Maraviroc Prescribing Information
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
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.
Maraviroc is indicated in combination with other antiretroviral agents for the treatment of only CCR5‑tropic human immunodeficiency virus type 1 (HIV‑1) infection in adult and pediatric patients 2 years of age and older weighing at least 10 kg.
- Maraviroc is not recommended in patients with dual/mixed- or CXCR4-tropic HIV- 1[see.]
12.4 MicrobiologyMechanism of ActionMaraviroc is a member of a therapeutic class called CCR5 co-receptor antagonists. Maraviroc selectively binds to the human chemokine receptor CCR5 present on the cell membrane, preventing the interaction of HIV-1 gp120 and CCR5 necessary for CCR5- tropic HIV-1 to enter cells. CXCR4-tropic and dual-tropic HIV-1 entry is not inhibited by maraviroc.
Antiviral Activity in Cell CultureMaraviroc inhibits the replication of CCR5-tropic laboratory strains and primary isolates of HIV-1 in models of acute peripheral blood leukocyte infection. The mean EC50value (50% effective concentration) for maraviroc against HIV-1 group M isolates (subtypes A to J and circulating recombinant form AE) and group O isolates ranged from 0.1 to 4.5 nM (0.05 to 2.3 ng per mL) in cell culture.
When used with other antiretroviral agents in cell culture, the combination of maraviroc was not antagonistic with non-nucleoside reverse transcriptase inhibitors (NNRTIs: efavirenz and nevirapine), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine), or protease inhibitors (PIs: amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir). Maraviroc was not antagonistic with the HIV-1 gp41 fusion inhibitor enfuvirtide. Maraviroc was not active against CXCR4-tropic and dual-tropic viruses (EC50value greater than 10 microM). The antiviral activity of maraviroc against HIV-2 has not been evaluated.
Resistance in Cell Culture:HIV-1 variants with reduced susceptibility to maraviroc have been selected in cell culture following serial passage of 2 CCR5-tropic viruses (CCl/85 and RU570). The maraviroc-resistant viruses remained CCR5-tropic with no evidence of a change from a CCR5-tropic virus to a CXCR4-using virus. Two amino acid residue substitutions in the V3-loop region of the HIV-1 envelope glycoprotein (gp160), A316T, and I323V (HXB2 numbering), were shown to be necessary for the maraviroc-resistant phenotype in the HIV-1 isolate CCl/85. In the RU570 isolate a 3-amino acid residue deletion in the V3 loop, QAI (HXB2 positions 315 to 317), was associated with maraviroc resistance. The relevance of the specific gp120 substitutions observed in maraviroc-resistant isolates selected in cell culture to clinical maraviroc resistance is not known. Maraviroc-resistant viruses were characterized phenotypically by concentration- response curves that did not reach 100% inhibition in phenotypic drug assays, rather than increases in EC50values.Cross-Resistance in Cell Culture:Maraviroc had antiviral activity against HIV‑1 clinical isolates resistant to NNRTIs, NRTIs, PIs, and the gp41 fusion inhibitor enfuvirtide in cell culture (EC50values ranged from 0.7 to 8.9 nM [0.36 to 4.57 ng per mL]). Maraviroc‑resistant viruses that emerged in cell culture remained susceptible to enfuvirtide and the protease inhibitor saquinavir.Clinical Resistance:Virologic failure on maraviroc can result from genotypic and phenotypic resistance to maraviroc, through outgrowth of undetected CXCR4-using virus present before maraviroc treatment (seeTropismbelow), through resistance to background therapy drugs (Table 15), or due to low exposure to maraviroc[see Clinical Pharmacology (12.2)].Antiretroviral Treatment-Experienced Adult Subjects (Trials A4001027 and A4001028):Week 48 data from treatment-experienced subjects failing maraviroc-containing regimens with CCR5-tropic virus (n = 58) have identified 22 viruses that had decreased susceptibility to maraviroc characterized in phenotypic drug assays by concentration- response curves that did not reach 100% inhibition. Additionally, CCR5-tropic virus from 2 of these treatment-failure subjects had greater than or equal to 3-fold shifts in EC50values for maraviroc at the time of failure.Fifteen of these viruses were sequenced in the gp120 encoding region and multiple amino acid substitutions with unique patterns in the heterogeneous V3 loop region were detected. Changes at either amino acid position 308 or 323 (HXB2 numbering) were seen in the V3 loop in 7 of the subjects with decreased maraviroc susceptibility. Substitutions outside the V3 loop of gp120 may also contribute to reduced susceptibility to maraviroc.
Antiretroviral Treatment-Naive Adult Subjects (Trial A4001026):Treatment-naive subjects receiving Maraviroc had more virologic failures and more treatment-emergent resistance to the background regimen drugs compared with those receiving efavirenz (Table 15).Table 15. Development of Resistance to Maraviroc or Efavirenz and Background Drugs in Antiretroviral Treatment-Naive Trial A4001026 for Patients with Only CCR5-Tropic Virus at Screening Using Enhanced Sensitivity TROFILE Assay MaravirocEfavirenzTotal N in dataset (as-treated) 273 241 Total virologic failures (as-treated) 85 (31%) 56 (23%) Evaluable virologic failures with post baseline genotypic and phenotypic data 73 43 Lamivudine resistance 39 (53%) 13 (30%) Zidovudine resistance 2 (3%) 0 Efavirenz resistance – 23 (53%) Phenotypic resistance to maraviroca 19 (26%) – aIncludes subjects failing with CXCR4- or dual/mixed-tropism because these viruses are not intrinsically susceptible to maraviroc. In an as‑treated analysis of treatment‑naive subjects at 96 weeks, 32 subjects failed a maraviroc‑containing regimen with CCR5‑tropic virus and had a tropism result at failure; 7 of these subjects had evidence of maraviroc phenotypic resistance defined as concentration‑response curves that did not reach 95% inhibition. One additional subject had a greater than or equal to 3‑fold shift in the EC50value for maraviroc at the time of failure. A clonal analysis of the V3 loop amino acid envelope sequences was performed from 6 of the 7 subjects. Changes in V3 loop amino acid sequence differed between each of these different subjects, even for those infected with the same virus clade, suggesting that there are multiple diverse pathways to maraviroc resistance. The subjects who failed with CCR5‑tropic virus and without a detectable maraviroc shift in susceptibility were not evaluated for genotypic resistance.
Of the 32 maraviroc virologic failures failing with CCR5‑tropic virus, 20 (63%) also had genotypic and/or phenotypic resistance to background drugs in the regimen (lamivudine, zidovudine).
Tropism:In both treatment‑experienced and treatment‑naive subjects, detection of CXCR4‑using virus prior to initiation of therapy has been associated with a reduced virologic response to maraviroc.Antiretroviral Treatment‑Experienced Subjects (Trials A4001027 and A4001028):In the majority of cases, treatment failure on maraviroc was associated with detection of CXCR4‑using virus (i.e., CXCR4- or dual/mixed‑tropic) which was not detected by the tropism assay prior to treatment. CXCR4‑using virus was detected at failure in approximately 55% of subjects who failed treatment on maraviroc by Week 48, as compared with 9% of subjects who experienced treatment failure in the placebo arm. To investigate the likely origin of the on‑treatment CXCR4‑using virus, a detailed clonal analysis was conducted on virus from 20 representative subjects (16 subjects from the maraviroc arms and 4 subjects from the placebo arm) in whom CXCR4‑using virus was detected at treatment failure. From analysis of amino acid sequence differences and phylogenetic data, it was determined that CXCR4‑using virus in these subjects emerged from a low level of pre-existing CXCR4‑using virus not detected by the tropism assay (which is population-based) prior to treatment rather than from a co-receptor switch from CCR5‑tropic virus to CXCR4‑using virus resulting from mutation in the virus.Detection of CXCR4‑using virus prior to initiation of therapy has been associated with a reduced virological response to maraviroc. Furthermore, subjects failing twice-daily maraviroc at Week 48 with CXCR4‑using virus had a lower median increase in CD4+ cell counts from baseline (+41 cells per mm3) than those subjects failing with CCR5‑tropic virus (+162 cell s per mm3). The median increase in CD4+ cell count in subjects failing in the placebo arm was +7 cell s per mm3.
Antiretroviral Treatment‑Naive Subjects (Trial A4001026):In a 96‑week trial of antiretroviral treatment‑naive subjects, 14% (12 of 85) who had only CCR5‑tropic virus at screening with an enhanced sensitivity tropism assay (TROFILE) and failed therapy on maraviroc had CXCR4‑using virus at the time of treatment failure. A detailed clonal analysis was conducted in 2 previously antiretroviral treatment‑naive subjects enrolled in a Phase 2a monotherapy trial who had CXCR4‑using virus detected after 10 days’ treatment with maraviroc. Consistent with the detailed clonal analysis conducted in treatment‑experienced subjects, the CXCR4‑using variants appear to emerge from outgrowth of a pre‑existing undetected CXCR4‑using virus. Screening with an enhanced sensitivity tropism assay reduced the number of maraviroc virologic failures with CXCR4- or dual/mixed‑tropic virus at failure to 12 compared with 24 when screening with the original tropism assay. All but one (11 of 12; 92%) of the maraviroc failures failing with CXCR4- or dual/mixed‑tropic virus also had genotypic and phenotypic resistance to the background drug lamivudine at failure and 33% (4 of 12) developed zidovudine-associated resistance substitutions.Subjects who had only CCR5‑tropic virus at baseline and failed maraviroc therapy with CXCR4‑using virus had a median increase in CD4+ cell counts from baseline of +113 cells per mm3while those subjects failing with CCR5‑tropic virus had an increase of +135 cells per mm3. The median increase in CD4+ cell count in subjects failing in the efavirenz arm was +95 cells per mm3.
Antiretroviral Treatment‑Experienced Pediatric Subjects (Trial A4001031):In the Week 48 analysis of Trial A4001031 (n = 103), the mechanisms of resistance to maraviroc observed in the treatment-experienced pediatric population were similar to those observed in adult populations: reasons for virologic failure included failing with CXCR4- or dual/mixed-tropic virus, evidence of reduced maraviroc susceptibility as measured by a decrease in maximal percentage inhibition (MPI), and emergence of resistance to background drug in the regimen.
Table 4 provides dosing recommendations for patients based on renal function and concomitant medications.
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 |
| 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. | |||||
There are no data to recommend specific doses of Maraviroc in pediatric patients with mild or moderate renal impairment
Recommended doses of Maraviroc for adult patients with impaired renal function (CrCl less than or equal to 80 mL per minute) are based on the results of a pharmacokinetic trial conducted in healthy adult subjects with various degrees of renal impairment. Maraviroc has not been studied in pediatric patients with renal impairment. There are no data to recommend specific doses of Maraviroc in pediatric patients with mild to moderate renal impairment
The pharmacokinetics of maraviroc in adult subjects with mild and moderate renal impairment was similar to that in subjects with normal renal function
If adult patients with severe renal impairment or ESRD not receiving a concomitant potent CYP3A inhibitor or inducer experience any symptoms of postural hypotension while taking Maraviroc 300 mg twice daily, the dose should be reduced to 150 mg twice daily. No trials have been performed in subjects with severe renal impairment or ESRD co-treated with potent CYP3A inhibitors or inducers. Hence, no dose of Maraviroc can be recommended, and Maraviroc is contraindicated for these patients
Maraviroc 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
Maraviroc 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.
Tablets:
- 150-mg blue, oval, film-coated tablets, debossed “I3” on one side and “24” on the other side.
- 300-mg blue, oval, film-coated tablets, debossed “I3” on one side and “25” on the other side.
Maraviroc 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
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.
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
The following adverse reactions are discussed in other sections of the labeling:
- Hepatotoxicity[see]
5.1 HepatotoxicityHepatotoxicity 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.
- Severe Skin and Hypersensitivity Reactions[see]
5.2 Severe Skin and Hypersensitivity ReactionsSevere, 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 (6.2)]. 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. - Cardiovascular Events[see]
5.3 Cardiovascular EventsEleven 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 ImpairmentAn 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)].