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):
NRTIs (nucleoside/nucleotide reverse transcriptase
inhibitors): emtricitabine and tenofovir.
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.
to the development of Atripla, these 3 FDA-approved
antiretrovirals have been administered as separate
pills in combination for the treatment of HIV
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.
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.
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).
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.
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.
DF is an acyclic nucleoside phosphonate diester
analog of adenosine monophosphate.
more information about each individual component
of Atripla, see the individual drug product labels
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.
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.
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
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.
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
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,
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
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.
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.
should not be coadministered with voriconazole,
because efavirenz significantly decreases voriconazole
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.
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.
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.
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
to search ClinicalTrials.gov for trials
that use efavirenz / emtricitabine / tenofovir.
Prescribing Information from the FDA web site
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]
T M Dando and A J Wagstaff. Emtricitabine/tenofovir
disoproxil fumarate. Drugs. 64(18): 2075-2084.
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.
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.
(Efavirenz / Emtricitabine / Tenofovir disoproxil
Gilead Sciences Inc
333 Lakeside Dr
Foster City, CA, 94404
PO Box 4500
Princeton, NJ, 08543-4500
Food and Drug Administration http://www.fda.gov.
Department of Health and Human Services