to 14 days of age.

Cohort

2 received SELZENTRY twice daily for 6 weeks beginning within 3 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 a 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 3 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 a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and Subcutaneous Tissue Disorders Stevens‑Johnson syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), toxic epidermal necrolysis (TEN).

AND PRECAUTIONS

• Hepatotoxicity 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 B and/or C virus, additional monitoring may be warranted. ( 5.1 )
• Severe 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 )
• More cardiovascular events, including myocardial ischemia and/or infarction, were observed in treatment-experienced subjects who received SELZENTRY. Additional monitoring may be warranted. ( 5.3 )
• If 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> . These events occurred approximately 1 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 B and/or C 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) <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> . 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 a 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 3 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, 3 subjects (0.8%) who received SELZENTRY had events related to ischemic heart disease and 5 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 a greater frequency than in placebo. However, when SELZENTRY was given at the recommended dose in HIV-1–infected adult subjects in Phase 3 trials, postural hypotension was seen at a 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 Impairment An 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 a 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-Barré 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 C infections, were comparable in the treatment groups during the Phase 3 adult treatment‑experienced trials of SELZENTRY. While there was a higher rate of certain upper respiratory tract infections reported in the treatment arm receiving SELZENTRY compared with placebo (23% versus 13%), there was a lower rate of pneumonia (2% versus 5%) reported in subjects receiving SELZENTRY. A 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 C 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 drug’s 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.

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&apos;s wort ( Hypericum perforatum ) or products containing St. John&apos;s wort is not recommended. Coadministration of maraviroc with St. John&apos;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 ) ].