Atripla

Efavirenz/emtricitabine/tenofovir disoproxil tablets

BRISTOL-MYERS SQUIBB/GILEAD

Once-daily combination tablet approved for HIV infection

Efficacy. The efficacy of the efavirenz/ emtricitabine/tenofovir disoproxil combination tablet was evaluated in a randomized, open-label, active-controlled multicenter study in 511 antiretroviral treatment-naïve HIV-1- infected patients. Patients received either emtricitabine and tenofovir disoproxil in combination with efavirenz or zidovudine/lamivudine in a fixed-dose combination. Efficacy analyses were based on trial data through 48 weeks of therapy. The proportion of patients receiving the efavirenz/ emtricitabine/tenofovir disoproxil combination that were classified as responders (confirmed HIV-1 RNA <400 copies/mL) was 84%. This is compared with the 73% proportion of responders observed in the group receiving zidovudine/lamivudine. In addition, 80% and 70% of patients in the efavirenz/emtricitabine/ tenofovir disoproxil and zidovudine/lamivudine groups, respectively, achieved and maintained HIV-1 RNA <50 copies/mL. The mean increase in baseline CD4 cell count was 190 cells/mm³ in the efavirenz/emtricitabine/tenofovir disoproxil group and 158 cells/mm³ in the zidovudine/ lamivudine group.

Safety. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, alone or in combination with other antiretroviral agents. The efavirenz/ emtricitabine/ tenofovir disoproxil combination is not indicated for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of the combination have not been established in patients co-infected with HBV and HIV. Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued treatment with tenofovir disoproxil or emtricitabine. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue treatment with the efavirenz/emtricitabine/tenofovir disoproxil combination and are co-infected with HIV and HBV. In these patients, initiation of anti-hepatitis B therapy may be warranted. The efavirenz/emtricitabine/tenofovir disoproxil combination should not be administered concurrently with astemizole, cisapride, midazolam, triazolam, or ergot derivatives because competition for CYP3A4 by efavirenz could result in inhibition of metabolism of these drugs and create the potential for serious and/or life-threatening adverse events (eg, cardiac arrhythmias, prolonged sedation, or respiratory depression). The combination should not be administered concomitantly with voriconazole because efavirenz significantly decreases voriconazole plasma concentrations. Coadministration of NNRTIs such as efavirenz with St John's wort is expected to substantially decrease NNRTI concentrations and may result in suboptimal levels of efavirenz. Serious psychiatric adverse events such as severe depression, suicide attempts, aggressive behavior, delusions, paranoia, and psychosis-like symptoms have been reported in patients treated with efavirenz. Central nervous system adverse events such as convulsions, dizziness, insomnia, impaired concentration, drowsiness, and abnormal dreams have likewise been reported in patients treated with efavirenz. Patients with creatine clearance <50 mL/min should not receive the efavirenz/emtricitabine/tenofovir disoproxil combination, and the combination should be avoided with concurrent or recent use of a nephrotoxic agent. Caution should be exercised when administering the efavirenz/ emtricitabine/tenofovir disoproxil combination in patients with hepatic impairment. Patients treated with efavirenz have reported new-onset skin rash, including Grade 4 rash such as erythema multiforme and Stevens-Johnson syndrome. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten resolution of the rash. Decreases in bone mineral density (BMD) at the lumbar spine and hip have been observed in patients treated with the efavirenz/emtricitabine/tenofovir disoproxil combination. The most commonly reported adverse events associated with the efavirenz/emtricitabine/tenofovir disoproxil combination include anxiety, arthralgia, increased cough, dyspepsia, fever, myalgia, pain, paresthesia, pneumonia, rhinitis, and rash event.

Dosing. The recommended dose of the efavirenz/emtricitabine/tenofovir disoproxil combination is 1 tablet once daily taken on an empty stomach. Dosing at bedtime may improve the tolerability of nervous system symptoms.