Maraviroc

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 d a Potent CYP3A inhibitors (with or without a CYP3A inducer) including: clarithromycin, cobicistat, elvitegravir/ritonavir, itraconazole, ketoconazole, nefazodone, protease inhibitors (except tipranavir/ritonavir), telithromycin. b 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. c Potent and moderate CYP3A inducers (without a potent CYP3A inhibitor) including: carbamazepine, efavirenz, etravirine, phenobarbital, phenytoin, and rifampin. d 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 Concomitant Medications Dosage (Volume of Solution) 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 (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 c 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) d Not recommended d a PotentCYP3A inhibitors(with or without a CYP3A inducer) including:clarithromycin, cobicistat,elvitegravir/ritonavir, itraconazole,ketoconazole,nefazodone,proteaseinhibitors (excepttipranavir/ritonavir), telithromycin. b Insufficient data areavailable to recommend use. c Noninteractingconcomitantmedicationsincluding all medicationsthatare not potent CYP3A inhibitorsor inducers such as: dolutegravir, enfuvirtide,nevirapine, all NRTIs,raltegravir, and tipranavir/ritonavir. d Potent and moderateCYP3A inducers (without a potent CYP3A inhibitor)including: carbamazepine,efavirenz,etravirine, phenobarbital,phenytoin, and rifampin. Administer the oral solution using the included press-in bottle adapter and the appropriate oral dosing syringe: for doses of 2.5 mL, use the 3-mL syringe; for doses greater than 2.5 mL, use the 10-mL syringe. 2.5 Recommended Dosage in Patients with Renal Impairment Adult 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 Tablets 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) a 150 mg twice daily 150 mg twice daily 150 mg twice daily Contraindicated Contraindicated Noninteracting concomitant medications b 300 mg twice daily 300 mg twice daily 300 mg twice daily 300 mg twice daily 300 mg twice daily c Potent and moderate CYP3A inducers (without a potent CYP3A inhibitor) d 600 mg twice daily 600 mg twice daily 600 mg twice daily Contraindicated Contraindicated a Potent CYP3A inhibitors (with or without a 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 NRTIs, raltegravir, and tipranavir/ritonavir. c Dosage of maraviroc tablets should be reduced to 150 mg twice daily if there are any symptoms of postural hypotension [ see Contraindications ( 4 ) , Warnings and Precautions ( 5.3 )] . d Potent and moderate CYP3A inducers (without a potent CYP3A inhibitor) including: carbamazepine, efavirenz, etravirine, phenobarbital, phenytoin, and rifampin. Pediatric Patients There are no data to recommend specific doses of maraviroc tablets in pediatric patients with mild or moderate renal impairment [ see Use in Specific Populations ( 8.6 ) ]. Additionally, maraviroc tablets are contraindicated for pediatric patients with severe renal impairment or end-stage renal disease (ESRD) on regular hemodialysis who are receiving potent CYP3A inhibitors or inducers [ see Contraindications ( 4 ) ].

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 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 a 300-mg dose equivalent. b PYE = Patient-years of exposure. Laboratory Abnormalities: Table 6 shows the treatment-emergent Grade 3 to 4 laboratory abnormalities that occurred in greater than 2% of subjects receiving maraviroc. Table 6. Maximum Shift in Laboratory Test Values (without Regard to Baseline) ≥2% of Grade 3 to 4 Abnormalities (ACTG Criteria) in Trials A4001027 and A4001028 (Pooled Analysis, 48 Weeks) Laboratory Parameter Preferred Term Limit Maraviroc Twice Daily + OBT (n = 421) a % Placebo + OBT (n = 207) a % Aspartate aminotransferase >5.0 x ULN 4.8 2.9 Alanine aminotransferase >5.0 x ULN 2.6 3.4 Total bilirubin >2.5 x ULN 5.5 5.3 Amylase >2.0 x ULN 5.7 5.8 Lipase >2.0 x ULN 4.9 6.3 Absolute neutrophil count <750/mm 3 4.3 2.4 ULN = Upper limit of normal. a Percentages based on total subjects evaluated for each laboratory parameter. Treatment-Naive Subjects: Treatment-Emergent Adverse Events: Treatment-emergent adverse events, regardless of causality, from Trial A4001026, a double-blind, comparative, controlled trial in which 721 treatment-naive subjects received maraviroc 300 mg twice daily (n = 360) or efavirenz 600 mg once daily (n = 361) in combination with lamivudine/zidovudine (COMBIVIR) for 96 weeks, are summarized in Table 7. Selected events occurring in greater than or equal to 2% of subjects and at a numerically higher rate in subjects treated with maraviroc are included; events that occurred at the same or higher rate on efavirenz are not displayed. Table 7. Selected Treatment-Emergent Adverse Events (All Causality) ≥2% on maraviroc (and at a Higher Rate Compared with Efavirenz) in Trial A4001026 (96 Weeks) Body System/ Adverse Event Maraviroc tablets 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 Parasthesias and dyesthesias 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 to 4 Abnormalities (ACTG Criteria) in Trial A4001026 (96 Weeks) Laboratory Parameter Preferred Term Limit Maraviroc 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 >5.0 x ULN 3.9 4.0 Creatine kinase >10.0 x ULN 3.9 4.8 Amylase >2.0 x ULN 4.3 6.0 Absolute neutrophil count <750/mm 3 5.7 4.9 Hemoglobin <7.0 g/dL 2.9 2.3 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. Less Common Adverse Events in Clinical Trials: The following adverse events occurred in less than 2% of subjects treated with maraviroc or at a rate similar to the comparator. These events have been included because of their seriousness and either increased frequency on maraviroc or are potential risks due to the mechanism of action. Events attributed to the subject’s underlying HIV-1 infection are not listed. Blood and Lymphatic System: Marrow depression and hypoplastic anemia. Cardiac Disorders: Unstable angina, acute cardiac failure, coronary artery disease, coronary artery occlusion, myocardial infarction, myocardial ischemia. Hepatobiliary Disorders: Hepatic cirrhosis, hepatic failure, cholestatic jaundice, portal vein thrombosis, jaundice. Infections and Infestations : Endocarditis, infective myositis, viral meningitis, pneumonia, treponema infections, septic shock, Clostridium difficile colitis, meningitis. Musculoskeletal and Connective Tissue Disorders: Myositis, osteonecrosis, rhabdomyolysis, blood CK increased. Neoplasms Benign, Malignant, and Unspecified (Including Cysts and Polyps): Abdominal neoplasm, anal cancer, basal cell carcinoma, 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 maraviroc twice daily in combination with OBT. The dose of maraviroc was based on body surface area (BSA) and on whether the subject was receiving potent CYP3A inhibitors and/or inducers. The median duration of therapy with maraviroc was 131 weeks with 72% of subjects receiving study treatment for greater than 48 weeks and 62% of subjects receiving study treatment for 96 weeks. In these 103 children and adolescents, the safety profile through 96 weeks was similar to that for adults. Most of the adverse reactions reported were mild to moderate; severe (Grade 3 and 4) adverse reactions occurred in 2% of subjects. The most common adverse reactions (all grades) reported with twice-daily therapy with maraviroc were vomiting (12%), abdominal pain (4%), diarrhea (4%), nausea (4%), and dizziness (3%). Three subjects (3%) discontinued due to adverse events. Maraviroc-related gastrointestinal adverse events through 48 weeks (nausea, vomiting, diarrhea, constipation, and abdominal pain/cramps) were observed more commonly in subjects who received the maraviroc oral solution (21%) compared with those who received maraviroc tablets (16%). Subjects were permitted to change formulations after Week 48. 6.2 Postmarketing Experience The following adverse events have been identified during post-approval use of maraviroc. Because these reactions are reported voluntarily from 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).

12.3 Pharmacokinetics Table 11. Mean Maraviroc Pharmacokinetic Parameters in Adults Patient Population Maraviroc Dose n AUC 12 (ng.h/mL) C max (ng/mL) C min (ng/mL) Healthy volunteers (Phase 1) 300 mg twice daily 64 2,908 888 43.1 Asymptomatic HIV subjects (Phase 2a) 300 mg twice daily 8 2,550 618 33.6 Treatment-experienced HIV subjects (Phase 3) a 300 mg twice daily 94 1,513 266 37.2 150 mg twice daily (+ CYP3A inhibitor) 375 2,463 332 101 Treatment-naiveHIV subjects (Phase 2b/3) a 300 mg twice daily 344 1,865 287 60 a The estimated exposure is lower compared with other trials possibly due to sparse sampling, food effect, compliance, and concomitant medications. Absorption Peak maraviroc plasma concentrations are attained 0.5 to 4 hours following single oral doses of 1 to1,200 mg administered to uninfected volunteers. The pharmacokinetics of oral maraviroc are not dose proportional over the dose range. The absolute bioavailability of a 100-mg dose is 23% and is predicted to be 33% at 300 mg. Maraviroc is a substrate for the efflux transporter P-gp. Effect of Food on Oral Absorption: Coadministration of a 300-mg tablet with a high-fat breakfast reduced maraviroc C max and AUC by 33% and coadministration of 75 mg of oral solution with a high-fat breakfast reduced maraviroc AUC by 73% in healthy adult volunteers. Studies with the tablet formulation demonstrated a 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 ) ]. Distribution Maraviroc is bound (approximately 76%) to human plasma proteins, and shows moderate affinity for albumin and alpha-1 acid glycoprotein. The volume of distribution of maraviroc is approximately 194 L. Elimination Metabolism : Trials in humans and in vitro studies using human liver microsomes and expressed enzymes have demonstrated that maraviroc is principally metabolized by the cytochrome P450 system to metabolites that are essentially inactive against HIV-1. In vitro studies indicate that CYP3A is the major enzyme responsible for maraviroc metabolism. In vitro studies also indicate that polymorphic enzymes CYP2C9, CYP2D6, and CYP2C19 do not contribute significantly to the metabolism of maraviroc. Maraviroc is the major circulating component (~42% drug-related radioactivity) following a single oral dose of 300 mg [ 14 C]-maraviroc. The most significant circulating metabolite in humans is a 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. A mass balance/excretion trial was conducted using a single 300-mg dose of 14 C-labeled maraviroc. Approximately 20% of the radiolabel was recovered in the urine and 76% was recovered in the feces over 168 hours. Maraviroc was the major component present in urine (mean of 8% dose) and feces (mean of 25% dose). The remainder was excreted as metabolites. Specific Populations Patients with Hepatic Impairment: Maraviroc is primarily metabolized and eliminated by the liver. A trial compared the pharmacokinetics of a single 300-mg dose of maraviroc in subjects with mild (Child-Pugh Class A, n = 8) and moderate (Child-Pugh Class B, n = 8) hepatic impairment with pharmacokinetics in healthy subjects (n = 8). The mean C max and AUC were 11% and 25% higher, respectively, for subjects with mild hepatic impairment, and 32% and 46% higher, respectively, for subjects with moderate hepatic impairment compared with subjects with normal hepatic function. These changes do not warrant a dose adjustment. Maraviroc concentrations are higher when maraviroc 150 mg is administered with a potent CYP3A inhibitor compared with following administration of 300 mg without a CYP3A inhibitor, so patients with moderate hepatic impairment who receive maraviroc 150 mg with a 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: A trial compared the pharmacokinetics of a single 300-mg dose of maraviroc in adult subjects with severe renal impairment (CrCl less than 30 mL per minute, n = 6) and ESRD (n = 6) with healthy volunteers (n = 6). Geometric mean ratios for maraviroc C max and AUC inf were 2.4-fold and 3.2-fold higher, respectively, for subjects with severe renal impairment, and 1.7-fold and 2.0-fold higher, respectively, for subjects with ESRD as compared with subjects with normal renal function in this trial. Hemodialysis had a minimal effect on maraviroc clearance and exposure in subjects with ESRD. Exposures observed in subjects with severe renal impairment and ESRD were within the range observed in previous 300-mg single-dose trials of maraviroc in healthy volunteers with normal renal function. However, maraviroc exposures in the subjects with normal renal function in this trial were 50% lower than those observed in previous trials. Based on the results of this trial, no dose adjustment is recommended for patients with renal impairment receiving maraviroc without a potent CYP3A inhibitor or inducer. However, if patients with severe renal impairment or ESRD experience any symptoms of postural hypotension while taking maraviroc 300 mg twice daily, their dose should be reduced to 150 mg twice daily [ see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.3 ) ]. In addition, the trial compared the pharmacokinetics of multiple-dose maraviroc in combination with saquinavir/ritonavir 1,000/100 mg twice daily (a potent CYP3A inhibitor combination) for 7 days in subjects with mild renal impairment (CrCl greater than 50 and less than or equal to 80 mL per minute, n = 6) and moderate renal impairment (CrCl greater than or equal to 30 and less than or equal to 50 mL per minute, n = 6) with healthy volunteers with normal renal function (n = 6). Subjects received 150 mg of maraviroc at different dose frequencies (healthy volunteers – every 12 hours; mild renal impairment – every 24 hours; moderate renal impairment – every 48 hours). Compared with healthy volunteers (dosed every 12 hours), geometric mean ratios for maraviroc AUC tau , C max and C min were 50% higher, 20% higher, and 43% lower, respectively, for subjects with mild renal impairment (dosed every 24 hours). Geometric mean ratios for maraviroc AUC tau , C max and C min were 16% higher, 29% lower, and 85% lower, respectively, for subjects with moderate renal impairment (dosed every 48 hours) compared with healthy volunteers (dosed every 12 hours). Based on the data from this trial, no adjustment in dose is recommended for patients with mild or moderate renal impairment [ see Dosage and Administration ( 2.3 ) ]. Pediatric Patients: Aged 2 to Less Than 18 Years : The pharmacokinetics of maraviroc were evaluated in CCR5-tropic, HIV-1–infected, treatment-experienced pediatric subjects aged 2 to less than 18 years. In the dose-finding stage of Trial A4001031, doses were administered with food on intensive pharmacokinetic evaluation days and optimized to achieve an average concentration over the dosing interval (C avg ) of greater than 100 ng per mL. Throughout the trial, on non-intensive pharmacokinetic evaluation days maraviroc was taken with or without food. The initial dose of maraviroc was based on BSA and concomitant medication category (i.e., presence of CYP3A inhibitors and/or inducers). The conversion of dosing to a 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 2 to less than 18 years receiving potent CYP3A inhibitors with or without a potent CYP3A inducer were similar to those observed in adults (Table 12). Table 12. Maraviroc Pharmacokinetic Parameters in Treatment-Experienced Pediatric Patients Receiving Maraviroc with Potent CYP3A Inhibitors (with or without a Potent CYP3A Inducer) Weight Dose of Maraviroc Maraviroc Pharmacokinetic Parameter a Geometric Mean AUC 12 (ng.h/mL) C avg (ng/mL) C max (ng/mL) C min (ng/mL) 10 kg to <20 kg 50 mg twice daily 2,349 196 324 78 20 kg to <30 kg 75 mg twice daily 3,020 252 394 118 30 kg to <40 kg 100 mg twice daily 3,229 269 430 126 ≥40 kg 150 mg twice daily 4,044 337 563 152 a Model-predicted steady-state pharmacokinetic parameters are presented . Aged from Birth to Less Than 6 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 6 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 7 days, and 25 neonates received maraviroc twice daily up to 6 weeks of age without exposure to potent CYP3A inhibitors and/or inducers. Maraviroc pharmacokinetic parameters in neonates weighing at least 2 kg at birth (Table 13) were similar to those observed in adults. Exposure to maternal efavirenz both in utero (for a minimum of 2 weeks immediately prior to delivery) and after birth while breastfeeding did not have a meaningful impact on maraviroc pharmacokinetic parameters. Table 13. Maraviroc Pharmacokinetic Parameters in Full-Term Neonates (Birth Up to 6 Weeks of Age) Receiving Maraviroc with Noninteracting Concomitant Medications a Pharmacokinetic Sampling Time n Median Dose (range) Maraviroc Pharmacokinetic Parameter Geometric Mean AUC 12 (ng.h/mL) C avg (ng/mL) C max (ng/mL) C min (ng/mL) Day 1 13 30 mg (20 to 40 mg) single dose 3,510 b 292 380 - Week 1 25 25 mg (20 to 30 mg) twice daily 1,216 101 262 23 Week 4 25 30 mg (20 to 40 mg) twice daily 1,385 115 295 43 a Noninteracting concomitant medications include all medications that are not potent CYP3A inhibitors or inducers. b AUCinf calculated for single-dose pharmacokinetics. Clinical pharmacokinetic data with maraviroc in pediatric patients aged older than 6 weeks to less than 2 years are not available and clinical pharmacokinetic data in pediatric patients aged 2 to less than 18 years receiving noninteracting concomitant medications are limited. Based on population pharmacokinetic modeling and simulation, the recommended dosing regimen of maraviroc for this population is predicted to result in similar maraviroc exposures when compared with exposures achieved in adults receiving maraviroc 300 mg twice daily (with noninteracting concomitant medications) [see Dosage and Administration ( 2.4 )]. Geriatric Patients: Pharmacokinetics of maraviroc have not been fully evaluated in the elderly (aged 65 years and older). Based on population pharmacokinetic analyses, age did not have a 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 2 clinical CYP3A5 genotype analyses for race, no dosage adjustment is recommended based on race or gender. Drug Interaction Studies Effect of Concomitant Drugs on the Pharmacokinetics of Maraviroc: Maraviroc is a 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 C max and AUC of maraviroc (Table 14). The CYP3A and/or P-gp inducers rifampin, etravirine, and efavirenz decreased the Cmax and AUC of maraviroc (Table 14). While not studied, potent CYP3A and/or P-gp inducers carbamazepine, phenobarbital, and phenytoin are expected to decrease maraviroc concentrations. Based on in vitro study results, maraviroc is also a 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 Maraviroc Coadministered Drug and Dose n Dose of maraviroc Ratio (90% CI) of Maraviroc Pharmacokinetic Parameters with/without Coadministered Drug (No Effect = 1.00) C min AUC tau C max CYP3A and/or P-gp Inhibitors Ketoconazole 400 mg q.d. 12 100 mg b.i.d. 3.75 (3.01, 4.69) 5.00 (3.98, 6.29) 3.38 (2.38, 4.78) Ritonavir 100 mg b.i.d. 8 100 mg b.i.d. 4.55 (3.37, 6.13) 2.61 (1.92, 3.56) 1.28 (0.79, 2.09) Saquinavir (soft gel capsules) /ritonavir 1,000 mg/100 mg b.i.d. 11 100 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. 11 300 mg b.i.d. 9.24 (7.98, 10.7) 3.95 (3.43, 4.56) 1.97 (1.66, 2.34) Atazanavir 400 mg q.d. 12 300 mg b.i.d. 4.19 (3.65, 4.80) 3.57 (3.30, 3.87) 2.09 (1.72, 2.55) Atazanavir/ritonavir 300 mg/100 mg q.d. 12 300 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. 12 150 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. 11 150 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 Inducers Efavirenz 600 mg q.d. 12 100 mg b.i.d. 0.55 (0.43, 0.72) 0.55 (0.49, 0.62) 0.49 (0.38, 0.63) Efavirenz 600 mg q.d. 12 200 mg b.i.d. (+ efavirenz): 100 mg b.i.d. (alone) 1.09 (0.89, 1.35) 1.15 (0.98, 1.35) 1.16 (0.87, 1.55) Rifampicin 600 mg q.d. 12 100 mg b.i.d. 0.22 (0.17, 0.28) 0.37 (0.33, 0.41) 0.34 (0.26, 0.43) Rifampicin 600 mg q.d. 12 200 mg b.i.d. (+ rifampicin): 100 mg b.i.d. (alone) 0.66 (0.54, 0.82) 1.04 (0.89, 1.22) 0.97 (0.72, 1.29) Etravirine 200 mg b.i.d. 14 300 mg b.i.d. 0.61 (0.53, 0.71) 0.47 (0.38, 0.58) 0.40 (0.28, 0.57) Nevirapine a 200 mg b.i.d. (+ lamivudine 150 mg b.i.d., tenofovir 300 mg q.d.) 8 300 mg single dose - 1.01 (0.65, 1.55) 1.54 (0.94, 2.51) CYP3A and/or P-gp Inhibitors and Inducers Lopinavir/ritonavir + efavirenz 400 mg/100 mg b.i.d. + 600 mg q.d. 11 300 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. 11 100 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. 10 150 mg b.i.d. 5.27 (4.51, 6.15) 3.10 (2.57, 3.74) 1.77 (1.20, 2.60) Fosamprenavir/ritonavir 700 mg/100 mg b.i.d. 14 300 mg b.i.d. 4.74 (4.03, 5.57) 2.49 (2.19, 2.82) 1.52 (1.27, 1.82) Fosamprenavir/ritonavir 1,400 mg/100 mg q.d. 14 300 mg q.d. 1.80 (1.53, 2.13) 2.26 (1.99, 2.58) 1.45 (1.20, 1.74) Tipranavir/ritonavir 500 mg/200 mg b.i.d. 12 150 mg b.i.d. 1.80 (1.55, 2.09) 1.02 (0.85, 1.23) 0.86 (0.61, 1.21) Other Raltegravir 400 mg b.i.d. 17 300 mg b.i.d. 0.90 (0.85, 0.96) 0.86 (0.80, 0.92) 0.79 (0.67, 0.94) a Compared with historical data. Effect of Maraviroc on the Pharmacokinetics of Concomitant Drugs : Maraviroc is unlikely to inhibit the metabolism of coadministered drugs metabolized by the following cytochrome P 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 a 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 C min and AUC of amprenavir by 36% and 35%, respectively. Coadministration of fosamprenavir 1,400 mg/ritonavir 100 mg once daily and maraviroc 300 mg once daily decreased the C min and AUC of amprenavir by 15% and 30%, respectively. No dosage adjustment is necessary when maraviroc tablets are dosed 150 mg twice daily in combination with fosamprenavir/ritonavir dosed once or twice daily. Fosamprenavir should be given with ritonavir when coadministered with maraviroc tablets. Maraviroc had no significant effect on the pharmacokinetics of elvitegravir, zidovudine, or lamivudine. Maraviroc decreased the C min and AUC of raltegravir by 27% and 37%, respectively, which is not clinically significant. Maraviroc had no clinically relevant effect on the pharmacokinetics of midazolam, the oral contraceptives ethinylestradiol and levonorgestrel, no effect on the urinary 6β-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 μM. 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.