Efavirenz/Emtricitabine/Tenofovir Dosage

Usual Adult Dose for HIV Infection

1 tablet orally once a day at bedtime on an empty stomach

Renal Dose Adjustments

CrCl less than 50 mL/min: Not recommended.

Liver Dose Adjustments

Mild hepatic impairment: The manufacturer recommends caution when administering this drug to patients with this degree of liver dysfunction due to the extensive metabolism of efavirenz by CYP450 enzymes.

Moderate or severe hepatic impairment: Not recommended.

Precautions

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir, in combination other antiretrovirals. Risk factors for lactic acidosis may include female gender, obesity, and prolonged nucleoside exposure. Caution is recommended in patients with risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with efavirenz/emtricitabine/tenofovir should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity.

It is recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B virus (HBV) before initiating antiretroviral therapy. Efavirenz/emtricitabine/tenofovir is not approved for the treatment of chronic HBV infection and its safety and efficacy have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients coinfected with HBV and HIV-1 after discontinuation of emtricitabine or tenofovir and were associated with liver failure and liver decompensation in some of the emtricitabine-treated patients. Coinfected patients should be closely monitored with clinical and laboratory follow-up for at least several months after discontinuation of efavirenz/emtricitabine/tenofovir, and antihepatitis B therapy should be initiated if indicated.

Efavirenz has been associated with severe psychiatric adverse effects during clinical trials including severe depression, suicidal ideation, nonfatal suicide attempts, aggressive behavior, paranoid reactions, and manic reactions. Delusions, psychosis-like behavior, and death by suicide have been reported during postmarketing use. The risk may be increased in patients with a history of injectable drug use, psychiatric history, or use of psychiatric medications. Patients should seek immediate medical attention if they experience serious psychiatric effects. The potential benefits versus the risk of continued treatment should be carefully evaluated.

Nervous system adverse effects, including but not limited to dizziness, insomnia, impaired concentration, somnolence, abnormal dreams, and hallucinations may occur frequently during treatment with efavirenz. These symptoms generally occur during the first or second day of therapy and often resolve after 2 to 4 weeks. Dosing at bedtime may improve the tolerability of these effects. Patients should be cautioned that efavirenz may impair the mental abilities necessary for performing potentially hazardous tasks such as driving or operating machinery and that the CNS effects may be additive with concomitant use of alcohol or medications that depress the CNS. Discontinuation may be necessary if severe psychiatric symptoms develop.

Convulsions have occurred during efavirenz treatment, generally in patients with a history of seizures. Caution is recommended in all patients with a seizure history and plasma level monitoring may be recommended in patients concomitantly taking anticonvulsive medications metabolized by the liver.

The manufacturer recommends avoiding pregnancy during treatment with efavirenz. Barrier contraception must always be used in combination with other methods of contraception (e.g., hormonal) during efavirenz treatment. Use of adequate contraception for 12 weeks following efavirenz discontinuation is recommended. Pregnancy testing is recommended for women of childbearing potential prior to starting efavirenz therapy. Patients should be advised of the potential harm to the fetus if they become pregnant while taking efavirenz or if it is administered during the first trimester.

Renal impairment, including acute renal failure and Fanconi syndrome, has been reported with tenofovir. Creatinine clearance should be calculated in all patients before starting efavirenz/emtricitabine/tenofovir treatment and during treatment when clinically appropriate. Routine monitoring of calculated creatinine clearance and serum phosphorus is recommended for patients at risk of or with a history of renal dysfunction, including patients with previous renal events while using adefovir. Efavirenz/emtricitabine/tenofovir should be avoided in patients who are currently using or have recently used nephrotoxic drugs.

Monitoring of liver enzymes before and during efavirenz therapy is recommended in patients treated concomitantly with hepatotoxic drugs, in patients with underlying liver disease (including hepatitis B or C infection), and in patients with marked transaminase elevations. Monitoring of liver enzymes should be considered in patients without preexisting liver dysfunction or other risk factors. The benefit of continued therapy with efavirenz should be weighed against the unknown risks of significant hepatotoxicity in patients with persistent serum transaminase elevations (to greater than 5 times the upper limit of normal).

Patients should notify their physician if a rash develops. Efavirenz/emtricitabine/tenofovir should be withdrawn if the rash is severe, such as that associated with blistering, desquamation, mucosal involvement, or fever. However, in most adult patients who developed a rash during efavirenz clinical trials (26%), the rash was usually a mild or moderate maculopapular skin eruption that occurred within the first 2 weeks of therapy and resolved within 1 month despite continued use of the drug. The use of antihistamines and/or corticosteroids may help, particularly if efavirenz/emtricitabine/tenofovir therapy is reinstated after an interruption due to rash.

Tenofovir has been associated with decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism. Assessment of BMD should be considered for patients who have a history of pathological bone fracture or other risk factors for osteoporosis or bone loss. Consultation is recommended if bone abnormalities are suspected or observed.

Immune reconstitution syndrome has occurred during combination antiretroviral therapy. Patients responding to therapy may develop an inflammatory response to indolent or residual opportunistic infections and require evaluation and treatment.

Coadministration with related drugs that contain the same active components is not recommended. Due to similarities between emtricitabine and lamivudine, efavirenz/emtricitabine/tenofovir should not be coadministered with drugs containing lamivudine. Efavirenz/emtricitabine/tenofovir should not be administered in combination with adefovir dipivoxil.

The potential for HIV-1 cross-resistance among nonnucleoside reverse transcriptase inhibitors (NNRTI) exists but has not been fully explored. It is unknown what effect efavirenz/emtricitabine/tenofovir therapy will have on the activity of subsequently administered NNRTIs. Selection of antiretroviral agents for a patient's medication regimen should be done carefully.

Safety and effectiveness have not been established in pediatric patients (less than 18 years of age); efavirenz/emtricitabine/tenofovir is not recommended for use in these patients.

Dialysis

Hemodialysis removes approximately 30% of the emtricitabine dose over a 3-hour dialysis period starting within 1.5 hours of dosing. Tenofovir is removed by hemodialysis with an extraction coefficient of approximately 54% and approximately 10% of the tenofovir dose is removed over a 4-hour hemodialysis session. Hemodialysis is unlikely to significantly remove efavirenz from the blood.

There are no data on the peritoneal dialysis clearance of efavirenz/emtricitabine/tenofovir.

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