HIGHLIGHTS OF PRESCRIBING INFORMATION serum phosphorus, urine glucose and urine protein before initiating treatment with ATRIPLA and periodically during These highlights do not include all the information needed to use treatment. Avoid administering ATRIPLA with concurrent or recent ATRIPLA safely and effectively. See full prescribing information use of nephrotoxic drugs. (5.7) for ATRIPLA. ® • Pregnancy: Fetal harm may occur when administered to a ATRIPLA (efavirenz/emtricitabine/tenofovir disoproxil fumarate) pregnant woman during the first trimester. Women should be tablets, for oral use apprised of the potential harm to the fetus. A pregnancy registry Initial U.S. Approval: 2006 is available. (5.8, 8.1) WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH • Rash: Discontinue if severe rash develops. (5.9, 6.1) STEATOSIS and POST TREATMENT EXACERBATION OF • Hepatotoxicity: Monitor liver function tests before and during HEPATITIS B treatment in patients with underlying hepatic disease, including See full prescribing information for complete boxed warning. hepatitis B or C coinfection, marked transaminase elevations, or who are taking medications associated with liver toxicity. Among • Lactic acidosis and severe hepatomegaly with steatosis, reported cases of hepatic failure, a few occurred in patients with including fatal cases, have been reported with the use of no pre-existing hepatic disease. (5.10, 6.3, 8.6) nucleoside analogs, including tenofovir disoproxil fumarate, a component of ATRIPLA. (5.1) • Decreases in bone mineral density (BMD): Consider assessment of BMD in patients with a history of pathological fracture or other • ATRIPLA is not approved for the treatment of chronic risk factors for osteoporosis or bone loss. (5.11) hepatitis B virus (HBV) infection. Severe acute exacerbations of hepatitis B have been reported in patients • Convulsions: Use caution in patients with a history of seizures. coinfected with HBV and HIV-1 who have discontinued (5.12) EMTRIVA or VIREAD, two of the components of ATRIPLA. • Immune reconstitution syndrome: May necessitate further Hepatic function should be monitored closely in these evaluation and treatment. (5.13) patients. If appropriate, initiation of anti-hepatitis B therapy may be warranted. (5.2) • Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy. (5.14) -------------------------------INDICATIONS AND USAGE------------------------- • ATRIPLA, a combination of 2 nucleoside analog HIV-1 reverse Coadministration with other products: Do not use with drugs transcriptase inhibitors and 1 non-nucleoside HIV-1 reverse containing emtricitabine or tenofovir disoproxil fumarate including transcriptase inhibitor, is indicated for use alone as a complete COMPLERA, EMTRIVA, STRIBILD, TRUVADA, or VIREAD; or regimen or in combination with other antiretroviral agents for the with drugs containing lamivudine. SUSTIVA (efavirenz) should not be coadministered with ATRIPLA unless required for dose- treatment of HIV-1 infection in adults and pediatric patients 12 years of adjustment when coadministered with rifampin. (5.4) Do not age and older. (1) administer in combination with HEPSERA. (5.2) ---------------------------DOSAGE AND ADMINISTRATION-------------------- --------------------------------ADVERSE REACTIONS----------------------------- • Recommended dose in adults and pediatric patients (12 years of Most common adverse reactions (incidence greater than or equal to age and older and weighing at least 40 kg): One tablet once daily 10%) observed in an active-controlled clinical trial of efavirenz, taken orally on an empty stomach, preferably at bedtime. (2) emtricitabine, and tenofovir DF are diarrhea, nausea, fatigue, • Dose in renal impairment: Should not be administered in patients headache, dizziness, depression, insomnia, abnormal dreams, and with estimated creatinine clearance below 50 mL/min. (2) rash. (6) • With rifampin coadministration, an additional 200 mg/day of To report SUSPECTED ADVERSE REACTIONS, contact Gilead efavirenz is recommended for patients weighing 50 kg or more. Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or (2) www.fda.gov/medwatch --------------------------DOSAGE FORMS AND STRENGTHS----------------- ---------------------------------DRUG INTERACTIONS---------------------------- Tablet containing 600 mg of efavirenz, 200 mg of emtricitabine and • Efavirenz: Coadministration of efavirenz can alter the 300 mg of tenofovir disoproxil fumarate. (3) concentrations of other drugs and other drugs may alter the concentrations of efavirenz. The potential for drug-drug ---------------------------------CONTRAINDICATIONS----------------------------- interactions must be considered before and during therapy. (4.2, 7.1, 12.3) • Previously demonstrated hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to • Didanosine: Tenofovir disoproxil fumarate increases didanosine efavirenz, a component of ATRIPLA. (4.1) concentrations. Use with caution and monitor for evidence of didanosine toxicity (e.g., pancreatitis, neuropathy) when • Coadministration with voriconazole due to a significant drug coadministered. Consider dose reductions or discontinuations of interaction with efavirenz, a component of ATRIPLA, that may didanosine if warranted. (7.2) decrease the therapeutic effectiveness of voriconazole and increase the risk of efavirenz-associated side effects. (4.2) • HIV-1 protease inhibitors: Coadministration of ATRIPLA with either lopinavir/ritonavir or darunavir and ritonavir increases ---------------------------WARNINGS AND PRECAUTIONS-------------------- tenofovir concentrations. Monitor for evidence of tenofovir toxicity. • Serious psychiatric symptoms: Immediate medical evaluation is Coadministration of ATRIPLA with either atazanavir or atazanavir recommended. (5.5, 6.1) and ritonavir is not recommended. (7.3) • Nervous system symptoms (NSS): NSS are frequent, usually --------------------------USE IN SPECIFIC POPULATIONS------------------ begin 1-2 days after initiating therapy and resolve in 2-4 weeks. • Pregnancy: Women should avoid pregnancy while receiving Dosing at bedtime may improve tolerability. NSS are not ATRIPLA and for 12 weeks after discontinuation. (5.8) predictive of onset of psychiatric symptoms. (2, 5.6) • Nursing mothers: Women infected with HIV should be instructed • New onset or worsening renal impairment: Can include acute not to breastfeed. (8.3) renal failure and Fanconi syndrome. Assess estimated creatinine clearance before initiating treatment with ATRIPLA. In patients at risk for renal dysfunction, assess estimated creatinine clearance, Bristol-Myers Squibb and Gilead Sciences, LLC 1 • Hepatic impairment: ATRIPLA is not recommended for patients with moderate or severe hepatic impairment. Use caution in patients with mild hepatic impairment. (5.10, 8.6) • Pediatrics: The incidence of rash was higher than in adults. (5.9, 6.1) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved patient labeling. Revised: 02/2016 Bristol-Myers Squibb and Gilead Sciences, LLC 2 FULL PRESCRIBING INFORMATION: CONTENTS* 7 DRUG INTERACTIONS WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY 7.1 Efavirenz WITH STEATOSIS and POST TREATMENT EXACERBATION OF HEPATITIS B 7.2 Emtricitabine and Tenofovir Disoproxil Fumarate 1 INDICATIONS AND USAGE 7.3 Efavirenz, Emtricitabine and Tenofovir Disoproxil Fumarate 2 DOSAGE AND ADMINISTRATION 7.4 Efavirenz Assay Interference 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 8 USE IN SPECIFIC POPULATIONS 4.1 Hypersensitivity 8.1 Pregnancy 4.2 Contraindicated Drugs 8.3 Nursing Mothers 5 WARNINGS AND PRECAUTIONS 8.4 Pediatric Use 5.1 Lactic Acidosis/Severe Hepatomegaly with Steatosis 8.5 Geriatric Use 5.2 Patients Coinfected with HIV-1 and HBV 8.6 Hepatic Impairment 5.3 Drug Interactions 8.7 Renal Impairment 5.4 Coadministration with Related Products 10 OVERDOSAGE 5.5 Psychiatric Symptoms 11 DESCRIPTION 5.6 Nervous System Symptoms 12 CLINICAL PHARMACOLOGY 5.7 New Onset or Worsening Renal Impairment 12.1 Mechanism of Action 5.8 Reproductive Risk Potential 12.3 Pharmacokinetics 5.9 Rash 12.4 Microbiology 5.10 Hepatotoxicity 13 NONCLINICAL TOXICOLOGY 5.11 Bone Effects of Tenofovir DF 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 5.12 Convulsions 13.2 Animal Toxicology and/or Pharmacology 5.13 Immune Reconstitution Syndrome 14 CLINICAL STUDIES 5.14 Fat Redistribution 16 HOW SUPPLIED/STORAGE AND HANDLING 6 ADVERSE REACTIONS 17 PATIENT COUNSELING INFORMATION 6.1 Adverse Reactions from Clinical Trials Experience * Sections or subsections omitted from the full prescribing information 6.2 Laboratory Abnormalities are not listed 6.3 Postmarketing Experience Bristol-Myers Squibb and Gilead Sciences, LLC 3 FULL PRESCRIBING INFORMATION WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATION OF HEPATITIS B Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate, a component of ATRIPLA, in combination with other antiretrovirals [See Warnings and Precautions (5.1)]. ATRIPLA is not approved for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of ATRIPLA have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued EMTRIVA or VIREAD, which are components of