2.1 Testing Prior to Initiation and During Treatment with ATRIPLA

Prior to or when initiating ATRIPLA, test patients for hepatitis B virus infection [see Warnings and Precautions (5.1)].

Prior to initiation and during use of ATRIPLA, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus [see Warnings and Precautions (5.7)].

Monitor hepatic function prior to and during treatment with ATRIPLA [see Warnings and Precautions (5.3)].

Perform pregnancy testing before initiation of ATRIPLA in adolescents and adults of childbearing potential [see Warnings and Precautions (5.8), Use in Specific Populations (8.1, 8.3)].

2.2 Recommended Dosage for Adults and Pediatric Patients Weighing at Least 40 kg

ATRIPLA is a three-drug fixed-dose combination product containing 600 mg of efavirenz (EFV), 200 mg of emtricitabine (FTC), and 300 mg of tenofovir disoproxil fumarate (TDF). The recommended dosage of ATRIPLA in adults and pediatric patients weighing at least 40 kg is one tablet once daily taken orally on an empty stomach. Dosing at bedtime may improve the tolerability of nervous system symptoms [see Clinical Pharmacology (12.3)].

2.3 Not Recommended in Patients with Moderate or Severe Renal Impairment

ATRIPLA is not recommended in patients with moderate or severe renal impairment (estimated creatinine clearance below 50 mL/min) [see Warnings and Precautions (5.7), Use in Specific Populations (8.6)].

2.4 Not Recommended in Patients with Moderate to Severe Hepatic Impairment

ATRIPLA is not recommended in patients with moderate to severe hepatic impairment (Child-Pugh B or C) [see Warnings and Precautions (5.3) and Use in Specific Populations (8.7)].

2.5 Dosage Adjustment with Rifampin

If ATRIPLA is co-administered with rifampin in patients weighing 50 kg or more, take one tablet of ATRIPLA once daily followed by one additional 200 mg per day of efavirenz [see Drug Interactions (7.3) and Clinical Pharmacology (12.3)].

5.1 Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV

All patients should be tested for the presence of chronic HBV before or when initiating antiretroviral therapy [see Dosage and Administration (2.1)]. Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued FTC or TDF, two of the components of ATRIPLA. Patients who are coinfected with HIV-1 and HBV should be closely monitored, with both clinical and laboratory follow-up for at least several months after stopping treatment with ATRIPLA. If appropriate, initiation of anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.

5.2 Rash

In controlled clinical trials, 26% (266/1,008) of adult subjects treated with 600 mg EFV experienced new-onset skin rash compared with 17% (111/635) of those treated in control groups. Rash associated with blistering, moist desquamation, or ulceration occurred in 0.9% (9/1,008) of subjects treated with EFV. The incidence of Grade 4 rash (e.g., erythema multiforme, Stevens-Johnson syndrome) in adult subjects treated with EFV in all trials 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 EFV (median time to onset of rash in adults was 11 days) and, in most subjects continuing therapy with EFV, rash resolves within 1 month (median duration, 16 days). The discontinuation rate for rash in adult clinical trials was 1.7% (17/1,008). 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. For patients who have had a life-threatening cutaneous reaction (e.g., Stevens-Johnson syndrome), alternative therapy should be considered [see Contraindications (4)].

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

Rash was reported in 59 of 182 pediatric subjects (32%) treated with EFV [see Adverse Reactions (6.1)]. Two pediatric subjects experienced Grade 3 rash (confluent rash with fever, generalized rash), and four subjects had Grade 4 rash (erythema multiforme). The median time to onset of rash in pediatric subjects was 28 days (range 3−1,642 days). Prophylaxis with appropriate antihistamines before initiating therapy with ATRIPLA in pediatric patients should be considered.

5.3 Hepatotoxicity

Postmarketing cases of hepatitis, including fulminant hepatitis progressing to liver failure requiring transplantation or resulting in death, have been reported in patients treated with EFV, a component of ATRIPLA. Reports have included patients with underlying hepatic disease, including coinfection with hepatitis B or C, and patients without pre-existing hepatic disease or other identifiable risk factors [see Warnings and Precautions (5.1)].

ATRIPLA is not recommended for patients with moderate or severe hepatic impairment. Careful monitoring is recommended for patients with mild hepatic impairment receiving ATRIPLA [see Adverse Reactions (6.2) and Use in Specific Populations (8.7)].

Monitoring of liver enzymes before and during treatment is recommended for all patients [see Dosage and Administration (2.1)]. Consider discontinuing ATRIPLA in patients with persistent elevations of serum transaminases to greater than five times the upper limit of the normal range.

Discontinue ATRIPLA if elevation of serum transaminases is accompanied by clinical signs or symptoms of hepatitis or hepatic decompensation [see Adverse Reactions (6.1)].

5.4 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions

The concomitant use of ATRIPLA and other drugs may result in potentially significant drug interactions [see Contraindications (4) and Drug Interactions (7.3)], some of which may lead to:

• Loss of therapeutic effect of concomitant drug or ATRIPLA and possible development of resistance.
• Possible clinically significant adverse reaction from greater exposures of ATRIPLA or concomitant drug.

QTc prolongation has been observed with the use of EFV [see Drug Interactions (7.1) and Clinical Pharmacology (12.2)]. Consider alternatives to ATRIPLA when coadministered with a drug with a known risk of Torsade de Pointes or when administered to patients at higher risk of Torsade de Pointes.

See Table 3 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during ATRIPLA therapy and review concomitant medications during ATRIPLA therapy [see Dosage and Administration (2.5), Contraindications (4), and Drug Interactions (7)].

5.5 Psychiatric Symptoms

Serious psychiatric adverse experiences have been reported in patients treated with EFV, a component of ATRIPLA. In controlled trials of 1,008 subjects treated with regimens containing EFV for a mean of 2.1 years and 635 subjects treated with control regimens for a mean of 1.5 years, the frequency (regardless of causality) of specific serious psychiatric events among subjects who received EFV 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, NCT00002410), a Phase 3 randomized, open-label trial of EFV-containing regimens versus controls in 1,266 subjects (median follow-up 180 weeks, 102 weeks, and 76 weeks for subjects treated with EFV + zidovudine + lamivudine, EFV + indinavir, and indinavir + zidovudine + lamivudine, respectively), treatment with EFV 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 trial entry; similar associations were observed in both the EFV and control treatment groups. In Study 006, onset of new serious psychiatric symptoms occurred throughout the trial for both EFV-treated and control-treated subjects. One percent of EFV-treated subjects 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 EFV cannot be determined from these reports. Postmarketing cases of catatonia have also been reported and may be associated with increased EFV exposure. 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 EFV, and if so, to determine whether the risks of continued therapy outweigh the benefits [see Adverse Reactions (6)].

5.6 Nervous System Symptoms

Fifty-three percent (531/1,008) of subjects receiving EFV in controlled trials reported central nervous system symptoms (any grade, regardless of causality) compared to 25% (156/635) of subjects receiving control regimens. These symptoms included dizziness (28.1% of the 1,008 subjects), 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 to moderate (50.7%); symptoms were severe in 2.0% of subjects. Overall, 2.1% of subjects 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 subjects treated with regimens containing EFV and from 3% to 5% in subjects 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 and Precautions (5.5)]. Dosing at bedtime may improve the tolerability of these nervous system symptoms [see Dosage and Administration (2.2)].

Analysis of long-term data from Study 006 showed that, beyond 24 weeks of therapy, the incidences of new-onset nervous system symptoms among EFV-treated subjects were generally similar to those in the indinavir-containing control arm.

Late-onset neurotoxicity, including ataxia and encephalopathy (impaired consciousness, confusion, psychomotor slowing, psychosis, delirium), may occur months to years after beginning EFV therapy. Some events of late-onset neurotoxicity have occurred in patients with CYP2B6 genetic polymorphisms which are associated with increased EFV levels despite standard dosing of EFV. Patients presenting with signs and symptoms of serious neurologic adverse experiences should be evaluated promptly to assess the possibility that these events may be related to EFV use, and whether discontinuation of ATRIPLA is warranted.

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.

5.7 New Onset or Worsening Renal Impairment

Emtricitabine and tenofovir are principally eliminated by the kidney; however, EFV is not. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of TDF, a component of ATRIPLA [see Adverse Reactions (6.2)].

Prior to initiation and during use of ATRIPLA, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. ATRIPLA is not recommended in patients with moderate or severe renal impairment (estimated creatinine clearance below 50 mL/min).

ATRIPLA should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs [NSAIDs]) [see Drug Interactions (7.2)]. Cases of acute renal failure after initiation of high-dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on TDF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction.

Persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in patients at risk of renal dysfunction.

Discontinue ATRIPLA in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.

5.8 Embryo-Fetal Toxicity

Efavirenz may cause fetal harm when administered during the first trimester of pregnancy. Advise adults and adolescents of childbearing potential who are receiving ATRIPLA to avoid pregnancy while receiving ATRIPLA and for 12 weeks after discontinuation [see Dosage and Administration (2.1), Use in Specific Populations (8.1, 8.3)].

5.9 Bone Loss and Mineralization Defects

5.10 Convulsions

Convulsions have been observed in adult and pediatric patients receiving EFV, 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 Drug Interactions (7.3)].

5.11 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, including TDF and FTC, components of ATRIPLA, alone or in combination with other antiretrovirals. 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).

5.12 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 jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves' disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

5.13 Fat Redistribution

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

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of EFV, FTC, or TDF. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

7.1 Efavirenz

Efavirenz has been shown in vivo to induce CYP3A and CYP2B6. Other compounds that are substrates of CYP3A or CYP2B6 may have decreased plasma concentrations when coadministered with EFV.

Drugs that induce CYP3A activity (e.g., phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of EFV, resulting in lowered plasma concentrations [see Dosage and Administration (2.2)].

There is limited information available on the potential for a pharmacodynamic interaction between EFV and drugs that prolong the QTc interval. QTc prolongation has been observed with the use of EFV [see Clinical Pharmacology (12.2)]. Consider alternatives to ATRIPLA when coadministered with a drug with a known risk of Torsade de Pointes.

7.2 Drugs Affecting Renal Function

FTC and tenofovir are primarily eliminated by the kidneys [see Clinical Pharmacology (12.3)]. Coadministration of ATRIPLA with drugs that are eliminated by active tubular secretion may increase concentrations of FTC, tenofovir, and/or the coadministered drug. Some examples include, but are not limited to, acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.7)]. Drugs that decrease renal function may increase concentrations of FTC and/or tenofovir.

7.3 Established and Potentially Significant Interactions

Other important drug interaction information for ATRIPLA is summarized in Table 3. The drug interactions described are based on trials conducted with either ATRIPLA, the components of ATRIPLA (EFV, FTC, or TDF) as individual agents, or are potential drug interactions [see Clinical Pharmacology (12.3)].

7.4 Efavirenz Assay Interference

Cannabinoid Test Interaction: Efavirenz does not bind to cannabinoid receptors. False-positive urine cannabinoid test results have been reported with some screening assays in uninfected and HIV-infected subjects receiving EFV. Confirmation of positive screening tests for cannabinoids by a more specific method is recommended.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

The effectiveness and safety of ATRIPLA as a complete regimen for the treatment of HIV-1 infection was established in pediatric patients with body weight greater than or equal to 40 kg [see Dosage and Administration (2.2)]. Use of ATRIPLA in this age group is supported by adequate and well-controlled studies of ATRIPLA in adults with HIV-1 infection and data from pediatric studies of the individual components of ATRIPLA (EFV, FTC, and TDF).

ATRIPLA should only be administered to pediatric patients with a body weight greater than or equal to 40 kg. Because ATRIPLA is a fixed-dose combination tablet, the dose of ATRIPLA cannot be adjusted for patients of lower weight [see Warnings and Precautions (5.2, 5.9), Adverse Reactions (6.1), and Clinical Pharmacology (12.3)].

8.5 Geriatric Use

Clinical trials of EFV, FTC, or TDF 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 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.

8.6 Renal Impairment

Because ATRIPLA is a fixed-dose combination, and cannot be dose adjusted, it is not recommended in patients with moderate or severe renal impairment (estimated creatinine clearance below 50 mL/min) [see Dosage and Administration (2.3), Warnings and Precautions (5.7)].

8.7 Hepatic Impairment

ATRIPLA is not recommended for patients with moderate or severe hepatic impairment because there are insufficient data to determine an appropriate dose. Patients with mild hepatic impairment may be treated with ATRIPLA at the approved dose. Because of the extensive cytochrome P450-mediated metabolism of EFV and limited clinical experience in patients with hepatic impairment, caution should be exercised in administering ATRIPLA to these patients [see Dosage and Administration (2.4), Warnings and Precautions (5.3), and Clinical Pharmacology (12.3)].

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

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

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

Efavirenz: EFV 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 (less than 10 µg/mL).

Emtricitabine: The chemical name of FTC is 5-fluoro-1-(2R,5S)-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. FTC 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 DF: TDF is a fumaric acid salt of the bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. The chemical name of TDF 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:

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

12.1 Mechanism of Action

ATRIPLA is a fixed-dose combination of antiviral drugs EFV, FTC, and TDF [see Microbiology (12.4)].

12.2 Pharmacodynamics

12.3 Pharmacokinetics

12.4 Microbiology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

Study 934: Data through 144 weeks are reported for Study 934, a randomized, open-label, active-controlled multicenter trial comparing FTC + TDF administered in combination with EFV versus zidovudine/lamivudine fixed-dose combination administered in combination with EFV in 511 antiretroviral-naïve subjects. From Weeks 96 to 144 of the trial, subjects received FTC/TDF fixed-dose combination with EFV in place of FTC + TDF with EFV. Subjects 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). Subjects were stratified by baseline CD4+ cell count (< or ≥200 cells/mm3), and 41% had CD4+ cell counts <200 cells/mm3. Fifty-one percent (51%) of subjects had baseline viral loads >100,000 copies/mL. Treatment outcomes through 48 and 144 weeks for those subjects who did not have EFV resistance at baseline (N=487) are presented in Table 8.

Through Week 48, 84% and 73% of subjects in the FTC + TDF group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <400 copies/mL (71% and 58% through Week 144). The difference in the proportion of subjects 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 trial. In addition, 80% and 70% of subjects in the FTC + TDF group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <50 copies/mL through Week 48 (64% and 56% through Week 144). The mean increase from baseline in CD4+ cell count was 190 cells/mm3 in the FTC + TDF group and 158 cells/mm3 in the zidovudine/lamivudine group at Week 48 (312 and 271 cells/mm3 at Week 144).

Through 48 weeks, 7 subjects in the FTC + TDF group and 5 subjects in the zidovudine/lamivudine group experienced a new CDC Class C event (10 and 6 subjects through 144 weeks).

Study 073: Study 073 was a 48-week open-label, randomized clinical trial in subjects with stable virologic suppression on combination antiretroviral therapy consisting of at least two NRTIs administered in combination with a protease inhibitor (with or without ritonavir) or a NNRTI.

To be enrolled, subjects were to have HIV-1 RNA <200 copies/mL for at least 12 weeks on their current regimen prior to trial entry with no known HIV-1 substitutions conferring resistance to the components of ATRIPLA and no history of virologic failure.

The trial compared the efficacy of switching to ATRIPLA or staying on the baseline antiretroviral regimen (SBR). Subjects were randomized in a 2:1 ratio to switch to ATRIPLA (N=203) or stay on SBR (N=97). Subjects had a mean age of 43 years (range 22–73 years); 88% were male, 68% were white, 29% were Black or African-American, and 3% were of other races. At baseline, median CD4+ cell count was 516 cells/mm3, and 96% had HIV-1 RNA <50 copies/mL. The median time since onset of antiretroviral therapy was 3 years, and 88% of subjects were receiving their first antiretroviral regimen at trial enrollment.

At Week 48, 89% and 87% of subjects who switched to ATRIPLA maintained HIV RNA <200 copies/mL and <50 copies/mL, respectively, compared to 88% and 85% who remained on SBR; this difference was not statistically significant. No changes in CD4+ cell counts from baseline to Week 48 were observed in either treatment arm.

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

• Keep container tightly closed.
• Dispense only in original container.

Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV

Inform patients that severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued FTC or TDF, and may occur with discontinuation of ATRIPLA. Advise patients not to discontinue ATRIPLA without first informing their healthcare provider. All patients should be tested for HBV infection before or when starting ATRIPLA and those who are infected with HBV need close medical follow-up for several months after stopping ATRIPLA to monitor for exacerbations of hepatitis [see Warnings and Precautions (5.1)].

Rash

Inform patients that a common side effect is rash, and that rashes usually go away without any change in treatment. However, since rash may be serious, advise patients to contact their physician promptly if rash occurs [see Warnings and Precautions (5.2)].

Hepatotoxicity

Inform patients to watch for early warning signs of liver inflammation or failure, such as fatigue, weakness, lack of appetite, nausea and vomiting, as well as later signs such as jaundice, confusion, abdominal swelling, and discolored feces, and to consult their health care professional without delay if such symptoms occur [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)].

Drug Interactions

Advise patients that ATRIPLA may interact with many drugs; therefore, advise patients to report to their healthcare provider the use of any other medication, including other drugs for treatment of hepatitis C virus [see Warnings and Precautions (5.4) and Drug Interactions (7)].

Psychiatric Symptoms

• Inform patients that serious psychiatric symptoms including severe depression, suicide attempts, aggressive behavior, delusions, paranoia, psychosis-like symptoms, and catatonia have been reported in patients receiving EFV, a component of ATRIPLA [see Warnings and Precautions (5.5)].
• Advise patients to seek immediate medical evaluation if they experience severe psychiatric adverse experiences.
• Advise patients to inform their physician of any history of mental illness or substance abuse.

Nervous System Symptoms

• Inform patients that central nervous system symptoms (NSS) including dizziness, insomnia, impaired concentration, drowsiness, and abnormal dreams, are commonly reported during the first weeks of therapy with EFV, a component of ATRIPLA. Dosing at bedtime may improve the tolerability of these symptoms, which are likely to improve with continued therapy.
• Alert patients to the potential for additive effects when ATRIPLA is used concomitantly with alcohol or psychoactive drugs.
• Instruct patients that if they experience NSS to avoid potentially hazardous tasks such as driving or operating machinery [see Warnings and Precautions (5.6) and Dosage and Administration (2.2)].
• Inform patients that there is a risk of developing late-onset neurotoxicity, including ataxia and encephalopathy, which may occur months to years after beginning therapy with EFV, a component of ATRIPLA [see Warnings and Precautions (5.6)].

New Onset or Worsening Renal Impairment

Inform patients that renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported. Advise patients to avoid using ATRIPLA with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple NSAIDs) [see Warnings and Precautions (5.7)].

Embryo-Fetal Toxicity

Apprise patients of the potential harm to the fetus if ATRIPLA is used during the first trimester of pregnancy, or if the patient becomes pregnant while taking this drug. Instruct adults and adolescents of childbearing potential receiving ATRIPLA to avoid pregnancy and to notify their healthcare provider if they become pregnant or plan to become pregnant while taking ATRIPLA [see Warnings and Precautions (5.8)]. A reliable form of barrier contraception must always be used in combination with other methods of contraception, including oral or other hormonal contraception. Because of the long half-life of EFV, recommend use of adequate contraceptive measures for 12 weeks after discontinuation of ATRIPLA [see Use in Specific Populations (8.1, 8.3)].

Bone Loss and Mineralization Defects

Inform patients that decreases in bone mineral density have been observed with the use of TDF, a component of ATRIPLA. Advise patients that bone mineral density monitoring may be performed in patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss [see Warnings and Precautions (5.9)].

Convulsions

Inform patients that convulsions have been reported with the use of EFV, a component of ATRIPLA. Patients who are receiving concomitant anticonvulsant medications primarily metabolized by the liver may require periodic monitoring of plasma levels [see Warnings and Precautions (5.10) and Drug Interactions (7.3)].

Lactic Acidosis and Severe Hepatomegaly

Inform patients that lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Treatment with ATRIPLA should be suspended in any patient who develops clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see Warnings and Precautions (5.11)].

Immune Reconstitution Syndrome

Inform patients that in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the body's immune response, enabling the body to fight infections that may have been present with no obvious symptoms. Advise patients to inform their healthcare provider immediately of any symptoms of infection [see Warnings and Precautions (5.12)].

Fat Redistribution

Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy, including ATRIPLA and that the cause and long-term health effects of these conditions are not known [see Warnings and Precautions (5.13)].

Dosing Instructions

Advise patients to take ATRIPLA orally on an empty stomach and that it is important to take ATRIPLA on a regular dosing schedule to avoid missing doses. Advise patients that dosing at bedtime may improve the tolerability of nervous system symptoms [see Dosage and Administration (2.1)].

Pregnancy Registry

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to ATRIPLA during pregnancy [see Use in Specific Populations (8.1)].

Lactation

Instruct patients not to breastfeed because HIV-1 can be passed to the baby in the breast milk [see Use in Specific Populations (8.2)].