Efavirenz, Emtricitabine and Tenofovir Disoproxil Fumarate: The following adverse reactions are discussed in other sections of the labeling:

• Lactic Acidosis/Severe Hepatomegaly with Steatosis [See BOXED WARNING, WARNINGS and PRECAUTIONS].
• Severe Acute Exacerbations of Hepatitis B [See BOXED WARNING, WARNINGS and PRECAUTIONS].
• Psychiatric Symptoms [See WARNINGS and PRECAUTIONS],
• Nervous System Symptoms [See WARNINGS and PRECAUTIONS],
• New Onset or Worsening Renal Impairment [See WARNINGS and PRECAUTIONS].
• Rash [See WARNINGS and PRECAUTIONS].
• Decreases in Bone Mineral Density [See WARNINGS and PRECAUTIONS].
• Immune Reconstitution Syndrome [See WARNINGS and PRECAUTIONS].
• Drug Interactions [See CONTRAINDICATIONS, WARNINGS and PRECAUTIONS and DRUG INTERACTIONS]

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

Adverse Reactions from 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.

Study 934 was an open-label active-controlled study in which 511 antiretroviral-naive patients received either emtricitabine + tenofovir DF administered in combination with efavirenz (N=257) or zidovudine/lamivudine administered in combination with efavirenz (N=254).

The most common adverse reactions (incidence ≥ 10%, any severity) occurring in Study 934, include diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. Adverse reactions observed in Study 934 were generally consistent with those seen in previous studies of the individual components (Table 2).

Table 2: Selected Treatment-Emergent Adverse Reactions^a (Grades 2-4) Reported in ≥ 5% in Either Treatment Group in Study 934 (0-144 Weeks)

In addition to the adverse reactions in Study 934, the following adverse reactions were observed in clinical trials of efavirenz, emtricitabine, or tenofovir DF in combination with other antiretroviral agents.

Efavirenz: The most significant adverse reactions observed in patients treated with efavirenz are nervous system symptoms [See WARNINGS and PRECAUTIONS],psychiatric symptoms[See WARNINGS and PRECAUTIONS], and rash [See WARNINGS and PRECAUTIONS.

Selected adverse reactions of moderate-severe intensity observed in 2% of efavirenz­treated patients in two controlled clinical trials included pain, impaired concentration, abnormal dreams, somnolence, anorexia, dyspepsia, abdominal pain, nervousness, and pruritus.

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

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

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

Laboratory Abnormalities

Efavirenz, Emtricitabine and Tenofovir Disoproxil Fumarate: Laboratory abnormalities observed in Study 934 were generally consistent with those seen in previous studies (Table 3).

Table 3: Significant Laboratory Abnormalities Reported in ≥ 1% of Patients in Either Treatment Group in Study 934 (0-144 Weeks)

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

Hepatic Events: In Study 934, 19 patients treated with efavirenz, emtricitabine, and tenofovir DF and 20 patients treated with efavirenz and fixed-dose zidovudine/lamivudine were hepatitis B surface antigen or hepatitis C antibody positive. Among these coinfected patients, one patient (1/19) in the efavirenz, emtricitabine and tenofovir DF arm had elevations in transaminases to greater than five times ULN through 144 weeks. In the fixed-dose zidovudine/lamivudine arm, two patients (2/20) had elevations in transaminases to greater than five times ULN through 144 weeks. No HBV and/or HCV coinfected patient discontinued from the study due to hepatobiliary disorders [See WARNINGS and PRECAUTIONS].

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of efavirenz, emtricitabine, or tenofovir DF. 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.

Efavirenz

Cardiac Disorders
Palpitations

Ear and Labyrinth Disorders
Tinnitus

Endocrine Disorders
Gynecomastia

Eye Disorders
Abnormal vision

Gastrointestinal Disorders
Constipation, malabsorption

General Disorders and Administration Site Conditions
Asthenia

Hepatobiliary Disorders
Hepatic enzyme increase, hepatic failure, hepatitis

Immune System Disorders
Allergic reactions

Metabolism and Nutrition Disorders
Redistribution/accumulation of body fat [See WARNINGS and PRECAUTIONS], Hypercholesterolemia, hypertriglyceridemia

Musculoskeletal and Connective Tissue Disorders
Arthralgia, myalgia, myopathy

Nervous System Disorders
Abnormal coordination, ataxia, convulsions, hypoesthesia, paresthesia, neuropathy, tremor

Psychiatric Disorders
Aggressive reactions, agitation, delusions, emotional lability, mania, neurosis, paranoia, psychosis, suicide

Respiratory, Thoracic and Mediastinal disorders
Dyspnea

Skin and Subcutaneous Tissue Disorders
Flushing, erythema multiforme, nail disorders, photoallergic dermatitis, skin discoloration, Stevens-Johnson syndrome

Emtricitabine: No postmarketing adverse reactions have been identified for inclusion in this section.

Tenofovir Disoproxil Fumarate

Immune System Disorders
Allergic reaction

Metabolism and Nutrition Disorders
Hypophosphatemia, lactic acidosis

Respiratory, Thoracic, and Mediastinal Disorders
Dyspnea

Gastrointestinal Disorders
Abdominal pain, increased amylase, pancreatitis

Hepatobiliary disorders
Increased liver enzymes (most commonly AST, ALT, gamma GT), hepatitis

Skin and Subcutaneous Tissue Disorders
Rash

Musculoskeletal and Connective Tissue Disorders
Myopathy, osteomalacia (both associated with proximal renal tubulopathy)

Renal and Urinary Disorders
Renal insufficiency, renal failure, acute renal failure, Fanconi syndrome, proximal tubulopathy, proteinuria, increased creatinine, acute tubular necrosis, nephrogenic diabetes insipidus, polyuria, interstitial nephritis (including acute cases)

General Disorders and Administration Site Conditions
Asthenia

This section describes clinically relevant drug interactions with ATRIPLA. Drug interaction studies are described elsewhere in the labeling [see CLINICAL PHARMACOLOGY].

Efavirenz

Efavirenz has been shown in vivo to induce CYP3A. Other compounds that are substrates of CYP3A 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 that induce CYP3A 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, acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, and valganciclovir.

Coadministration of tenofovir DF and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine­associated adverse reactions. Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions [for didanosine dosing adjustment recommendations, seeTable 4]. Suppression of CD4⁺ cell counts has been observed in patients receiving tenofovir DF with didanosine 400 mg daily.

Lopinavir/ritonavir has been shown to increase tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving lopinavir/ritonavir with ATRIPLA should be monitored for tenofovir-associated adverse reactions. ATRIPLA should be discontinued in patients who develop tenofovir-associated adverse reactions [See Table 4].

Coadminstration of atazanavir with ATRIPLA is not recommended since coadministration of atazanavir with either efavirenz or tenofovir DF has been shown to decrease plasma concentrations of atazanavir. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA [See Table 4].

Efavirenz, Emtricitabine and Tenofovir Disoproxil Fumarate

Other important drug interaction information for ATRIPLA is summarized in Table 1 and Table 4. 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 [for pharmacokinetics data see CLINICAL PHARMACOLOGY, Tables 5-9]. The tables include potentially significant interactions, but are not all inclusive.

Table 4: Established and Other Potentially Significant^a Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction

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.

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