Introduction

The FDA approved Atripla for the treatment of HIV-1 infection in adults on July 12, 2006. Atripla is a fixed-dose combination tablet containing three antiretroviral medications that belong to two separate classes of drugs:
NNRTIs (non-nucleoside reverse transcriptase inhibitors): efavirenz and 
NRTIs (nucleoside/nucleotide reverse transcriptase inhibitors): emtricitabine and tenofovir.

One tablet of Atripla is equivalent to one 600 mg tablet of the NNRTI efavirenz, and one tablet of Truvada, a fixed-dose combination tablet containing two NRTIs, emtricitabine 200 mg and tenofovir disoproxil fumarate (tenofovir DF) 300 mg.

Prior to the development of Atripla, these 3 FDA-approved antiretrovirals have been administered as separate pills in combination for the treatment of HIV infection.

HIV/AIDS-related Uses

Atripla is indicated as a complete regimen or in combination with other antiretroviral medications. Clinical studies support use of Atripla in antiretroviral-naive patients. Atripla is not recommended for use in the pediatric population.

Dosing Information

Taken orally, Atripla is a film-coated tablet containing efavirenz 600 mg, emtricitabine 200 mg, and tenofovir DF 300 mg.

The recommended adult dose of Atripla is one tablet once daily on an empty stomach, alone or in combination with other antiretroviral medications.

Store tablets in a tightly closed container at 25 C (77 F), with excursions permitted to 15 C to 30 C (59 F to 86 F).

Pharmacology

One Atripla tablet is bioequivalent to one efavirenz tablet (600 mg), one emtricitabine capsule (200 mg), and one tenofovir DF tablet (300 mg) after single-dose administration to fasting healthy volunteers. Additive to synergistic antiviral effects were observed in combination studies evaluating the antiviral activity of emtricitabine and efavirenz together, efavirenz and tenofovir together, and emtricitabine and tenofovir together.

Efavirenz is an NNRTI. Efavirenz activity is mediated predominantly by noncompetitive inhibition of HIV-1 reverse transcriptase (RT). Emtricitabine is a synthetic nucleoside analog of cytidine.

Tenofovir DF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate.

For more information about each individual component of Atripla, see the individual drug product labels for efavirenz, emtricitabine, and tenofovir DF.

In HIV infected patients, time-to-peak plasma concentrations (Cmax) of efavirenz were approximately 3 to 5 hours, and steady-state plasma concentrations were reached in 6 to 10 days. In 35 patients receiving efavirenz 600 mg once daily, mean Cmax was 12.9 g/mL, and the mean area under the concentration-time curve (AUC) was 184 g hr/mL.

In vitro studies suggest cytochrome P (CYP) 3A4 and CYP2B6 are the major isozymes responsible for efavirenz metabolism. Efavirenz has been shown to induce P450 enzymes, resulting in induction of its own metabolism. Efavirenz has a terminal half-life of 52 to 76 hours after single doses and 40 to 55 hours after multiple doses. Between 14% and 34% of efavirenz, mostly as metabolites, is eliminated renally; 16% to 61%, mostly as parent drug, is recovered in the feces.

Following oral administration, emtricitabine is rapidly absorbed, with Cmax occurring at 1 to 2 hours post-dose. Following multiple dose oral administration of emtricitabine to 20 HIV-infected patients, the steady-state mean Cmax was 1.8 g/mL, and the mean AUC was 10.0 g hr/mL. The mean absolute bioavailability of emtricitabine was 93%. Following a single oral dose, the half-life is approximately 10 hours. Approximately 86% of emtricitabine is recovered in the urine and 13% is recovered as metabolites.

Following oral administration of a single 300 mg dose of tenofovir DF to fasting patients, mean Cmax (achieved in approximately 1 hour) was 296 ng/mL, and mean AUC was 2,287 ng hr/mL. The oral bioavailability of tenofovir from tenofovir DF in fasting patients is approximately 25%. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose, the terminal elimination half-life is approximately 17 hours. Approximately 79% to 80% of an IV dose is recovered unchanged in the urine.

Atripla is in FDA Pregnancy Category D. There are no adequate and well-controlled studies of Atripla in pregnant women. Pregnancy should be avoided in women receiving Atripla. Barrier contraception should always be used in combination with other methods of contraception. Atripla should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus, such as in pregnant women without other therapeutic options. To monitor fetal outcomes of pregnant women, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients who become pregnant online at http://www.APRegistry.com or by calling 1-800-258-4263.

As of July 2005, the Antiretroviral Pregnancy Registry has received prospective reports of 282 pregnancies exposed to efavirenz-containing regimens, nearly all of which were first-trimester exposures (277 pregnancies). Birth defects occurred in 5 of 228 live births (first-trimester exposure) and 1 of 14 live births (second/third-trimester exposure). None of these prospectively reported defects were neural tube defects. However, there have been four retrospective reports of findings consistent with neural tube defects, including meningomyelocele. All mothers were exposed to efavirenz-containing regimens in the first trimester. Although a causal relationship of these events to the use of efavirenz has not been established, similar defects have been observed in preclinical studies of efavirenz.

HIV-1 isolates with reduced susceptibility to the combination of emtricitabine and tenofovir have been selected in cell culture and in clinical studies. Genotypic analysis of these isolates identified the M184V/I and/or K65R amino acid substitutions in the viral reverse transcriptase. The most frequently observed amino acid substitution in clinical studies with efavirenz is K103N. Reduced susceptibility to emtricitabine is associated with the M184V/I mutation. Reduced susceptibility to tenofovir selected in cell culture was expressed as a K65R mutation.

In a clinical study of treatment-naïve patients receiving efavirenz in combination with emtricitabine and tenofovir DF or with zidovudine/lamivudine, genotypic resistance to efavirenz, predominantly the K103N substitution, was the most common form of resistance that developed. Resistance to efavirenz occurred in 9/12 (75%) patients in the emtricitabine/tenofovir DF group and in 16/22 (73%) patients in the zidovudine/lamivudine group.


Adverse Events/Toxicity

Adverse effects commonly associated with efavirenz use include impaired concentration, anorexia, abdominal pain, anxiety, and pruritus. Pancreatitis has been reported, although a causal relationship with efavirenz has not been established.

Adverse effects that occurred in at least 5% of patients receiving emtricitabine and tenofovir DF include anxiety, arthralgia, increased cough, dyspepsia, fever, myalgia, abdominal pain, peripheral neuropathy, rash, pruritis, urticaria, and paresthesia. Skin discoloration has been reported with higher frequency among emtricitabine-treated patients. The hyperpigmentation of the palms and soles was generally mild and asymptomatic. (For more information on adverse effects of each drug, please see individual product labels for efavirenz, emtricitabine, and tenofovir DF.)

Study 934 reported adverse events associated with the combination of efavirenz and Truvada (emtricitabine and tenofovir DF). The most common adverse reactions were diarrhea, nausea, fatigue, dizziness, headache, and rash. In HIV-infected patients taking Atripla, elevated fasting cholesterol and serum amylase were noted in 15% and 7% in patients, respectively.

Drug and Food Interactions

Atripla should be taken on an empty stomach. However, Atripla has not been evaluated in the presence of food. Administration of efavirenz with a high-fat meal increased the mean maximum plasma concentrations significantly compared with the fasted state.


Contraindications

Atripla is contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the product.

Tenofovir DF and efavirenz have not been studied in patients younger than 3 years of age or weighing less than 13 kg (28.7 lbs). Atripla is not recommended for pediatric administration.

Atripla should not be administered concurrently with midazolam, triazolam, or ergot derivatives, because competition for CYP3A4 liver enzymes by efavirenz could result in inhibitor of metabolism of these drugs and create the potential for serious adverse events, including cardiac arrhythmias and respiratory depression.

Atripla should not be coadministered with voriconazole, because efavirenz significantly decreases voriconazole plasma concentrations.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with other antiretrovirals.

Atripla is not indicated for use in patients coinfected with HIV and chronic hepatitis B virus (HBV). The safety of Atripla has not been established in patients coinfected with HIV and HBV.

Hepatic function should be monitored closely for at least several months in patients who discontinue Atripla and are coinfected with HIV and HBV. If appropriate, initiation of HBV therapy may be warranted.

Severe acute exacerbations of HBV have been reported in patients who have discontinued emtricitabine or tenofovir DF.

Because of the nature of the fixed-dose combination tablet, Atripla should not be used in combination with the individual component medications efavirenz, emtricitabine, and tenofovir DF. In addition, because of similarities between emtricitabine and lamivudine, Atripla should not be coadministered with drugs containing lamivudine, including the brand medications Combivir, Epivir, Epzicom, or Trizivir.

Clinical Trials

Click here to search ClinicalTrials.gov for trials that use efavirenz / emtricitabine / tenofovir.

More Information

Atripla Prescribing Information from the FDA web site [PDF]. A more current version may be available on the manufacturer's web site. [http://www.atripla.com/images/7_2006_GS_21_937_001_ATRIPLA_US_PI.pdf]

PMID/15341498 T M Dando and A J Wagstaff. Emtricitabine/tenofovir disoproxil fumarate. Drugs. 64(18): 2075-2084. 2004.

PMID/16421366 J E Gallant, E DeJesus, J R Arribas, and others (Study 934 Group). Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. New England Journal of Medicine 354(3): 251-260. January 19, 2006.

PMID/16556093 B G Gazzard. Use of tenofovir disoproxil fumarate and emtricitabine combination in HIV-infected patients. Expert Opinion in Pharmacotherapy 7(6): 793-802. April 2006.

Manufacturer Information

Atripla (Efavirenz / Emtricitabine / Tenofovir disoproxil fumarate)

Gilead Sciences Inc
333 Lakeside Dr
Foster City, CA, 94404
(800) 445-3235

Bristol-Myers Squibb Co
PO Box 4500
Princeton, NJ, 08543-4500
(800) 321-1335

08/08/06

Sources

US Food and Drug Administration http://www.fda.gov.

US Department of Health and Human Services  http://www.hhs.gov.

www.atripla.com
www.sustiva.com
www.emtriva.com
www.viread.com
www.gilead.com
www.bms.com