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ATRIPLA Label and ATRIPLA General Information

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atripla (efavirenz, emtricitabine and tenofovir disoproxil fumarate)  tablet, multilayer 
[Gilead Sciences, Inc.]

Rx Only

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:

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:

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:

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 a, ß, ?, and d 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 a, ß, e, and mitochondrial DNA polymerase ?.

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 a, ß, and mitochondrial DNA polymerase ?.

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:

• the use of ATRIPLA has not been shown to reduce the risk of transmission of HIV to others through sexual contact or blood contamination,
• the long term effects of ATRIPLA are unknown,
• ATRIPLA Tablets are for oral ingestion only,
• it is important to take ATRIPLA on a regular dosing schedule to avoid missing doses,
• redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known.
• ATRIPLA should not be coadministered with SUSTIVA, EMTRIVA, VIREAD, or TRUVADA, or drugs containing lamivudine, including COMBIVIR, EPIVIR, EPIVIR-HBV, EPZICOM, or TRIZIVIR.

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 d