Rx Drugs Info

atripla (efavirenz, emtricitabine and tenofovir disoproxil fumaratetablet, multilayer 
[Gilead Sciences, Inc.]

Rx Only

WARNING

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 ANTIRETROVIRALS (SEE WARNINGS).

ATRIPLA IS NOT INDICATED FOR THE TREATMENT OF CHRONIC HEPATITIS B VIRUS (HBV) INFECTION AND THE SAFETY AND EFFICACY OF ATRIPLA HAVE NOT BEEN ESTABLISHED IN PATIENTS COINFECTED WITH HBV AND HIV. SEVERE ACUTE EXACERBATIONS OF HEPATITIS B HAVE BEEN REPORTED IN PATIENTS WHO HAVE DISCONTINUED EMTRIVA® OR VIREAD®. HEPATIC FUNCTION SHOULD BE MONITORED CLOSELY WITH BOTH CLINICAL AND LABORATORY FOLLOW-UP FOR AT LEAST SEVERAL MONTHS IN PATIENTS WHO DISCONTINUE ATRIPLA AND ARE COINFECTED WITH HIV AND HBV. IF APPROPRIATE, INITIATION OF ANTI-HEPATITIS B THERAPY MAY BE WARRANTED (SEE WARNINGS).

DESCRIPTION

ATRIPLA™ is a fixed dose combination tablet containing efavirenz, emtricitabine, and tenofovir disoproxil fumarate (tenofovir DF). SUSTIVA® is the brand name for efavirenz, a non-nucleoside reverse transcriptase inhibitor. EMTRIVA is the brand name for emtricitabine, a synthetic nucleoside analog of cytidine. VIREAD is the brand name for tenofovir DF, which is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5'-monophosphate. VIREAD and EMTRIVA are the components of TRUVADA®.

ATRIPLA Tablets are for oral administration. Each tablet contains 600 mg of efavirenz, 200 mg of emtricitabine, and 300 mg of tenofovir DF (which is equivalent to 245 mg of tenofovir disoproxil) as active ingredients. The tablets include the following inactive ingredients:   croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The tablets are film-coated with a coating material containing black iron oxide, polyethylene glycol, polyvinyl alcohol, red iron oxide, talc, and titanium dioxide.

Efavirenz

Efavirenz is chemically described as (S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one. Its molecular formula is C14H9ClF3NO2 and its structural formula is:

Image from Drug Label Content

Efavirenz is a white to slightly pink crystalline powder with a molecular mass of 315.68. It is practically insoluble in water (<10 µg/mL).

Emtricitabine

The chemical name of emtricitabine is 5-fluoro-1-(2R,5S)-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Emtricitabine is the (-) enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5-position.

It has a molecular formula of C8H10FN3O3S and a molecular weight of 247.24. It has the following structural formula:

Image from Drug Label Content

Emtricitabine is a white to off-white crystalline powder with a solubility of approximately 112 mg/mL in water at 25 °C.

Tenofovir disoproxil fumarate

Tenofovir DF is a fumaric acid salt of the bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. The chemical name of tenofovir disoproxil fumarate is 9-[(R)-2[[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has a molecular formula of C19H30N5O10P • C4H4O4 and a molecular weight of 635.52. It has the following structural formula:

Image from Drug Label Content

Tenofovir DF is a white to off-white crystalline powder with a solubility of 13.4 mg/mL in water at 25 °C.

MICROBIOLOGY

For additional information on Mechanism of Action, Antiviral Activity, Resistance and Cross Resistance, please consult the SUSTIVA, EMTRIVA and VIREAD prescribing information.

Mechanism of Action

Efavirenz

Efavirenz is a non-nucleoside reverse transcriptase inhibitor of HIV-1. Efavirenz activity is mediated predominantly by noncompetitive inhibition of HIV-1 reverse transcriptase (RT). HIV-2 RT and human cellular DNA polymerases α, β, γ, and δ are not inhibited by efavirenz.

Emtricitabine

Emtricitabine, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 RT by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5'-triphosphate is a weak inhibitor of mammalian DNA polymerase α, β, ε, and mitochondrial DNA polymerase γ.

Tenofovir disoproxil fumarate

Tenofovir DF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir DF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine 5'-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.

Antiviral Activity

Efavirenz, emtricitabine, and tenofovir disoproxil fumarate

In combination studies evaluating the antiviral activity in cell culture of emtricitabine and efavirenz together, efavirenz and tenofovir together, and emtricitabine and tenofovir together, additive to synergistic antiviral effects were observed.

Efavirenz

The concentration of efavirenz inhibiting replication of wild-type laboratory adapted strains and clinical isolates in cell culture by 90–95% (EC90–95) ranged from 1.7–25 nM in lymphoblastoid cell lines, peripheral blood mononuclear cells, and macrophage/monocyte cultures. Efavirenz demonstrated additive antiviral activity against HIV-1 in cell culture when combined with non-nucleoside reverse transcriptase inhibitors (NNRTIs) (delavirdine and nevirapine), nucleoside reverse transcriptase inhibitors (NRTIs) (abacavir, didanosine, lamivudine, stavudine, zalcitabine, and zidovudine), protease inhibitors (PIs) (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), and the fusion inhibitor enfuvirtide. Efavirenz demonstrated additive to antagonistic antiviral activity in cell culture with atazanavir. Efavirenz demonstrated antiviral activity against most non-clade B isolates (subtypes A, AE, AG, C, D, F, G, J, and N), but had reduced antiviral activity against group O viruses. Efavirenz is not active against HIV-2.

Emtricitabine

The antiviral activity in cell culture of emtricitabine against laboratory and clinical isolates of HIV was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells. The 50% effective concentration (EC50) values for emtricitabine were in the range of 0.0013–0.64 µM (0.0003–0.158 µg/mL). In drug combination studies of emtricitabine with NRTIs (abacavir, lamivudine, stavudine, zalcitabine, and zidovudine), NNRTIs (delavirdine, efavirenz, and nevirapine), and PIs (amprenavir, nelfinavir, ritonavir, and saquinavir), additive to synergistic effects were observed. Emtricitabine displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC50 values ranged from 0.007–0.075 µM) and showed strain specific activity against HIV-2 (EC50 values ranged from 0.007–1.5 µM).

Tenofovir disoproxil fumarate

The antiviral activity in cell culture of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC50 values for tenofovir were in the range of 0.04–8.5 µM. In drug combination studies of tenofovir with NRTIs (abacavir, didanosine, lamivudine, stavudine, zalcitabine, and zidovudine), NNRTIs (delavirdine, efavirenz, and nevirapine), and PIs (amprenavir, indinavir, nelfinavir, ritonavir, and saquinavir), additive to synergistic effects were observed. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC50 values ranged from 0.5–2.2 µM) and showed strain specific activity against HIV-2 (EC50 values ranged from 1.6 µM to 4.9 µM).

Resistance

Efavirenz, emtricitabine, and tenofovir disoproxil fumarate

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 RT.

In a clinical study of treatment-naïve patients (Study 934, see Description of Clinical Studies) resistance analysis was performed on HIV isolates from all virologic failure patients with >400 copies/mL of HIV-1 RNA at Week 48 or early discontinuations. 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%) analyzed patients in the emtricitabine + tenofovir DF group and in 16/22 (73%) analyzed patients in the zidovudine/lamivudine fixed-dose combination group. The M184V amino acid substitution, associated with resistance to emtricitabine and lamivudine, was observed in 2/12 (17%) analyzed patient isolates in the emtricitabine + tenofovir DF group and in 7/22 (32%) analyzed patient isolates in the zidovudine/lamivudine group. Through 48 weeks of Study 934, no patients developed a detectable K65R mutation in their HIV as analyzed through standard genotypic analysis. Insufficient data are available to assess the development of the K65R mutation upon prolonged exposure to this regimen.

In a clinical study of treatment-naïve patients, isolates from 8 of 47 patients receiving tenofovir DF developed the K65R substitution through 144 weeks of therapy; 7 of these occurred in the first 48 weeks of treatment and one at Week 96. In treatment experienced patients, 14/304 (5%) of tenofovir DF treated patients with virologic failure through Week 96 showed >1.4 fold (median 2.7) reduced susceptibility to tenofovir. Genotypic analysis of the resistant isolates showed a mutation in the HIV-1 RT gene resulting in the K65R amino acid substitution.

Efavirenz

Clinical isolates with reduced susceptibility in cell culture to efavirenz have been obtained. The most frequently observed amino acid substitution in clinical studies with efavirenz is K103N (54%). One or more RT substitutions at amino acid positions 98, 100, 101, 103, 106, 108, 188, 190, 225, 227, and 230 were observed in patients failing treatment with efavirenz in combination with other antiretrovirals. Other resistance mutations observed to emerge commonly included L100I (7%), K101E/Q/R (14%), V108I (11%), G190S/T/A (7%), P225H (18%), and M230I/L (11%).

HIV-1 isolates with reduced susceptibility to efavirenz (>380-fold increase in EC90 value) emerged rapidly under selection in cell culture. Genotypic characterization of these viruses identified mutations resulting in single amino acid substitutions L100I or V179D, double substitutions L100I/V108I, and triple substitutions L100I/V179D/ Y181C in RT.

Emtricitabine

Emtricitabine-resistant isolates of HIV have been selected in cell culture and in clinical studies. Genotypic analysis of these isolates showed that the reduced susceptibility to emtricitabine was associated with a mutation in the HIV RT gene at codon 184 which resulted in an amino acid substitution of methionine by valine or isoleucine (M184V/I).

Tenofovir disoproxil fumarate

HIV-1 isolates with reduced susceptibility to tenofovir have been selected in cell culture. These viruses expressed a K65R mutation in RT and showed a 2–4 fold reduction in susceptibility to tenofovir.

Cross-resistance

Efavirenz, emtricitabine, and tenofovir disoproxil fumarate

Cross-resistance has been recognized among NNRTIs. Cross resistance has also been recognized among certain NRTIs. The M184V/I and/or K65R substitutions selected in cell culture by the combination of emtricitabine and tenofovir are also observed in some HIV-1 isolates from subjects failing treatment with tenofovir in combination with either lamivudine or emtricitabine, and either abacavir or didanosine. Therefore, cross-resistance among these drugs may occur in patients whose virus harbors either or both of these amino acid substitutions.

Efavirenz

Clinical isolates previously characterized as efavirenz-resistant were also phenotypically resistant in cell culture to delavirdine and nevirapine compared to baseline. Delavirdine- and/or nevirapine-resistant clinical viral isolates with NNRTI resistance-associated substitutions (A98G, L100I, K101E/P, K103N/S, V106A, Y181X, Y188X, G190X, P225H, F227L, or M230L) showed reduced susceptibility to efavirenz in cell culture. Greater than 90% of NRTI-resistant isolates tested in cell culture retained susceptibility to efavirenz.

Emtricitabine

Emtricitabine-resistant isolates (M184V/I) were cross-resistant to lamivudine and zalcitabine but retained susceptibility in cell culture to didanosine, stavudine, tenofovir, zidovudine, and NNRTIs (delavirdine, efavirenz, and nevirapine). HIV-1 isolates containing the K65R substitution, selected in vivo by abacavir, didanosine, tenofovir, and zalcitabine, demonstrated reduced susceptibility to inhibition by emtricitabine. Viruses harboring mutations conferring reduced susceptibility to stavudine and zidovudine (M41L, D67N, K70R, L210W, T215Y/F, and K219Q/E) or didanosine (L74V) remained sensitive to emtricitabine.

Tenofovir disoproxil fumarate

The K65R mutation selected by tenofovir is also selected in some HIV-1 infected patients treated with abacavir, didanosine, or zalcitabine. HIV-1 isolates with the K65R mutation also showed reduced susceptibility to emtricitabine and lamivudine. Therefore, cross-resistance among these drugs may occur in patients whose virus harbors the K65R mutation. HIV-1 isolates from patients (N=20) whose HIV-1 expressed a mean of 3 zidovudine-associated RT amino acid substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) showed a 3.1-fold decrease in the susceptibility to tenofovir. Multinucleoside resistant HIV-1 with a T69S double insertion mutation in the RT showed reduced susceptibility to tenofovir.

CLINICAL PHARMACOLOGY

Pharmacokinetics in Adults

ATRIPLA

One ATRIPLA Tablet is bioequivalent to one SUSTIVA Tablet (600 mg) plus one EMTRIVA Capsule (200 mg) plus one VIREAD Tablet (300 mg) following single-dose administration to fasting healthy subjects (N=45).

Efavirenz

In HIV-infected patients time-to-peak plasma concentrations were approximately 3–5 hours and steady-state plasma concentrations were reached in 6–10 days. In 35 patients receiving efavirenz 600 mg once daily, steady-state Cmax was 12.9 ± 3.7 µM (mean ± SD), Cmin was 5.6 ± 3.2 µM, and AUC was 184 ± 73 µM∙hr. Efavirenz is highly bound (approximately 99.5–99.75%) to human plasma proteins, predominantly albumin. Following administration of 14C-labeled efavirenz, 14–34% of the dose was recovered in the urine (mostly as metabolites) and 16–61% was recovered in feces (mostly as parent drug). In vitro studies suggest CYP3A4 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 52–76 hours after single doses and 40–55 hours after multiple doses.

Emtricitabine

Following oral administration, emtricitabine is rapidly absorbed with peak plasma concentrations occurring at 1–2 hours post-dose. Following multiple dose oral administration of emtricitabine to 20 HIV-infected subjects, the steady-state plasma emtricitabine Cmax was 1.8 ± 0.7 µg/mL (mean ± SD) and the AUC over a 24-hour dosing interval was 10.0 ± 3.1 µg∙hr/mL. The mean steady state plasma trough concentration at 24 hours post-dose was 0.09 µg/mL. The mean absolute bioavailability of emtricitabine was 93%. In vitro binding of emtricitabine to human plasma proteins is <4% and is independent of concentration over the range of 0.02–200 µg/mL. Following administration of radiolabelled emtricitabine, approximately 86% is recovered in the urine and 13% is recovered as metabolites. The metabolites of emtricitabine include 3'-sulfoxide diastereomers and their glucuronic acid conjugate. Emtricitabine is eliminated by a combination of glomerular filtration and active tubular secretion with a renal clearance in adults with normal renal function of 213 ± 89 mL/min (mean ± SD). Following a single oral dose, the plasma emtricitabine half-life is approximately 10 hours.

Tenofovir disoproxil fumarate

Following oral administration of a single 300 mg dose of tenofovir DF to HIV-1 infected patients in the fasted state, maximum serum concentrations (Cmax) were achieved in 1.0 ± 0.4 hrs (mean ± SD) and Cmax and AUC values were 296 ± 90 ng/mL and 2287 ± 685 ng∙hr/mL, respectively. The oral bioavailability of tenofovir from tenofovir DF in fasted patients is approximately 25%. In vitro binding of tenofovir to human plasma proteins is <0.7% and is independent of concentration over the range of 0.01–25 µg/mL. Approximately 70–80% of the intravenous dose of tenofovir is recovered as unchanged drug in the urine. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion with a renal clearance in adults with normal renal function of 243 ± 33 mL/min (mean ± SD). Following a single oral dose, the terminal elimination half-life of tenofovir is approximately 17 hours.

Effects of Food on Oral Absorption

ATRIPLA has not been evaluated in the presence of food. Administration of efavirenz tablets with a high fat meal increased the mean AUC and Cmax of efavirenz by 28% and 79%, respectively, compared to administration in the fasted state. Compared to fasted administration, dosing of tenofovir DF and emtricitabine in combination with either a high fat meal or a light meal increased the mean AUC and Cmax of tenofovir by 35% and 15%, respectively, without affecting emtricitabine exposures (see DOSAGE AND ADMINISTRATION and PRECAUTIONS, Information for Patients).

Special Populations

Race

Efavirenz

The pharmacokinetics of efavirenz in patients appear to be similar among the racial groups studied.

Emtricitabine

No pharmacokinetic differences due to race have been identified following the administration of emtricitabine.

Tenofovir disoproxil fumarate

There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations following the administration of tenofovir DF.

Gender

Efavirenz, emtricitabine, and tenofovir disoproxil fumarate

Efavirenz, emtricitabine, and tenofovir pharmacokinetics are similar in male and female patients.

Pediatric Patients and Geriatric Patients

Pharmacokinetic studies of tenofovir DF have not been performed in pediatric patients (<18 years). Efavirenz has not been studied in pediatric patients below 3 years of age or who weigh less than 13 kg. Emtricitabine has been studied in pediatric patients from 3 months to 17 years of age. ATRIPLA is not recommended for pediatric administration. Pharmacokinetics of efavirenz, emtricitabine and tenofovir have not been fully evaluated in the elderly (>65 years) (see PRECAUTIONS, Pediatric Use, Geriatric Use).

Patients with Impaired Renal Function

Efavirenz

The pharmacokinetics of efavirenz have not been studied in patients with renal insufficiency; however, less than 1% of efavirenz is excreted unchanged in the urine, so the impact of renal impairment on efavirenz elimination should be minimal.

Emtricitabine and tenofovir disoproxil fumarate

The pharmacokinetics of emtricitabine and tenofovir DF are altered in patients with renal impairment. In patients with creatinine clearance <50 mL/min, Cmax and AUC0–∞ of emtricitabine and tenofovir were increased (see WARNINGS, Renal Impairment).

Patients with Hepatic Impairment

Efavirenz

The pharmacokinetics of efavirenz have not been adequately studied in patients with hepatic impairment (see PRECAUTIONS, Liver Enzymes).

Emtricitabine

The pharmacokinetics of emtricitabine have not been studied in patients with hepatic impairment; however, emtricitabine is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.

Tenofovir disoproxil fumarate

The pharmacokinetics of tenofovir following a 300 mg dose of tenofovir DF have been studied in non-HIV infected patients with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in patients with hepatic impairment compared with unimpaired patients.

Pregnancy

(see WARNINGS, Reproductive Risk Potential)

Nursing Mothers

(see PRECAUTIONS, Nursing Mothers)

Drug Interactions

(see CONTRAINDICATIONS and PRECAUTIONS, Drug Interactions)

ATRIPLA

The drug interactions described are based on studies conducted with efavirenz, emtricitabine, or tenofovir DF as individual agents; no drug interaction studies have been conducted using ATRIPLA.

Efavirenz

The steady-state pharmacokinetics of efavirenz and tenofovir were unaffected when efavirenz and tenofovir DF were administered together versus each agent dosed alone. Specific drug interaction studies have not been performed with efavirenz and NRTIs other than tenofovir, lamivudine, and zidovudine. Clinically significant interactions would not be expected based on NRTIs elimination pathways.

Efavirenz has been shown in vivo to cause hepatic enzyme induction, thus increasing the biotransformation of some drugs metabolized by CYP3A4. In vitro studies have shown that efavirenz inhibited P450 isozymes 2C9, 2C19, and 3A4 with Ki values (8.5–17 µM) in the range of observed efavirenz plasma concentrations. In in vitro studies, efavirenz did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 (Ki values 82–160 µM) only at concentrations well above those achieved clinically. Coadministration of efavirenz with drugs primarily metabolized by 2C9, 2C19, and 3A4 isozymes may result in altered plasma concentrations of the coadministered drug. Drugs which induce CYP3A4 activity would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations.

Drug interaction studies were performed with efavirenz and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interaction. There was no clinically significant interaction observed between efavirenz and zidovudine, lamivudine, azithromycin, fluconazole, lorazepam, cetirizine, or paroxetine. Single doses of famotidine or an aluminum and magnesium antacid with simethicone had no effects on efavirenz exposures. The effects of coadministration of efavirenz on Cmax AUC, and Cmin are summarized in Table 1 (effect of other drugs on efavirenz) and Table 2 (effect of efavirenz on other drugs). For information regarding clinical recommendations see PRECAUTIONS, Drug Interactions.

Table 1 Drug Interactions: Changes in Pharmacokinetic Parameters for Efavirenz in the Presence of the Coadministered Drug
Mean % Change of Efavirenz Pharmacokinetic Parameters* (90% CI)
Coadministered Drug Dose of Coadministered Drug (mg) Efavirenz Dose (mg) N Cmax AUC Cmin
NA = not available
*
Increase = ↑; Decrease = ↓; No Effect = ↔
Parallel-group design; N for efavirenz + lopinavir/ritonavir, N for efavirenz alone.
95% CI
§
Soft Gelatin Capsule
90% CI not available
Indinavir 800 mg q8h × 14 days 200 mg × 14 days 11
Lopinavir/ritonavir 400/100 mg q12h × 9 days 600 mg × 9 days 11,
12
↓ 16
(↓38 to ↑ 15)
↓ 16
(↓42 to ↑ 20)
Nelfinavir 750 mg q8h × 7 days 600 mg × 7 days 10 ↓ 12
(↓32 to ↑ 13)
↓ 12
(↓35 to ↑ 18)
↓ 21
(↓ 53 to ↑ 33)
Ritonavir 500 mg q12h × 8 days 600 mg × 10 days 9 ↑ 14
(↑ 4 to ↑ 26)
↑ 21
(↑ 10 to ↑ 34)
↑ 25
(↑7 to ↑ 46)
Saquinavir SGC§ 1200 mg q8h ×10 days 600 mg × 10 days 13 ↓ 13
(↓5 to ↓ 20)
↓ 12
(↓4 to ↓ 19)
↓ 14
(↓2 to ↓ 24)
Clarithromycin 500 mg q12h × 7 days 400 mg ×7 days 12 ↑ 11
(↑ 3 to ↑ 19)
Rifabutin 300 mg qd × 14 days 600 mg × 14 days 11 ↓ 12
(↓24 to ↑ 1)
Rifampin 600 mg × 7 days 600 mg × 7 days 12 ↓ 20
(↓11 to ↓ 28)
↓ 26
(↓15 to ↓ 36)
↓ 32
(↓15 to ↓ 46)
Carbamazepine 200 mg qd × 3 days, 200 mg bid × 3 days, then 400 mg qd × 15 days 600 mg × 35 days 14 ↓ 21
(↓15 to ↓ 26)
↓36
(↓32 to ↓ 40)
↓ 47
(↓41 to ↓ 53)
Ethinyl estradiol 50 µg single dose 400 mg × 10 days 13
Sertraline 50 mg qd × 14 days 600 mg × 14 days 13 ↑ 11
(↑6 to ↑16)
Voriconazole 400 mg po q12h × 1 day then 200 mg po q12h × 8 days 400 mg × 9 days ↑ 38 ↑44 NA
Table 2 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Efavirenz
Mean % Change of Coadministered Drug Pharmacokinetic Parameters* (90% CI)
Coadministered Drug Dose of
Coadministered Drug (mg)
Efavirenz Dose (mg) N Cmax AUC Cmin
NA = not available
*
Increase = ↑; Decrease = ↓; No Effect = ↔
Compared with atazanavir 400 mg qd alone.
Comparator dose of indinavir was 800 mg q8h × 10 days.
§
Parallel-group design; N for efavirenz + lopinavir/ritonavir, N for lopinavir/ritonavir alone.
Values are for lopinavir. The pharmacokinetics of ritonavir 100 mg q12h are unaffected by concurrent efavirenz.
#
95% CI
Þ
Soft Gelatin Capsule
ß
90% CI not available
Atazanavir 400 mg qd with a light meal d 1–20 600 mg qd with
a light meal d 7–20
27 ↓ 59
(↓ 49 to
↓ 67)
↓ 74
(↓ 68 to
↓ 78)
↓ 93
(↓ 90 to
↓ 95)
400 mg qd d 1–6, then 300 mg qd d 7–20 with ritonavir 100 mg qd and a light meal 600 mg qd 2 h after atazanavir and ritonavir d 7–20 13 ↑ 14
(↓ 17 to
↑ 58)
↑ 39
(↑ 2 to
↑ 88)
↑ 48
(↑ 24 to
↑ 76)
Indinavir 1000 mg q8h × 10 days 600 mg × 10 days 20
After morning dose ↓ 33
(↓ 26 to
↓ 39)
↓ 39
(↓ 24 to
↓ 51)
After afternoon dose ↓ 37
(↓ 26 to
↓ 46)
↓ 52
(↓ 47 to
↓ 57)
After evening dose ↓ 29
(↓ 11 to
↓ 43)
↓ 46
(↓ 37 to
↓ 54)
↓ 57
(↓ 50 to
↓ 63)
Lopinavir/ritonavir 400/100 mg q12h × 9 days 600 mg × 9 days 11, 7§ ↓ 19
(↓36 to
↑ 3)
↓ 39
(↓ 3 to
↓ 62)
Nelfinavir 750 mg q8h × 7 days 600 mg × 7 days 10 ↑ 21
(↑ 10 to
↑ 33)
↑ 20
(↑ 8 to
↑ 34)
Metabolite
AG-1402
↓ 40
(↓ 30 to
↓ 48)
↓ 37
(↓ 25 to
↓ 48)
↓ 43
(↓ 21 to
↓ 59)
Ritonavir 500 mg q12h × 8 days 600 mg × 10 days 11
After AM dose ↑ 24
(↑ 12 to
↑ 38)
↑ 18
(↑ 6 to
↑ 33)
↑ 42
(↑ 9 to
↑ 86)#
After PM dose ↑ 24
(↑ 3 to
↑ 50)#
Saquinavir
SGCÞ
1200 mg q8h × 10 days 600 mg × 10 days 12 ↓ 50
(↓ 28 to
↓ 66)
↓ 62
(↓ 45 to
↓ 74)
↓ 56
(↓ 16 to
↓ 77)#
Clarithromycin 500 mg q12h × 7 days 400 mg × 7 days 11 ↓ 26
(↓ 15 to
↓ 35)
↓ 39
(↓ 30 to
↓ 46)
↓ 53
(↓ 42 to
↓ 63)
14-OH metabolite ↑ 49
(↑ 32 to
↑ 69)
↑ 34
(↑ 18 to
↑ 53)
↑ 26
(↑ 9 to
↑ 45)
Rifabutin 300 mg qd × 14 days 600 mg × 14 days 9 ↓ 32
(↓ 15 to
↓ 46)
↓ 38
(↓ 28 to
↓ 47)
↓ 45
(↓ 31 to
↓ 56)
Carbamazepine 200 mg qd × 3 days,
200 mg bid × 3 days,
then 400 mg qd ×
29 days
600 mg ×
14 days
12 ↓ 20
(↓ 15 to
↓ 24)
↓ 27
(↓ 20 to
↓ 33)
↓ 35
(↓ 24 to
↓ 44)
Epoxide
metabolite
↓ 13
(↓ 30 to
↑ 7)
Ethinyl estradiol 50 µg single dose 400 mg × 10 days 13 ↑ 37
(↑ 25 to
↑ 51)
NA
Methadone Stable maintenance
35–100 mg daily
600 mg × 14–
21 days
11 ↓ 45
(↓ 25 to
↓ 59)
↓ 52
(↓ 33 to
↓ 66)
NA
Sertraline 50 mg qd × 14 days 600 mg × 14 days 13 ↓ 29
(↓ 15 to
↓ 40)
↓ 39
(↓ 27 to
↓ 50)
↓ 46
(↓ 31 to
↓ 58)
Voriconazole 400 mg po q12h × 1 day then 200 mg po q12h × 8 days 400 mg × 9 days ↓ 61ß ↓ 77ß NA

Emtricitabine and tenofovir disoproxil fumarate

The steady-state pharmacokinetics of emtricitabine and tenofovir were unaffected when emtricitabine and tenofovir DF were administered together versus each agent dosed alone.

In vitro and clinical pharmacokinetic drug-drug interaction studies have shown the potential for CYP450 mediated interactions involving emtricitabine and tenofovir with other medicinal products is low.

Emtricitabine and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. No drug-drug interactions due to competition for renal excretion have been observed; however, coadministration of emtricitabine and tenofovir DF with drugs that are eliminated by active tubular secretion may increase concentrations of emtricitabine, tenofovir, and/or the coadministered drug.

Drugs that decrease renal function may increase concentrations of emtricitabine and/or tenofovir.

No clinically significant drug interactions have been observed between emtricitabine and famciclovir, indinavir, stavudine, zidovudine and tenofovir DF. Similarly, no clinically significant drug interactions have been observed between tenofovir DF and abacavir, adefovir dipivoxil, ribavirin, efavirenz, emtricitabine, indinavir, lamivudine, lopinavir/ritonavir, methadone, oral contraceptives, nelfinavir, and saquinavir/ritonavir in studies conducted in healthy volunteers.

Following multiple dosing to HIV-negative subjects receiving either chronic methadone maintenance therapy, oral contraceptives, or single doses of ribavirin, steady-state tenofovir pharmacokinetics were similar to those observed in previous studies, indicating a lack of clinically significant drug interactions between these agents and tenofovir DF.

The effects of coadministered drugs on the Cmax, AUC, and Cmin of tenofovir are shown in Table 3. The effects of coadministration of tenofovir DF on Cmax, AUC, and Cmin of coadministered drugs are shown in Tables 4 and 5.

Table 3 Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir in the Presence of the Coadministered Drug*,
Coadministered Drug Dose of Coadministered Drug (mg) N Mean % Change of Tenofovir Pharmacokinetic Parameters
(90% CI)
Cmax AUC Cmin
*
All interaction studies conducted in healthy volunteers.
Patients received tenofovir DF 300 mg once daily
Increase = ↑; Decrease = ↓; No Effect = ↔
§
REYATAZ® Prescribing Information (Bristol-Myers Squibb Company)
Atazanavir§ 400 once daily× 14 days 33 ↑ 14
(↑8 to ↑20)
↑ 24
(↑21 to ↑ 28)
↑ 22
(↑15 to ↑ 30)
Didanosine
(enteric-coated)
400 once 25
Didanosine
(buffered)
250 or 400 once daily × 7 days 14
Lopinavir/ritonavir 400/100 twice daily × 14 days 24 ↑ 32
(↑25 to ↑38)
↑ 51
(↑37 to ↑ 66)
Table 4 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Tenofovir Disoproxil Fumarate*,
Coadministered
Drug
Dose of Coadministered Drug (mg) N Mean % Change of Coadministered Drug
Pharmacokinetic Parameters
(90% CI)
Cmax AUC Cmin
*
All interaction studies conducted in healthy volunteers.
Patients received tenofovir DF 300 mg once daily.
Increase = ↑; Decrease = ↓; No Effect = ↔
§
REYATAZ Prescribing Information (Bristol-Myers Squibb Company)
In HIV-infected patients, addition of tenofovir DF to atazanavir 300 mg plus ritonavir 100 mg, resulted in AUC and Cmin values of atazanavir that were 2.3- and 4-fold higher than the respective values observed for atazanavir 400 mg when given alone.
Atazanavir§ 400 once daily × 14 days 34 ↓ 21
(↓ 27 to ↓ 14)
↓ 25
(↓ 30 to ↓ 19)
↓ 40
(↓ 48 to ↓ 32)
Atazanavir/ritonavir
300/100 once daily × 42 days
10 ↓ 28
(↓ 50 to ↑ 5)
↓ 25
(↓ 42 to ↓ 3)
↓ 23
(↓ 46 to ↑ 10)
Lopinavir Lopinavir/ritonavir
400/100 twice daily × 14 days
24
Ritonavir Lopinavir/ritonavir
400/100 twice daily × 14 days
24

Coadministration of tenofovir DF with didanosine results in changes in the pharmacokinetics of didanosine that may be of clinical significance. Table 5 summarizes the effects of tenofovir DF on the pharmacokinetics of didanosine. Concomitant dosing of tenofovir DF with didanosine buffered tablets or enteric-coated capsules significantly increases the Cmax and AUC of didanosine. When didanosine 250 mg enteric-coated capsules were administered with tenofovir DF, systemic exposures of didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions. The mechanism of this interaction is unknown (for didanosine dosing adjustment recommendations, see Table 8 in PRECAUTIONS, Drug Interactions).

Table 5 Drug Interactions: Changes in Pharmacokinetic Parameters for Didanosine in the Presence of Tenofovir Disoproxil Fumarate*,
Didanosine Dose (mg)/Method of Administration,§ Tenofovir DF
Method of Administration,§
N Mean % Change (90% CI) vs. Didanosine 400 mg Alone, Fasted
Cmax AUC
*
All interaction studies conducted in healthy volunteers.
Patients received tenofovir DF 300 mg once daily.
See PRECAUTIONS regarding use of didanosine with ATRIPLA.
§
Administration with food was with a light meal (~373 kcal, 20% fat).
Increase = ↑ Decrease = ↓; No Effect = ↔
#
Includes 4 subjects weighing <60 kg receiving ddI 250 mg.
Buffered tablets
400 once daily#× 7 days Fasted 1 hour after
didanosine
14 ↑ 28
(↑ 11 to ↑ 48)
↑ 44
(↑ 31 to ↑ 59)
Enteric coated capsules
400 once, fasted With food, 2 hr after didanosine 26 ↑ 48
(↑ 25 to ↑ 76)
↑ 48
(↑ 31 to ↑ 67)
400 once, with food Simultaneously with didanosine 26 ↑64
(↑ 41 to ↑ 89)
↑ 60
(↑ 44 to ↑ 79)
250 once, fasted With food, 2 hr after didanosine 28 ↓10
(↓ 22 to ↑ 3)
250 once, fasted Simultaneously with didanosine 28 ↑14
(0 to ↑ 31)
250 once, with food Simultaneously with
didanosine
28 ↓ 29
(↓ 39 to ↓ 18)
↓ 11
(↓ 23 to ↑ 2)

Efavirenz Assay Interference

Cannabinoid Test Interaction: Efavirenz does not bind to cannabinoid receptors. False-positive urine cannabinoid test results have been observed in non-HIV-infected volunteers receiving efavirenz when the Microgenics CEDIA® DAU Multi-Level THC assay was used for screening. Negative results were obtained when more specific confirmatory testing was performed with gas chromatography/mass spectrometry. For more information, please consult the SUSTIVA prescribing information.

INDICATIONS AND USAGE

ATRIPLA is indicated for use alone as a complete regimen or in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults.

Description of Clinical Studies

Clinical Study 934 supports the use of ATRIPLA Tablets in antiretroviral treatment naïve HIV-1 infected patients. Additional data in support of the use of ATRIPLA in treatment naïve patients can be found in the prescribing information for VIREAD.

In antiretroviral treatment-experienced patients, the use of ATRIPLA Tablets may be considered for patients with HIV strains that are expected to be susceptible to the components of ATRIPLA as assessed by treatment history or by genotypic or phenotypic testing (see MICROBIOLOGY, Drug Resistance and Cross Resistance).

Study 934: Emtricitabine + Tenofovir Disoproxil Fumarate + Efavirenz Compared with Zidovudine/Lamivudine + Efavirenz

Data through 48 weeks are reported for Study 934, a randomized, open-label, active-controlled multicenter study comparing emtricitabine + tenofovir DF administered in combination with efavirenz versus zidovudine/lamivudine fixed-dose combination administered in combination with efavirenz in 511 antiretroviral-naïve patients. Patients had a mean age of 38 years (range 18–80), 86% were male, 59% were Caucasian and 23% were Black. The mean baseline CD4 cell count was 245 cells/mm3 (range 2–1191) and median baseline plasma HIV-1 RNA was 5.01 log10 copies/mL (range 3.56–6.54). Patients were stratified by baseline CD4 count (< or ≥ 200 cells/mm3) and 41% had CD4 cell counts <200 cells/mm3. Fifty-one percent (51%) of patients had baseline viral loads >100,000 copies/mL. Treatment outcomes through 48 weeks for those patients who did not have efavirenz resistance at baseline (n=487) are presented in Table 6.

Table 6 Outcomes of Randomized Treatment at Week 48 (Study 934)
Outcome at Week 48 FTC + TDF + EFV
(N=244)
AZT/3TC+ EFV
(N=243)
% %
*
Patients achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Week 48.
Includes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Week 48.
Includes lost to follow-up, patient withdrawal, noncompliance, protocol violation and other reasons.
Responder* 84% 73%
Virologic failure 2% 4%
  Rebound 1% 3%
  Never suppressed through week 48 0% 0%
  Change in antiretroviral regimen 1% 1%
Death <1% 1%
Discontinued due to adverse event 4% 9%
Discontinued for other reasons 10% 14%

The difference in the proportion of patients who achieved and maintained HIV-1 RNA <400 copies/mL through 48 weeks largely results from the higher number of discontinuations due to adverse events and other reasons in the zidovudine/lamivudine group in this open-label study. In addition, 80% and 70% of patients in the emtricitabine + tenofovir DF and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <50 copies/mL. The mean increase from baseline in CD4 cell count was 190 cells/mm3 in the emtricitabine + tenofovir DF group, and 158 cells/mm3 for the zidovudine/lamivudine group.

Through 48 weeks, 7 patients in the emtricitabine + tenofovir DF group and 5 patients in the zidovudine/lamivudine group experienced a new CDC Class C event.

CONTRAINDICATIONS

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

ATRIPLA 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). ATRIPLA should not be administered concurrently with voriconazole because efavirenz significantly decreases voriconazole plasma concentrations (see CLINICAL PHARMACOLOGY and PRECAUTIONS, Drug Interactions).

WARNINGS

Lactic Acidosis/Severe Hepatomegaly with Steatosis

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 antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with ATRIPLA should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Patients with HIV and HBV Coinfection

It is recommended that all patients with HIV be tested for the presence of HBV before initiating antiretroviral therapy. ATRIPLA is not indicated for the treatment of chronic HBV infection and the safety and efficacy of ATRIPLA have not been established in patients co-infected with HBV and HIV. Severe acute exacerbations of hepatitis B have been reported in patients after the discontinuation of EMTRIVA and VIREAD. Hepatic function should be closely monitored with both clinical and laboratory follow up for at least several months in patients who discontinue ATRIPLA and are coinfected with HIV and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

ALERT

Find out about medicines that should NOT be taken with ATRIPLA.

This statement is also included on the product's bottle labels (see CONTRAINDICATIONS and PRECAUTIONS, Drug Interactions).

Coadministration with Related Drugs

Related drugs not for coadministration with ATRIPLA include EMTRIVA (emtricitabine), VIREAD (tenofovir DF), TRUVADA (emtricitabine/tenofovir DF), and SUSTIVA (efavirenz) which contain the same active components as ATRIPLA. Due to similarities between emtricitabine and lamivudine, ATRIPLA should not be coadministered with drugs containing lamivudine, including COMBIVIR®, EPIVIR®, EPIVIR-HBV®, EPZICOM™, or TRIZIVIR®.

Drug Interactions

(see CONTRAINDICATIONS, CLINICAL PHARMACOLOGY, Drug Interactions, and PRECAUTIONS, Drug Interactions)

Concomitant use of ATRIPLA and St. John's wort (Hypericum perforatum) or St. John's wort-containing products is not recommended. Coadministration of NNRTIs, including efavirenz, with St. John's wort is expected to substantially decrease NNRTI concentrations and may result in suboptimal levels of efavirenz and lead to loss of virologic response and possible resistance to efavirenz or to the class of NNRTIs.

Psychiatric Symptoms

Serious psychiatric adverse experiences have been reported in patients treated with efavirenz. In controlled trials of 1008 patients treated with regimens containing efavirenz for a mean of 2.1 years and 635 patients treated with control regimens for a mean of 1.5 years, the frequency of specific serious psychiatric events among patients who received efavirenz or control regimens, respectively, were: severe depression (2.4%, 0.9%), suicidal ideation (0.7%, 0.3%), nonfatal suicide attempts (0.5%, 0%), aggressive behavior (0.4%, 0.5%), paranoid reactions (0.4%, 0.3%), and manic reactions (0.2%, 0.3%). When psychiatric symptoms similar to those noted above were combined and evaluated as a group in a multifactorial analysis of data from Study AI266006 (006), treatment with efavirenz was associated with an increase in the occurrence of these selected psychiatric symptoms. Other factors associated with an increase in the occurrence of these psychiatric symptoms were history of injection drug use, psychiatric history, and receipt of psychiatric medication at study entry; similar associations were observed in both the efavirenz and control treatment groups. In Study 006, onset of new serious psychiatric symptoms occurred throughout the study for both efavirenz-treated and control-treated patients. One percent of efavirenz-treated patients discontinued or interrupted treatment because of one or more of these selected psychiatric symptoms. There have also been occasional postmarketing reports of death by suicide, delusions, and psychosis-like behavior, although a causal relationship to the use of efavirenz cannot be determined from these reports. Patients with serious psychiatric adverse experiences should seek immediate medical evaluation to assess the possibility that the symptoms may be related to the use of efavirenz, and if so, to determine whether the risks of continued therapy outweigh the benefits (see ADVERSE REACTIONS).

Nervous System Symptoms

Fifty-three percent of patients receiving efavirenz in controlled trials reported central nervous system symptoms compared to 25% of patients receiving control regimens. These symptoms included dizziness (28.1%), insomnia (16.3%), impaired concentration (8.3%), somnolence (7.0%), abnormal dreams (6.2%), and hallucinations (1.2%). Other reported symptoms were euphoria, confusion, agitation, amnesia, stupor, abnormal thinking, and depersonalization. The majority of these symptoms were mild-moderate (50.7%); symptoms were severe in 2.0% of patients. Overall, 2.1% of patients discontinued therapy as a result. These symptoms usually begin during the first or second day of therapy and generally resolve after the first 2–4 weeks of therapy. After 4 weeks of therapy, the prevalence of nervous system symptoms of at least moderate severity ranged from 5% to 9% in patients treated with regimens containing efavirenz and from 3% to 5% in patients treated with a control regimen. Patients should be informed that these common symptoms were likely to improve with continued therapy and were not predictive of subsequent onset of the less frequent psychiatric symptoms (see WARNINGS, Psychiatric Symptoms). Dosing at bedtime may improve the tolerability of these nervous system symptoms (see ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION).

Analysis of long-term data from Study 006, (median follow-up 180 weeks, 102 weeks, and 76 weeks for patients treated with efavirenz + zidovudine + lamivudine, efavirenz + indinavir, and indinavir + zidovudine + lamivudine, respectively) showed that, beyond 24 weeks of therapy, the incidences of new-onset nervous system symptoms among efavirenz-treated patients were generally similar to those in the indinavir-containing control arm.

Patients receiving ATRIPLA should be alerted to the potential for additive central nervous system effects when ATRIPLA is used concomitantly with alcohol or psychoactive drugs.

Patients who experience central nervous system symptoms such as dizziness, impaired concentration, and/or drowsiness should avoid potentially hazardous tasks such as driving or operating machinery.

Renal Impairment

Emtricitabine and tenofovir are principally eliminated by the kidney, however efavirenz is not. Since ATRIPLA is a combination product and the dose of the individual components cannot be altered, patients with creatinine clearance <50 mL/min should not receive ATRIPLA.

Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported in association with the use of tenofovir DF (see ADVERSE REACTIONS, Post Marketing Experience). The majority of these cases occurred in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents; however, some cases occurred in patients without identified risk factors.

ATRIPLA should be avoided with concurrent or recent use of a nephrotoxic agent. Patients at risk for, or with a history of, renal dysfunction and patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus.

Reproductive Risk Potential

Pregnancy Category D

Efavirenz may cause fetal harm when administered during the first trimester to a pregnant woman. Pregnancy should be avoided in women receiving ATRIPLA. Barrier contraception should always be used in combination with other methods of contraception (eg, oral or other hormonal contraceptives). Women of childbearing potential should undergo pregnancy testing before initiation of ATRIPLA. If this drug is used during the first trimester of pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus.

There are no adequate and well-controlled studies of ATRIPLA in pregnant women. 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.

Antiretroviral Pregnancy Registry

To monitor fetal outcomes of pregnant women, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients who become pregnant by calling (800) 258-4263.

Efavirenz

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.

Animal toxicology

Malformations have been observed in 3 of 20 fetuses/infants from efavirenz-treated cynomolgus monkeys (versus 0 of 20 concomitant controls) in a developmental toxicity study. The pregnant monkeys were dosed throughout pregnancy (postcoital days 20–150) with efavirenz 60 mg/kg daily, a dose which resulted in plasma drug concentrations similar to those in humans given 600 mg/day of efavirenz. Anencephaly and unilateral anophthalmia were observed in one fetus, microophthalmia was observed in another fetus, and cleft palate was observed in a third fetus. Efavirenz crosses the placenta in cynomolgus monkeys and produces fetal blood concentrations similar to maternal blood concentrations. Efavirenz has been shown to cross the placenta in rats and rabbits and produces fetal blood concentrations of efavirenz similar to maternal concentrations. An increase in fetal resorptions was observed in rats at efavirenz doses that produced peak plasma concentrations and AUC values in female rats equivalent to or lower than those achieved in humans given 600 mg once daily of efavirenz. Efavirenz produced no reproductive toxicities when given to pregnant rabbits at doses that produced peak plasma concentrations similar to and AUC values approximately half of those achieved in humans given 600 mg once daily of efavirenz.

PRECAUTIONS

Skin Rash

In controlled clinical trials, 26% (266/1008) of patients treated with 600 mg efavirenz experienced new-onset skin rash compared with 17% (111/635) of patients treated in control groups. Rash associated with blistering, moist desquamation, or ulceration occurred in 0.9% (9/1008) of patients treated with efavirenz. The incidence of Grade 4 rash (eg, erythema multiforme, Stevens-Johnson syndrome) in patients treated with efavirenz in all studies and expanded access was 0.1%. Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 2 weeks of initiating therapy with efavirenz (median time to onset of rash in adults was 11 days) and, in most patients continuing therapy with efavirenz, rash resolves within 1 month (median duration, 16 days). The discontinuation rate for rash in clinical trials was 1.7% (17/1008). ATRIPLA can be reinitiated in patients interrupting therapy because of rash. ATRIPLA should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement, or fever. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash.

Experience with efavirenz in patients who discontinued other antiretroviral agents of the NNRTI class is limited. Nineteen patients who discontinued nevirapine because of rash have been treated with efavirenz. Nine of these patients developed mild-to-moderate rash while receiving therapy with efavirenz, and two of these patients discontinued because of rash.

Liver Enzymes

In patients with known or suspected history of hepatitis B or C infection and in patients treated with other medications associated with liver toxicity, monitoring of liver enzymes is recommended (see WARNINGS, Patients with HIV and HBV Coinfection). In patients with persistent elevations of serum transaminases to greater than five times the upper limit of the normal range, the benefit of continued therapy with ATRIPLA needs to be weighed against the unknown risks of significant liver toxicity (see ADVERSE REACTIONS, Laboratory Abnormalities).

Because of the extensive cytochrome P450 mediated metabolism of efavirenz and limited clinical experience in patients with hepatic impairment, caution should be exercised in administering ATRIPLA to these patients.

Bone Effects

In a 144-week study of treatment naïve patients, decreases in bone mineral density (BMD) were seen at the lumbar spine and hip in both arms of the study. At Week 144, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in patients receiving tenofovir DF + lamivudine + efavirenz compared with patients receiving stavudine + lamivudine + efavirenz. Changes in BMD at the hip were similar between the two treatment groups. In both groups, the majority of the reduction in BMD occurred in the first 24–48 weeks of the study and this reduction was sustained through 144 weeks. Twenty-eight percent of tenofovir DF treated patients vs. 21% of the comparator patients lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 patients in the tenofovir DF group and 6 patients in the comparator group. Tenofovir DF was associated with significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C telopeptide, and urinary N telopeptide), suggesting increased bone turnover. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in patients receiving tenofovir DF. The effects of tenofovir DF associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. For additional information, please consult the tenofovir DF prescribing information.

Bone monitoring should be considered for HIV infected patients who have a history of pathologic bone fracture or are at risk for osteopenia. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained.

Convulsions

Convulsions have been observed in patients receiving efavirenz, generally in the presence of known medical history of seizures. Caution must be taken in any patient with a history of seizures.

Patients who are receiving concomitant anticonvulsant medications primarily metabolized by the liver, such as phenytoin, and phenobarbital, may require periodic monitoring of plasma levels (see PRECAUTIONS, Drug Interactions).

Animal toxicology

Nonsustained convulsions were observed in 6 of 20 monkeys receiving efavirenz at doses yielding plasma AUC values 4- to 13-fold greater than those in humans given the recommended dose.

Fat Redistribution

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including the components of ATRIPLA. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment.

Information for Patients

A statement to patients and healthcare providers is included on the product's bottle labels: ALERT: Find out about medicines that should NOT be taken with ATRIPLA. A Patient Package Insert (PPI) for ATRIPLA is available for patient information.

ATRIPLA is not a cure for HIV infection and patients may continue to experience illnesses associated with HIV infection, including opportunistic infections. Patients should remain under the care of a physician when using ATRIPLA.

Patients should be advised that:

Patients should be advised to take ATRIPLA on an empty stomach.

Patients should be informed that central nervous system symptoms including dizziness, insomnia, impaired concentration, drowsiness, and abnormal dreams are commonly reported during the first weeks of therapy with efavirenz. Dosing at bedtime may improve the tolerability of these symptoms, and these symptoms are likely to improve with continued therapy. Patients should be alerted to the potential for additive central nervous system effects when ATRIPLA is used concomitantly with alcohol or psychoactive drugs. Patients should be instructed that if they experience these symptoms they should avoid potentially hazardous tasks such as driving or operating machinery (see WARNINGS, Nervous System Symptoms, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION). In clinical trials, patients who develop central nervous system symptoms were not more likely to subsequently develop psychiatric symptoms (see WARNINGS, Psychiatric Symptoms).

Patients should also be informed that serious psychiatric symptoms including severe depression, suicide attempts, aggressive behavior, delusions, paranoia, and psychosis-like symptoms have also been reported in patients receiving efavirenz. Patients should be informed that if they experience severe psychiatric adverse experiences they should seek immediate medical evaluation to assess the possibility that the symptoms may be related to the use of ATRIPLA, and if so, to determine whether discontinuation of ATRIPLA may be required. Patients should also inform their physician of any history of mental illness or substance abuse (see WARNINGS, Psychiatric Symptoms).

Patients should be informed that another common side effect is rash. These rashes usually go away without any change in treatment. In a small number of patients, rash may be serious. Patients should be advised that they should contact their physician promptly if they develop a rash.

Women receiving ATRIPLA should be instructed to avoid pregnancy (see WARNINGS, Reproductive Risk Potential). A reliable form of barrier contraception should always be used in combination with other methods of contraception, including oral or other hormonal contraception, because the effects of efavirenz on hormonal contraceptives are not fully characterized. Women should be advised to notify their physician if they become pregnant or plan to become pregnant while taking ATRIPLA. If this drug is used during the first trimester of pregnancy, or if the patient becomes pregnant while taking this drug, she should be apprised of the potential harm to the fetus.

ATRIPLA may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other prescription, nonprescription medication, or herbal products, particularly St. John's wort.

Animal Toxicology

Tenofovir and tenofovir DF administered in toxicology studies to rats, dogs and monkeys at exposures (based on AUCs) greater than or equal to 6-fold those observed in humans caused bone toxicity. In monkeys the bone toxicity was diagnosed as osteomalacia. Osteomalacia observed in monkeys appeared to be reversible upon dose reduction or discontinuation of tenofovir. In rats and dogs, the bone toxicity manifested as reduced bone mineral density. The mechanism(s) underlying bone toxicity is unknown.

Evidence of renal toxicity was noted in 4 animal species administered tenofovir and tenofovir DF. Increases in serum creatinine, BUN, glycosuria, proteinuria, phosphaturia and/or calciuria and decreases in serum phosphate were observed to varying degrees in these animals. These toxicities were noted at exposures (based on AUCs) 2–20 times higher than those observed in humans. The relationship of the renal abnormalities, particularly the phosphaturia, to the bone toxicity is not known.

Drug Interactions

(see CONTRAINDICATIONS and CLINICAL PHARMACOLOGY, Drug Interactions)

Efavirenz

Efavirenz has been shown in vivo to induce CYP3A4. Other compounds that are substrates of CYP3A4 may have decreased plasma concentrations when coadministered with efavirenz. In vitro studies have demonstrated that efavirenz inhibits 2C9, 2C19, and 3A4 isozymes in the range of observed efavirenz plasma concentrations. Coadministration of efavirenz with drugs primarily metabolized by these isozymes may result in altered plasma concentrations of the coadministered drug. Therefore, appropriate dose adjustments may be necessary for these drugs.

Drugs which induce CYP3A4 activity (eg, phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations.

Emtricitabine and tenofovir disoproxil fumarate

Since emtricitabine and tenofovir are primarily eliminated by the kidneys, coadministration of ATRIPLA with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of emtricitabine, tenofovir, and/or other renally eliminated drugs. Some examples include, but are not limited to, adefovir dipivoxil, cidofovir, acyclovir, valacyclovir, ganciclovir, and valganciclovir.

Coadministration of tenofovir DF and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse events. Didanosine should be discontinued in patients who develop didanosine-associated adverse events (for didanosine dosing adjustment recommendations, see Table 8 in the PRECAUTIONS Section).

Atazanavir and lopinavir/ritonavir have been shown to increase tenofovir concentrations. The mechanism of this interaction is unknown. Higher tenofovir concentrations could potentiate tenofovir-associated adverse events, including renal disorders. Patients receiving either atazanavir or lopinavir/ritonavir with tenofovir DF should be monitored for tenofovir-associated adverse events. ATRIPLA should be discontinued in patients who develop tenofovir-associated adverse events (for atazanavir dosing adjustment recommendations, see Table 8 in the PRECAUTIONS Section).

Other important drug interaction information for ATRIPLA is summarized in Tables 7 and 8. The drug interactions described are based on studies conducted with efavirenz, emtricitabine or tenofovir DF as individual agents or are potential drug interactions; no drug interaction studies have been conducted using ATRIPLA. The tables include potentially significant interactions, but are not all inclusive.

Table 7 Drugs That Are Contraindicated or Not Recommended for Use With ATRIPLA
Drug Class: Drug Name Clinical Comment
Antifungal: voriconazole CONTRAINDICATED because efavirenz significantly decreases voriconazole plasma concentrations, and coadministration may decrease the therapeutic effectiveness of voriconazole. Also, voriconazole significantly increases efavirenz plasma concentrations, which may increase the risk of efavirenz-associated side effects. See Tables 1 and 2.
Antihistamine: astemizole CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Antimigraine: ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine) CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
Antiretrovirals: EMTRIVA, VIREAD, TRUVADA, SUSTIVA, COMBIVIR, EPIVIR, EPIVIR-HBV, EPZICOM, TRIZIVIR Not for use with ATRIPLA because the active ingredients of EMTRIVA (emtricitabine), VIREAD (tenofovir DF), TRUVADA (emtricitabine/tenofovir DF) and SUSTIVA (efavirenz) are components of ATRIPLA. Lamivudine, which is similar to emtricitabine, is a component of COMBIVIR, EPIVIR, EPIVIR-HBV, EPZICOM, and TRIZIVIR.
Benzodiazepines: midazolam, triazolam CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.
GI motility agent: cisapride CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
St. John's wort (Hypericum perforatum) NOT RECOMMENDED: Expected to substantially decrease plasma levels of efavirenz; has not been studied in combination with efavirenz.
Table 8 Established* and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name Effect Clinical Comment
*
See Tables 1–5
This table is not all inclusive.
Antiretroviral agents
Protease inhibitor:
  Amprenavir
↓ amprenavir concentration Efavirenz has the potential to decrease serum concentrations of amprenavir.
Protease inhibitor:
  Fosamprenavir calcium
↓ amprenavir concentration Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established.
Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor:
  Atazanavir
↓ atazanavir concentration

↑ tenofovir concentration
Plasma concentrations of atazanavir were decreased by both efavirenz and tenofovir DF. Sufficient data are not available to make a dosing recommendation for atazanavir or atazanavir/ritonavir with ATRIPLA. Therefore, co-administration of ATRIPLA and atazanavir is not recommended due to concerns regarding decreased atazanavir concentrations.
Protease inhibitor:
  Indinavir
↓ indinavir concentration The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz.
Protease inhibitor:
  Lopinavir/ritonavir
↓ lopinavir concentration

↑ tenofovir concentration
A dose increase of lopinavir/ritonavir to 600/150 mg (3 tablets) twice daily may be considered when used in combination with efavirenz in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). Patients should be monitored for tenofovir-associated adverse events. ATRIPLA should be discontinued in patients who develop tenofovir-associated adverse events.
Protease inhibitor:
  Ritonavir
↑ ritonavir concentration

↑ efavirenz concentration
When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (eg, dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir.
Protease inhibitor:
  Saquinavir
↓ saquinavir concentration Should not be used as sole protease inhibitor in combination with ATRIPLA.
NRTI:
  Didanosine
↑ didanosine concentration Higher didanosine concentrations could potentiate didanosine-associated adverse events, including pancreatitis, and neuropathy. In adults weighing >60 kg, the didanosine dose should be reduced to 250 mg if coadministered with ATRIPLA. Data are not available to recommend a dose adjustment of didanosine for patients weighing <60 kg. When co-administered, ATRIPLA and VIDEX® EC may be taken under fasted conditions or with a light meal (<400 kcal, 20% fat). Coadministration of didanosine buffered formulation with ATRIPLA should be under fasted conditions. Coadministration of ATRIPLA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse events. For additional information, please consult the Videx / Videx EC (didanosine) prescribing information.
Other agents
Anticoagulant:
  Warfarin
↑ or ↓ warfarin concentration Plasma concentrations and effects potentially increased or decreased by efavirenz.
Anticonvulsants:
  Carbamazepine
↓ carbamazepine concentration
↓ efavirenz concentration
There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used.
  Phenytoin
  Phenobarbital
↓ anticonvulsant concentration

↓ efavirenz concentration
Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressant:
  Sertraline
↓ sertraline concentration Increases in sertraline dose should be guided by clinical response.
Antifungals:
  Itraconazole
  Ketoconazole
↓ antifungal concentration Drug interaction studies with ATRIPLA and these imidazole and triazole antifungals have not been conducted. Efavirenz has the potential to decrease plasma concentrations of itraconazole and ketoconazole.
Anti-infective:
  Clarithromycin
↓ clarithromycin concentration

↑ 14-OH metabolite concentration
Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of ATRIPLA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA.
Antimycobacterial:
  Rifabutin
↓ rifabutin concentration Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
Antimycobacterial:
  Rifampin
↓ efavirenz concentration Clinical significance of reduced efavirenz concentrations is unknown.
HMG-CoA reductase inhibitors:
  Atorvastatin
  Pravastatin
  Simvastatin
↓ atorvastatin concentration

↓ pravastatin concentration

↓ simvastatin concentration
Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the complete prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Narcotic analgesic:
  Methadone
↓ methdone concentration Coadministration of efavirenz in HIV-infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.
Oral contraceptive:
  Ethinyl estradiol
↑ ethinyl estradiol concentration Clinical significance unknown. Because the potential interaction of efavirenz with oral contraceptives has not been fully characterized, a reliable method of barrier contraception should be used in addition to oral contraceptives.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Efavirenz

Long-term carcinogenicity studies in mice and rats were carried out with efavirenz. Mice were dosed with 0, 25, 75, 150, or 300 mg/kg/day for 2 years. Incidences of hepatocellular adenomas and carcinomas and pulmonary alveolar/bronchiolar adenomas were increased above background in females. No increases in tumor incidence above background were seen in males. In studies in which rats were administered efavirenz at doses of 0, 25, 50, or 100 mg/kg/day for 2 years, no increases in tumor incidence above background were observed. The systemic exposure (based on AUCs) in mice was approximately 1.7-fold that in humans receiving the 600-mg/day dose. The exposure in rats was lower than that in humans. The mechanism of the carcinogenic potential is unknown. However, in genetic toxicology assays, efavirenz showed no evidence of mutagenic or clastogenic activity in a battery of in vitro and in vivo studies. These included bacterial mutation assays in S. typhimurium and E. coli, mammalian mutation assays in Chinese hamster ovary cells, chromosome aberration assays in human peripheral blood lymphocytes or Chinese hamster ovary cells, and an in vivo mouse bone marrow micronucleus assay. Given the lack of genotoxic activity of efavirenz, the relevance to humans of neoplasms in efavirenz-treated mice is not known.

Efavirenz did not impair mating or fertility of male or female rats, and did not affect sperm of treated male rats. The reproductive performance of offspring born to female rats given efavirenz was not affected. As a result of the rapid clearance of efavirenz in rats, systemic drug exposures achieved in these studies were equivalent to or below those achieved in humans given therapeutic doses of efavirenz.

Emtricitabine

In long-term carcinogenicity studies of emtricitabine, no drug-related increases in tumor incidence were found in mice at doses up to 750 mg/kg/day (26 times the human systemic exposure at the therapeutic dose of 200 mg/day) or in rats at doses up to 600 mg/day (31 times the human systemic exposure at the therapeutic dose).

Emtricitabine was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or mouse micronucleus assays.

Emtricitabine did not affect fertility in male rats at approximately 140-fold or in male and female mice at approximately 60-fold higher exposures (AUC) than in humans given the recommended 200 mg daily dose. Fertility was normal in the offspring of mice exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60-fold higher than human exposures at the recommended 200 mg daily dose.

Tenofovir disoproxil fumarate

Long-term oral carcinogenicity studies of tenofovir DF in mice and rats were carried out at exposures up to approximately 16 times (mice) and 5 times (rats) those observed in humans at the therapeutic dose for HIV infection. At the high dose in female mice, liver adenomas were increased at exposures 16 times that in humans. In rats, the study was negative for carcinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose.

Tenofovir DF was mutagenic in the in vitro mouse lymphoma assay and negative in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, tenofovir DF was negative when administered to male mice.

There were no effects on fertility, mating performance or early embryonic development when tenofovir DF was administered to male rats at a dose equivalent to 10 times the human dose based on body surface area comparisons for 28 days prior to mating and to female rats for 15 days prior to mating through day seven of gestation. There was, however, an alteration of the estrous cycle in female rats.

Pregnancy

Pregnancy Category D

(see WARNINGS, Reproductive Risk Potential)

Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. Studies in rats have demonstrated that both efavirenz and tenofovir are secreted in milk. It is not known whether efavirenz, emtricitabine, or tenofovir is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving ATRIPLA.

Pediatric Use

ATRIPLA is not recommended for patients less than 18 years of age because it is a fixed-dose combination tablet containing a component, tenofovir DF, for which safety and efficacy have not been established in this age group.

Geriatric Use

Clinical studies of efavirenz, emtricitabine, or tenofovir DF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for the elderly patients should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

ADVERSE REACTIONS

For additional safety information about SUSTIVA (efavirenz), EMTRIVA (emtricitabine) or VIREAD (tenofovir DF) in combination with other antiretroviral agents, consult the Prescribing Information for these products.

In addition to the adverse events in study 934 (Table 9), the following adverse events were observed in clinical studies of efavirenz, emtricitabine, or tenofovir DF in combination with other antiretroviral agents.

Efavirenz: The most significant adverse events observed in patients treated with efavirenz are nervous system symptoms (see WARNINGS, Nervous System Symptoms), psychiatric symptoms (see WARNINGS, Psychiatric Symptoms), and rash (see PRECAUTIONS, Skin Rash).

Selected clinical adverse experiences of moderate or severe intensity observed in ≥2% of efavirenz-treated patients in two controlled clinical trials included pain, impaired concentration, anorexia, dyspepsia, abdominal pain, anxiety, nervousness, and pruritus.

Pancreatitis has been reported, although a causal relationship with efavirenz has not been established. Asymptomatic increases in serum amylase levels were observed in a significantly higher number of patients treated with efavirenz 600 mg than in control patients.

Emtricitabine and tenofovir disoproxil fumarate: Adverse events that occurred in at least 5% of patients receiving emtricitabine or tenofovir DF with other antiretroviral agents in clinical trials include anxiety, arthralgia, increased cough, dyspepsia, fever, myalgia, pain, abdominal pain, back pain, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), pneumonia, rhinitis and rash event (including rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, pustular rash and allergic reaction).

Skin discoloration has been reported with higher frequency among emtricitabine treated patients. Skin discoloration, manifested by hyperpigmentation on the palms and/or soles was generally mild and asymptomatic. The mechanism and clinical significance are unknown.

In addition to the laboratory abnormalities described above for Study 934 (Table 10), Grade 3/4 elevations of bilirubin (>2.5 × ULN), pancreatic amylase (>2.0 × ULN), serum glucose (<40 or >250 mg/dL), serum lipase (>2.0 × ULN), and urine glucose (≥3+) occurred in up to 3% of patients treated with emtricitabine or tenofovir DF with other antiretroviral agents in clinical trials.

Clinical Trials

Study 934 - Treatment Emergent Adverse Events

Study 934 was an open-label active-controlled study in which 511 antiretroviral-naïve patients received either emtricitabine + tenofovir DF administered in combination with efavirenz (N=257) or zidovudine/lamivudine administered in combination with efavirenz (N=254). Adverse events observed in this study, regardless of treatment relationship, are shown in Table 9.

Table 9 Selected Treatment-Emergent Adverse Events (Grades 2–4) Reported in ≥3% in Any Treatment Group in Study 934 (0–48 weeks)
FTC + TDF + EFV AZT/3TC + EFV
(N=257) (N=254)
Gastrointestinal Disorder
  Diarrhea 7% 4%
  Nausea 8% 6%
  Vomiting 1% 4%
General Disorders and Administration Site Condition
  Fatigue 7% 6%
Infections and Infestations
  Sinusitis 4% 2%
  Upper respiratory tract infections 3% 3%
  Nasopharyngitis 3% 1%
Nervous System Disorders
  Somnolence 3% 2%
  Headache 5% 4%
  Dizziness 8% 7%
Psychiatric Disorders
  Depression 4% 7%
  Insomnia 4% 5%
  Abnormal dreams 4% 3%
Skin and Subcutaneous Tissue Disorders
  Rash 5% 4%

Laboratory Abnormalities

Laboratory abnormalities observed in this study were generally consistent with those seen in other studies (Table 10).

Table 10 Significant Laboratory Abnormalities Reported in ≥1% in Any Treatment Group in Study 934 (0–48 weeks)
FTC + TDF + EFV AZT/3TC + EFV
(N=257) (N=254)
Any ≥ Grade 3 Laboratory Abnormality 25% 22%
Fasting Cholesterol
(>240 mg/mL)
15% 17%
Creatine Kinase
(M: >990 U/L)
(F: >845 U/L)
7% 6%
Serum Amylase (>175 U/L) 7% 3%
Alkaline Phosphatase (>550 U/L) 1% 0%
AST
(M: >180 U/L)
(F: >170 U/L)
3% 2%
ALT
(M: >215 U/L)
(F: >170 U/L)
2% 2%
Hemoglobin (<8.0 mg/dL) 0% 3%
Hyperglycemia (>250 mg/dL) 1% 1%
Hematuria (>75 RBC/HPF) 2% 2%
Neutrophil (<750/mm3) 3% 4%
Fasting Triglyceride (>750 mg/dL) 4% 2%

Lipids

In Study 934 at Week 48, the mean increase from baseline fasting triglyceride concentrations was 3 mg/dL for the tenofovir DF, emtricitabine and efavirenz group and 31 mg/dL for the zidovudine/lamivudine and efavirenz group. For fasting total, LDL, and HDL cholesterol concentrations, the mean increases from baseline were 21 mg/dL, 13 mg/dL, and 6 mg/dL, respectively, for the tenofovir DF group and 35 mg/dL, 20 mg/dL, and 9 mg/dL, respectively, for the zidovudine/lamivudine group.

Hepatic Events

In Study 934, 10 patients treated with efavirenz, emtricitabine, and tenofovir DF and 16 patients treated with efavirenz and fixed-dose zidovudine/lamivudine were hepatitis C antibody positive. Among these HCV coinfected patients, one patient (1/10) in the efavirenz, emtricitabine and tenofovir DF arm had elevations in ALT and AST to greater than five times ULN through 48 weeks. One patient (1/16) in the fixed-dose zidovudine/lamivudine arm had elevations in ALT to greater than five times ULN through 48 weeks. Nine patients treated with efavirenz, emtricitabine and tenofovir DF and 4 patients treated with efavirenz and fixed-dose zidovudine/lamivudine were hepatitis B surface antigen positive. None of these patients had treatment-emergent elevations in ALT and AST to greater than five times ULN through 48 weeks. No HBV and/or HCV coinfected patient discontinued from the study due to hepatobiliary disorders (see PRECAUTIONS, Liver Enzymes).

Post Marketing Experience

In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of efavirenz, emtricitabine, or tenofovir DF. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion because of a combination of their seriousness, frequency of reporting or potential causal connection

Efavirenz

CARDIAC DISORDERS

Palpitations

EAR AND LABYRINTH DISORDERS

Tinnitus

ENDOCRINE DISORDERS

Gynecomastia

EYE DISORDERS

Abnormal vision

GASTROINTESTINAL DISORDERS

Constipation, Malabsorption

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS

Asthenia

HEPATOBILIARY DISORDERS

Hepatic enzyme increase, Hepatic failure, Hepatitis

IMMUNE SYSTEM DISORDERS

Allergic reactions

METABOLISM AND NUTRITION DISORDERS

Redistribution/accumulation of body fat (see PRECAUTIONS, Fat Redistribution), Hypercholesterolemia, Hypertriglyceridemia

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS

Arthralgia, Myalgia, Myopathy

NERVOUS SYSTEM DISORDERS

Abnormal coordination, Ataxia, Convulsions, Hypoesthesia, Paresthesia, Nneuropathy, Tremor

PSYCHIATRIC DISORDERS

Aggressive reactions, Agitation, Delusions, Emotional lability, Mania, Neurosis, Paranoia, Psychosis, Suicide

RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS

Dyspnea

SKIN AND SUBCUTANEOUS TISSUE DISORDERS

Flushing, Erythema multiforme, Nail disorders, Photoallergic dermatitis, Skin discoloration, Stevens-Johnson syndrome

Emtricitabine

No additional events have been identified for inclusion in this section.

Tenofovir disoproxil fumarate

IMMUNE SYSTEM DISORDERS

Allergic reaction

METABOLISM AND NUTRITION DISORDERS

Hypophosphatemia, Lactic acidosis

RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS

Dyspnea

GASTROINTESTINAL DISORDERS

Abdominal pain, Increased amylase, Pancreatitis

HEPATOBILIARY DISORDERS

Increased liver enzymes, Hepatitis

RENAL AND URINARY DISORDERS

Renal insufficiency, Renal failure, Acute renal failure, Fanconi syndrome, Proximal tubulopathy, Proteinuria, Increased creatinine, Acute tubular necrosis, Nephrogenic diabetes insipidus, Polyuria, Nephritis

OVERDOSAGE

If overdose occurs, the patient should be monitored for evidence of toxicity, including monitoring of vital signs and observation of the patient's clinical status; standard supportive treatment should then be applied as necessary. Administration of activated charcoal may be used to aid removal of unabsorbed efavirenz. Hemodialysis can remove both emtricitabine and tenofovir DF (refer to detailed information below), but is unlikely to significantly remove efavirenz from the blood.

Efavirenz

Some patients accidentally taking 600 mg twice daily have reported increased nervous system symptoms. One patient experienced involuntary muscle contractions.

Emtricitabine

Limited clinical experience is available at doses higher than the therapeutic dose of emtricitabine. In one clinical pharmacology study single doses of emtricitabine 1200 mg were administered to 11 patients. No severe adverse reactions were reported.

Hemodialysis treatment removes approximately 30% of the emtricitabine dose over a 3-hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL/min and a dialysate flow rate of 600 mL/min). It is not known whether emtricitabine can be removed by peritoneal dialysis.

Tenofovir disoproxil fumarate

Limited clinical experience at doses higher than the therapeutic dose of tenofovir DF 300 mg is available. In one study, 600 mg tenofovir DF was administered to 8 patients orally for 28 days, and no severe adverse reactions were reported. The effects of higher doses are not known.

Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of tenofovir DF, a 4-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

DOSAGE AND ADMINISTRATION

Adults: The dose of ATRIPLA is one tablet once daily taken orally on an empty stomach. Dosing at bedtime may improve the tolerability of nervous system symptoms.

Pediatrics: ATRIPLA is not recommended for use in patients <18 years of age.

Renal Impairment

Because ATRIPLA is a fixed-dose combination, it should not be prescribed for patients requiring dosage adjustment such as those with moderate or severe renal impairment (creatinine clearance <50 mL/min).

HOW SUPPLIED

ATRIPLA is available as tablets. Each tablet contains 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir DF (which is equivalent to 245 mg of tenofovir disoproxil). The tablets are pink, capsule-shaped, film-coated, debossed with "123" on one side and plain-faced on the other side. Each bottle contains 30 tablets (NDC 15584-0101-1) and silica gel desiccant, and is closed with a child-resistant closure.

Store at 25 °C (77 °F); excursions permitted to 15–30 °C (59–86 °F) [see USP Controlled Room Temperature].

Bristol-Myers Squibb & Gilead Sciences, LLC
Foster City, CA 94404

July, 2006

GS-21-937-001

EMTRIVA, TRUVADA, and VIREAD are trademarks of Gilead Sciences, Inc. SUSTIVA is a trademark of Bristol-Myers Squibb Pharma Company. REYATAZ and VIDEX are trademarks of Bristol-Myers Squibb Company. Other brands listed are the trademarks of their respective owners and are not trademarks of Gilead Sciences, Inc, Bristol-Myers Squibb Company, or Bristol-Myers Squibb & Gilead Sciences, LLC.

© 2006 Bristol-Myers Squibb & Gilead Sciences, LLC

© 2006 Bristol-Myers Squibb Company

© 2006 Gilead Sciences, Inc.

Patient Information
ATRIPLA™ (uh TRIP luh) Tablets

ALERT: Find out about medicines that should NOT be taken with ATRIPLA.

Please also read the section " MEDICINES YOU SHOULD NOT TAKE WITH ATRIPLA."

Generic name: efavirenz, emtricitabine and tenofovir disoproxil fumarate (eh FAH vih renz, em tri SIT uh bean and te NOE' fo veer dye soe PROX il FYOU mar ate)

Read the Patient Information that comes with ATRIPLA before you start taking it and each time you get a refill since there may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. You should stay under a healthcare provider's care when taking ATRIPLA. Do not change or stop your medicine without first talking with your healthcare provider. Talk to your healthcare provider or pharmacist if you have any questions about ATRIPLA.

What is the most important information I should know about ATRIPLA?

What is ATRIPLA?

ATRIPLA contains 3 medicines, SUSTIVA® (efavirenz), EMTRIVA® (emtricitabine) and VIREAD® (tenofovir disoproxil fumarate also called tenofovir DF) combined in one pill. EMTRIVA and VIREAD are HIV (human immunodeficiency virus) nucleoside analog reverse transcriptase inhibitors (NRTIs) and SUSTIVA is an HIV non-nucleoside analog reverse transcriptase inhibitor (NNRTI). VIREAD and EMTRIVA are the components of TRUVADA®. ATRIPLA can be used alone as a complete regimen, or in combination with other anti-HIV medicines to treat people with HIV infection. ATRIPLA is for adults age 18 and over. ATRIPLA has not been studied in children under age 18 or adults over age 65.

HIV infection destroys CD4 (T) cells, which are important to the immune system. The immune system helps fight infection. After a large number of T cells are destroyed, acquired immune deficiency syndrome (AIDS) develops.

ATRIPLA helps block HIV reverse transcriptase, a viral chemical in your body (enzyme) that is needed for HIV to multiply. ATRIPLA lowers the amount of HIV in the blood (viral load). ATRIPLA may also help to increase the number of T cells (CD4 cells), allowing your immune system to improve. Lowering the amount of HIV in the blood lowers the chance of death or infections that happen when your immune system is weak (opportunistic infections).

Does ATRIPLA cure HIV-1 or AIDS?

ATRIPLA does not cure HIV infection or AIDS. The long-term effects of ATRIPLA are not known at this time. People taking ATRIPLA may still get opportunistic infections or other conditions that happen with HIV infection. Opportunistic infections are infections that develop because the immune system is weak. Some of these conditions are pneumonia, herpes virus infections, and Mycobacterium avium complex (MAC) infection. It is very important that you see your healthcare provider regularly while taking ATRIPLA.

Does ATRIPLA reduce the risk of passing HIV-1 to others?

ATRIPLA has not been shown to lower your chance of passing HIV to other people through sexual contact, sharing needles, or being exposed to your blood.

Who should not take ATRIPLA?

Together with your healthcare provider, you need to decide whether ATRIPLA is right for you.

Do not take ATRIPLA if you are allergic to ATRIPLA or any of its ingredients. The active ingredients of ATRIPLA are efavirenz, emtricitabine, and tenofovir DF. See the end of this leaflet for a complete list of ingredients.

What should I tell my healthcare provider before taking ATRIPLA?

Tell your healthcare provider if you:

What important information should I know about taking other medicines with ATRIPLA?

ATRIPLA may change the effect of other medicines, including the ones for HIV, and may cause serious side effects. Your healthcare provider may change your other medicines or change their doses. Other medicines, including herbal products, may affect ATRIPLA. For this reason, it is very important to let all your healthcare providers and pharmacists know what medications, herbal supplements, or vitamins you are taking.

MEDICINES YOU SHOULD NOT TAKE WITH ATRIPLA

It is also important to tell your healthcare provider if you are taking any of the following:

These are not all the medicines that may cause problems if you take ATRIPLA. Be sure to tell your healthcare provider about all medicines that you take.

Keep a complete list of all the prescription and nonprescription medicines as well as any herbal remedies that you are taking, how much you take, and how often you take them. Make a new list when medicines or herbal remedies are added or stopped, or if the dose changes. Give copies of this list to all of your healthcare providers and pharmacist every time you visit your healthcare provider or fill a prescription. This will give your healthcare provider a complete picture of the medicines you use. Then he or she can decide the best approach for your situation.

How should I take ATRIPLA?

What should I avoid while taking ATRIPLA?

What are the possible side effects of ATRIPLA?

ATRIPLA may cause the following serious side effects

Common side effects: Patients may have dizziness, headache, trouble sleeping, drowsiness, trouble concentrating, and/or unusual dreams during treatment with ATRIPLA. These side effects may be reduced if you take ATRIPLA at bedtime on an empty stomach. They also tend to go away after you have taken the medicine for a few weeks. If you have these common side effects, such as dizziness, it does not mean that you will also have serious psychiatric problems, such as severe depression, strange thoughts, or angry behavior. Tell your healthcare provider right away if any of these side effects continue or if they bother you. It is possible that these symptoms may be more severe if ATRIPLA is used with alcohol or mood altering (street) drugs.

If you are dizzy, have trouble concentrating, or are drowsy, avoid activities that may be dangerous, such as driving or operating machinery.

Rash may be common. Rashes usually go away without any change in treatment. In a small number of patients, rash may be serious. If you develop a rash, call your healthcare provider right away.

Other common side effects include tiredness, upset stomach, vomiting, gas, and diarrhea.

Other possible side effects with ATRIPLA include:

Tell your healthcare provider or pharmacist if you notice any side effects while taking ATRIPLA.

Contact your healthcare provider before stopping ATRIPLA because of side effects or for any other reason.

This is not a complete list of side effects possible with ATRIPLA. Ask your healthcare provider or pharmacist for a more complete list of side effects of ATRIPLA and all the medicines you will take.

How do I store ATRIPLA?

General information about ATRIPLA:

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use ATRIPLA for a condition for which it was not prescribed. Do not give ATRIPLA to other people, even if they have the same symptoms you have. It may harm them.

This leaflet summarizes the most important information about ATRIPLA. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about ATRIPLA that is written for health professionals.

Do not use ATRIPLA if the seal over bottle opening is broken or missing.

What are the ingredients of ATRIPLA?

Active Ingredients: efavirenz, emtricitabine, and tenofovir disoproxil fumarate

Inactive Ingredients: croscarmellose sodium, hydroxypropyl cellulose, microcrystalline cellulose, magnesium stearate, sodium lauryl sulfate.The film coating contains black iron oxide, polyethylene glycol, polyvinyl alcohol, red iron oxide, talc, and titanium dioxide.

Rx Only

July, 2006

GS-21-937-001

EMTRIVA, TRUVADA, and VIREAD are trademarks of Gilead Sciences, Inc. SUSTIVA is a trademark of Bristol-Myers Squibb Pharma Company. REYATAZ and VIDEX are trademarks of Bristol-Myers Squibb Company. PRAVACHOL® is a registered trademark of ER Squibb & Sons, LLC. Other brands listed are the trademarks of their respective owners and are not trademarks of Gilead Sciences, Inc, Bristol-Myers Squibb Company, or Bristol-Myers Squibb & Gilead Sciences, LLC.

© 2006 Bristol-Myers Squibb & Gilead Sciences, LLC

© 2006 Bristol-Myers Squibb Company

© 2006 Gilead Sciences, Inc.


ATRIPLA (efavirenz, emtricitabine and tenofovir disoproxil fumarate)
PRODUCT INFO
Product Code 15584-0101 Dosage Form TABLET, MULTILAYER
Route Of Administration ORAL DEA Schedule
INGREDIENTS
Name (Active Moiety) Type Strength
Efavirenz (Efavirenz) Active 600 MILLIGRAM  In 1 TABLET
Emtricitabine (Emtricitabine) Active 200 MILLIGRAM  In 1 TABLET
Tenofovir Disoproxil Fumarate (Tenofovir) Active 300 MILLIGRAM  In 1 TABLET
Croscarmellose Sodium Inactive 80 MILLIGRAM  In 1 TABLET
Hydroxypropyl cellulose Inactive 38.4 MILLIGRAM  In 1 TABLET
Magnesium Stearate Inactive 22.8 MILLIGRAM  In 1 TABLET
Microcrystalline Cellulose Inactive 226.8 MILLIGRAM  In 1 TABLET
Sodium lauryl sulfate Inactive 12 MILLIGRAM  In 1 TABLET
Opadry II Pink 85F94172 Inactive 44.4 MILLIGRAM  In 1 TABLET
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color PINK (pink) Score 1
Shape OVAL (CAPSULE) Symbol false
Imprint Code 123 Coating true
Size 20mm
PACKAGING
# NDC Package Description Multilevel Packaging
1 15584-0101-1 30 TABLET In 1 BOTTLE, PLASTIC None

Revised: 07/2006Gilead Sciences, Inc.

Data are from FDA and U.S. National Library of Medicine.