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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 [see Severe Skin and Hypersensitivity Reactions as follows]. 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 CELSENTRI 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 CELSENTRI 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 CELSENTRI to patients with pre-existing liver dysfunction or who are coinfected with hepatitis B and/or C virus, additional monitoring may be warranted. The safety and efficacy of CELSENTRI have not been specifically studied in patients with significant underlying liver disorders.
Severe Skin and Hypersensitivity Reactions: Severe, potentially life-threatening skin and hypersensitivity reactions have been reported in patients taking CELSENTRI, 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 Postmarketing Experience under Adverse Reactions]. The cases were characterized by features including rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure. Discontinue CELSENTRI 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 CELSENTRI 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: Eleven subjects (1.3%) who received CELSENTRI 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 CELSENTRI once daily + 309 on CELSENTRI 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 CELSENTRI, and the relative contribution of CELSENTRI to these events is not known.
In the Phase 2b/3 trial in treatment-naive adult subjects, 3 subjects (0.8%) who received CELSENTRI 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 CELSENTRI and efavirenz, respectively).
When CELSENTRI 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 CELSENTRI was given at the recommended dose in HIV-1 infected 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. CELSENTRI 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 CELSENTRI 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 Recommended Dosage Recommendations in Patients with Renal Impairment under Dosage & Administration].
Immune Reconstitution Syndrome: Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including CELSENTRI. 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], or 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.
Potential Risk of Infection: CELSENTRI 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 CELSENTRI. While there was a higher rate of certain upper respiratory tract infections reported in the treatment arm receiving CELSENTRI compared with placebo (23% versus 13%), there was a lower rate of pneumonia (2% versus 5%) reported in subjects receiving CELSENTRI. A higher incidence of Herpes virus infections (11 per 100 patient-years) was also reported in the treatment arm receiving CELSENTRI 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 CELSENTRI compared with 2.4 for efavirenz per 100 patient-years of exposure.
Patients should be monitored closely for evidence of infections while receiving CELSENTRI.
Potential Risk of Malignancy: While no increase in malignancy has been observed with CELSENTRI, 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 CELSENTRI 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 CELSENTRI and efavirenz, respectively.
Long-term follow-up is needed to more fully assess this risk.
Renal Impairment: Recommended doses of CELSENTRI 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.
The pharmacokinetics of maraviroc in adult subjects with mild and moderate renal impairment was similar to that in subjects with normal renal function [see Pharmacology: Pharmacokinetics under Actions]. A limited number of adult subjects with mild and moderate renal impairment in the Phase 3 clinical trials (n = 131 and n = 12, respectively) received the same dose of CELSENTRI as that administered to subjects with normal renal function. In these subjects there was no apparent difference in the adverse event profile for maraviroc compared with 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 CELSENTRI 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 CELSENTRI can be recommended, and CELSENTRI is contraindicated for these patients [see Cardiovascular Events as previously mentioned; Recommended Dosage Recommendations in Patients with Renal Impairment under Dosage & Administration; Contraindications; Pharmacology: Pharmacokinetics under Actions].
Hepatic Impairment: Maraviroc is principally metabolized by the liver; therefore, when administering this drug to patients with hepatic impairment, maraviroc concentrations may be increased. Maraviroc concentrations are higher when CELSENTRI 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 CELSENTRI 150 mg with a potent CYP3A inhibitor should be monitored closely for maraviroc-associated adverse events. Maraviroc has not been studied in subjects with severe hepatic impairment [see Hepatotoxicity as previously mentioned; Pharmacology: Pharmacokinetics under Actions].
Gender: Population pharmacokinetic analysis of pooled Phase 1/2a data indicated gender (female: n = 96, 23.2% of the total population) does not affect maraviroc concentrations. Dosage adjustment based on gender is not necessary.
Race: Population pharmacokinetic analysis of pooled Phase 1/2a data indicated exposure was 26.5% higher in Asians (N = 95) as compared with non-Asians (n = 318). However, a trial designed to evaluate pharmacokinetic differences between whites (n = 12) and Singaporeans (n = 12) showed no difference between these 2 populations. No dose adjustment based on race is needed.
Use in Children: The pharmacokinetics, safety and efficacy of maraviroc in patients younger than 18 years have not been established. Therefore, maraviroc should not be used in this patient population.
Use in the Elderly: There were insufficient numbers of subjects aged 65 and over in the clinical trials to determine whether they respond differently from younger subjects. In general, caution should be exercised when administering CELSENTRI in elderly patients, also reflecting the greater frequency of decreased hepatic and renal function, of concomitant disease and other drug therapy.
