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 )
Contraindications
Maraviroc tablets are contraindicated in patients with severe renal impairment or ESRD (CrCl less than 30 mL per minute) who are concomitantly taking potent CYP3A inhibitors or inducers [ see Warnings and Precautions ( 5.3 ) ].
Maraviroc tablets are contraindicated in patients with severe renal impairment or end-stage renal disease (ESRD) (CrCl less than 30 mL per minute) who are concomitantly taking potent CYP3A inhibitors or inducers. ( 4 )
Warnings and precautions
Hepatotoxicity accompanied by severe rash or systemic allergic reaction, including potentially life-threatening events, has been reported. Hepatic laboratory parameters including ALT, AST, and bilirubin should be obtained prior to starting maraviroc tablets 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 maraviroc tablets 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 maraviroc. This includes cases of Stevens-Johnson syndrome, hypersensitivity reaction, and toxic epidermal necrolysis. Immediately discontinue maraviroc 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 maraviroc. Additional monitoring may be warranted. ( 5.3 )
If patients with severe renal impairment or ESRD receiving maraviroc (without concomitant CYP3A inducers or inhibitors) experience postural hypotension, the dose of maraviroc should be reduced from 300 mg twice daily to 150 mg twice daily. ( 5.3 )
5.1Hepatotoxicity Hepatotoxicity
with allergic features including life-threatening events has been reported in clinical trials and postmarketing. Severe rash or evidence of systemic allergic reaction including drug-related rash with fever, eosinophilia, elevated IgE, or other systemic symptoms have been reported in conjunction with hepatotoxicity [ see Warnings and Precautions ( 5.2 ) ]. These events occurred approximately 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 maraviroc 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 maraviroc 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 maraviroc 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 maraviroc have not been specifically studied in patients with significant underlying liver disorders.
5.2Severe Skin and Hypersensitivity Reactions
Severe, potentially life-threatening skin and hypersensitivity reactions have been reported in patients taking maraviroc, in most cases concomitantly with other drugs associated with these reactions. These include cases of Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) [ see Adverse Reactions (6.3) ]. The cases were characterized by features including rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure.
Discontinue maraviroc 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 maraviroc 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.
5.3Cardiovascular Events
Eleven subjects (1.3%) who received maraviroc 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 maraviroc once daily + 309 on maraviroc 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 maraviroc, and the relative contribution of maraviroc to these events is not known.
In the Phase 2b/3 trial in treatment-naive adult subjects, 3 subjects (0.8%) who received maraviroc 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 maraviroc and efavirenz, respectively). When maraviroc 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 maraviroc 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. Maraviroc 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 maraviroc 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 ) ].
5.4Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including maraviroc. 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.
5.5Potential Risk of Infection
Maraviroc 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 maraviroc. While there was a higher rate of certain upper respiratory tract infections reported in the treatment arm receiving maraviroc compared with placebo (23% versus 13%), there was a lower rate of pneumonia (2% versus 5%) reported in subjects receiving maraviroc.
A higher incidence of Herpes virus infections (11 per 100 patient-years) w
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
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 ).
7.1Effect 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 ) ].
Pregnancy and breastfeeding
8.1Pregnancy Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to maraviroc 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 maraviroc 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.
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.
6.1Clinical 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 Gastrointest
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Composition
Active ingredients
MARAVIROC 300MG
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
