FDA label 969b3a71-6ed6-4604-a2aa-ab8fe3624bcb

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 ATRIPLA. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue ATRIPLA. If appropriate, initiation of anti-hepatitis B therapy may be warranted [See Warnings and Precautions (5.2) ] . WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATION OF HEPATITIS B See full prescribing information for complete boxed warning. 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. ( 5.1 ) ATRIPLA is not approved for the treatment of chronic hepatitis B virus (HBV) infection. Severe acute exacerbations of hepatitis B have been reported in patients coinfected with HBV and HIV-1 who have discontinued EMTRIVA or VIREAD, two of the components of ATRIPLA. Hepatic function should be monitored closely in these patients. If appropriate, initiation of anti-hepatitis B therapy may be warranted. ( 5.2 )

5 WARNINGS AND PRECAUTIONS Serious psychiatric symptoms: Immediate medical evaluation is recommended. ( 5.5 , 6.1 ) Nervous system symptoms (NSS): NSS are frequent, usually begin 1–2 days after initiating therapy and resolve in 2–4 weeks. Dosing at bedtime may improve tolerability. NSS are not predictive of onset of psychiatric symptoms. ( 2 , 5.6 ) New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Assess creatinine clearance (CrCl) before initiating treatment with ATRIPLA. Monitor CrCl and serum phosphorus in patients at risk. Avoid administering ATRIPLA with concurrent or recent use of nephrotoxic drugs. ( 5.7 ) Pregnancy: Fetal harm can occur when administered to a pregnant woman during the first trimester. Women should be apprised of the potential harm to the fetus. A pregnancy registry is available. ( 5.8 , 8.1 ) Rash: Discontinue if severe rash develops. ( 5.9 , 6.1 ) Hepatotoxicity: Monitor liver function tests before and during treatment in patients with underlying hepatic disease, including hepatitis B or C coinfection, marked transaminase elevations, or who are taking medications associated with liver toxicity. Among reported cases of hepatic failure, a few occurred in patients with no pre-existing hepatic disease. ( 5.10 , 6.3 , 8.6 ) Decreases in bone mineral density (BMD): Consider assessment of BMD in patients with a history of pathological fracture or other risk factors for osteoporosis or bone loss. ( 5.11 ) Convulsions: Use caution in patients with a history of seizures. ( 5.12 ) Immune reconstitution syndrome: May necessitate further evaluation and treatment. ( 5.13 ) Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy. ( 5.14 ) Coadministration with other products: Do not use with drugs containing emtricitabine or tenofovir disoproxil fumarate including COMPLERA, EMTRIVA, STRIBILD, TRUVADA, or VIREAD; or with drugs containing lamivudine. SUSTIVA (efavirenz) should not be coadministered with ATRIPLA unless required for dose-adjustment when coadministered with rifampin. ( 5.4 ) Do not administer in combination with HEPSERA. ( 5.2 ) 5.1 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 tenofovir DF, a component of ATRIPLA, 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). 5.2 Patients Coinfected with HIV-1 and HBV It is recommended that all patients with HIV-1 be tested for the presence of chronic HBV before initiating antiretroviral therapy. ATRIPLA is not approved for the treatment of chronic 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 are coinfected with HBV and HIV-1 and have discontinued emtricitabine or tenofovir DF, two of the components of ATRIPLA. In some patients infected with HBV and treated with emtricitabine, the exacerbations of hepatitis B were associated with liver decompensation and liver failure. 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. ATRIPLA should not be administered with HEPSERA ® (adefovir dipivoxil) [See Drug Interactions (7.2) ]. 5.3 Drug Interactions Efavirenz plasma concentrations may be altered by substrates, inhibitors, or inducers of CYP3A. Likewise, efavirenz may alter plasma concentrations of drugs metabolized by CYP3A or CYP2B6 [See Contraindications (4.2) , Drug Interactions (7.1) ] . 5.4 Coadministration with Related Products Related drugs not for coadministration with ATRIPLA include COMPLERA ® (emtricitabine/rilpivirine/tenofovir DF), EMTRIVA ® (emtricitabine), STRIBILD ® (elvitegravir/cobicistat/emtricitabine/tenofovir DF), TRUVADA ® (emtricitabine/tenofovir DF), and VIREAD ® (tenofovir DF), which contain the same active components as ATRIPLA. SUSTIVA ® (efavirenz) should not be coadministered with ATRIPLA unless needed for dose-adjustment (e.g. with rifampin) [See Dosage and Administration (2) , Drug Interactions (7.1) ] . Due to similarities between emtricitabine and lamivudine, ATRIPLA should not be coadministered with drugs containing lamivudine, including Combivir (lamivudine/zidovudine), Epivir, or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), or Trizivir (abacavir sulfate/lamivudine/zidovudine). 5.5 Psychiatric Symptoms Serious psychiatric adverse experiences have been reported in patients treated with efavirenz. In controlled trials of 1008 subjects treated with regimens containing efavirenz 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 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 trial 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 trial for both efavirenz-treated and control-treated subjects. One percent of efavirenz-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 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 (6) ]. 5.6 Nervous System Symptoms Fifty-three percent (531/1008) of subjects receiving efavirenz 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 1008 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-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 efavirenz 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) ] . Analysis of long-term data from Study 006, (median follow-up 180 weeks, 102 weeks, and 76 weeks for subjects 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 subjects 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. 5.7 New Onset or Worsening 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 below 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 with the use of tenofovir DF [See Adverse Reactions (6.3) ]. It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy with ATRIPLA. Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients at risk for renal impairment, including patients who have previously experienced renal events while receiving HEPSERA. ATRIPLA should be avoided with concurrent or recent use of a nephrotoxic agent. 5.8 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 must always be used in combination with other methods of contraception (e.g., oral or other hormonal contraceptives). Because of the long half-life of efavirenz, use of adequate contraceptive measures for 12 weeks after discontinuation of ATRIPLA is recommended. 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 trials 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 [See Use in Specific Populations (8.1) ] . 5.9 Rash In controlled clinical trials, 26% (266/1008) of subjects treated with 600 mg efavirenz experienced new-onset skin rash compared with 17% (111/635) of subjects treated in control groups. Rash associated with blistering, moist desquamation, or ulceration occurred in 0.9% (9/1008) of subjects treated with efavirenz. The incidence of Grade 4 rash (e.g., erythema multiforme, Stevens-Johnson syndrome) in subjects treated with efavirenz 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 efavirenz (median time to onset of rash in adults was 11 days) and, in most subjects 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. For patients who have had a life-threatening cutaneous reaction (eg, Stevens-Johnson syndrome), alternative therapy should be considered [See also Contraindications (4.1) ] . Experience with efavirenz 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 efavirenz. Nine of these subjects developed mild-to-moderate rash while receiving therapy with efavirenz, and two of these subjects discontinued because of rash. Rash was reported in 26 of 57 pediatric subjects (46%) treated with efavirenz [See Adverse Reactions (6.1) ]. One pediatric subject experienced Grade 3 rash (confluent rash with fever), and two subjects had Grade 4 rash (erythema multiforme). The median time to onset of rash in pediatric subjects was 8 days. Prophylaxis with appropriate antihistamines before initiating therapy with ATRIPLA in pediatric patients should be considered. 5.10 Hepatotoxicity Monitoring of liver enzymes before and during treatment is recommended for patients with underlying hepatic disease, including hepatitis B or C infection; patients with marked transaminase elevations; and patients treated with other medications associated with liver toxicity [See also Warnings and Precautions (5.2) ]. A few of the postmarketing reports of hepatic failure occurred in patients with no pre-existing hepatic disease or other identifiable risk factors [See Adverse Reactions (6.3) ]. Liver enzyme monitoring should also be considered for patients without pre-existing hepatic dysfunction or other risk factors. 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 (6.2) ]. 5.11 Decreases in Bone Mineral Density Assessment of bone mineral density (BMD) should be considered for patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. 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. In a 144-week trial of treatment-naive adult subjects receiving tenofovir DF, decreases in BMD were seen at the lumbar spine and hip in both arms of the trial. At Week 144, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving tenofovir DF + lamivudine + efavirenz compared with subjects 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 trial and this reduction was sustained through 144 weeks. Twenty-eight percent of tenofovir DF-treated subjects vs. 21% of the comparator subjects 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 subjects in the tenofovir DF group and 6 subjects 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 subjects receiving tenofovir DF. In a clinical trial of HIV-1 infected pediatric subjects 12 years of age and older (Study 321), bone effects were similar to adult subjects. Under normal circumstances BMD increases rapidly in this age group. In this trial, the mean rate of bone gain was less in the tenofovir DF-treated group compared to the placebo group. Six tenofovir DF-treated subjects and one placebo-treated subject had significant (greater than 4%) lumbar spine BMD loss at 48 weeks. Among 28 subjects receiving 96 weeks of tenofovir DF, Z-scores declined by -0.341 for lumbar spine and -0.458 for total body. Skeletal growth (height) appeared to be unaffected. Markers of bone turnover in tenofovir DF-treated pediatric subjects 12 years of age and older suggest increased bone turnover, consistent with the effects observed in adults. 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, consult the VIREAD prescribing information. Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with the use of tenofovir DF [See Adverse Reactions (6.3) ] . 5.12 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 Drug Interactions (7.3) ]. 5.13 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, and Guillain-Barré syndrome) 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. 5.14 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.

6 ADVERSE REACTIONS Most common adverse reactions (incidence greater than or equal to 10%) observed in an active-controlled clinical trial of efavirenz, emtricitabine, and tenofovir DF are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 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 (5.1) ]. Severe Acute Exacerbations of Hepatitis B [See Boxed Warning , Warnings and Precautions (5.2) ] . Psychiatric Symptoms [See Warnings and Precautions (5.5) ]. Nervous System Symptoms [See Warnings and Precautions (5.6) ]. New Onset or Worsening Renal Impairment [See Warnings and Precautions (5.7) ]. Rash [See Warnings and Precautions (5.9) ]. Hepatotoxicity [See Warnings and Precautions (5.10) ]. Decreases in Bone Mineral Density [See Warnings and Precautions (5.11) ]. Immune Reconstitution Syndrome [See Warnings and Precautions (5.13) ]. Drug Interactions [See Contraindications (4.2) , Warnings and Precautions (5.3) and Drug Interactions (7) ]. 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. 6.1 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. Clinical Trials in Adult Subjects Study 934 Study 934 was an open-label active-controlled trial in which 511 antiretroviral-naive subjects 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 greater than or equal to 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 trials of the individual components (Table 2). Table 2 Selected Treatment-Emergent Adverse Reactions Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. (Grades 2–4) Reported in ≥5% in Either Treatment Group in Study 934 (0–144 Weeks) FTC + TDF + EFV From Weeks 96 to 144 of the trial, subjects received emtricitabine/tenofovir DF administered in combination with efavirenz in place of emtricitabine + tenofovir DF with efavirenz. AZT/3TC + EFV N=257 N=254 Gastrointestinal Disorder Diarrhea 9% 5% Nausea 9% 7% Vomiting 2% 5% General Disorders and Administration Site Condition Fatigue 9% 8% Infections and Infestations Sinusitis 8% 4% Upper respiratory tract infections 8% 5% Nasopharyngitis 5% 3% Nervous System Disorders Headache 6% 5% Dizziness 8% 7% Psychiatric Disorders Anxiety 5% 4% Depression 9% 7% Insomnia 5% 7% Skin and Subcutaneous Tissue Disorders Rash Event Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and rash vesicular. 7% 9% Study 073 In Study 073, subjects with stable, virologic suppression on antiretroviral therapy and no history of virologic failure were randomized to receive ATRIPLA or to stay on their baseline regimen. The adverse reactions observed in Study 073 were generally consistent with those seen in Study 934 and those seen with the individual components of ATRIPLA when each was administered in combination with other antiretroviral agents. Efavirenz, Emtricitabine, or Tenofovir Disoproxil Fumarate In addition to the adverse reactions in Study 934 and Study 073 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 subjects treated with efavirenz are nervous system symptoms [See Warnings and Precautions (5.6) ], psychiatric symptoms [See Warnings and Precautions (5.5) ], and rash [See Warnings and Precautions (5.9) ] . Selected adverse reactions of moderate-severe intensity observed in greater than or equal to 2% of efavirenz-treated subjects 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 subjects treated with efavirenz 600 mg than in control subjects. Emtricitabine and Tenofovir Disoproxil Fumarate: Adverse reactions that occurred in at least 5% of treatment-experienced or treatment-naive subjects 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 subjects; it was manifested by hyperpigmentation on the palms and/or soles and was generally mild and asymptomatic. The mechanism and clinical significance are unknown. Clinical Trials in Pediatric Subjects Efavirenz: In a pediatric clinical trial in 57 NRTI-experienced subjects aged 3 to 16 years, the type and frequency of adverse experiences was generally similar to that of adult subjects with the exception of a higher incidence of rash, which was reported in 46% (26/57) of pediatric subjects compared to 26% of adults, and a higher frequency of Grade 3 or 4 rash reported in 5% (3/57) of pediatric subjects compared to 0.9% of adults [See Warnings and Precautions (5.9) ] . For additional information, please consult the SUSTIVA prescribing information. Emtricitabine: In addition to the adverse reactions reported in adults, anemia and hyperpigmentation were observed in 7% and 32%, respectively, of pediatric subjects (3 months to less than 18 years of age) who received treatment with emtricitabine in the larger of two open-label, uncontrolled pediatric trials (N=116). For additional information, please consult the EMTRIVA prescribing information. Tenofovir Disoproxil Fumarate: In a pediatric clinical trial conducted in subjects 12 to less than 18 years of age, the adverse reactions observed in pediatric subjects who received treatment with tenofovir DF were consistent with those observed in clinical trials of tenofovir DF in adults [See Warnings and Precautions (5.11) ] . 6.2 Laboratory Abnormalities Efavirenz, Emtricitabine and Tenofovir Disoproxil Fumarate: Laboratory abnormalities observed in Study 934 were generally consistent with those seen in previous trials (Table 3). Table 3 Significant Laboratory Abnormalities Reported in ≥1% of Subjects in Either Treatment Group in Study 934 (0–144 Weeks) FTC + TDF + EFV From Weeks 96 to 144 of the trial, subjects received emtricitabine/tenofovir DF administered in combination with efavirenz in place of emtricitabine + tenofovir DF with efavirenz. AZT/3TC + EFV N=257 N=254 Any ≥ Grade 3 Laboratory Abnormality 30% 26% Fasting Cholesterol (>240 mg/dL) 22% 24% Creatine Kinase (M: >990 U/L) (F: >845 U/L) 9% 7% Serum Amylase (>175 U/L) 8% 4% Alkaline Phosphatase (>550 U/L) 1% 0% AST (M: >180 U/L) (F: >170 U/L) 3% 3% ALT (M: >215 U/L) (F: >170 U/L) 2% 3% Hemoglobin (<8.0 mg/dL) 0% 4% Hyperglycemia (>250 mg/dL) 2% 1% Hematuria (>75 RBC/HPF) 3% 2% Glycosuria (≥3+) <1% 1% Neutrophils (<750/mm 3 ) 3% 5% Fasting Triglycerides (>750 mg/dL) 4% 2% Laboratory abnormalities observed in Study 073 were generally consistent with those in Study 934. In addition to the laboratory abnormalities described for Study 934 (Table 3), Grade 3/4 laboratory abnormalities of increased bilirubin (greater than 2.5 × upper limit of normal (ULN)), increased pancreatic amylase (greater than 2.0 × ULN), increased or decreased serum glucose (less than 40 or greater than 250 mg/dL), and increased serum lipase (greater than 2.0 × ULN) occurred in up to 3% of subjects treated with emtricitabine or tenofovir DF with other antiretroviral agents in clinical trials. Hepatic Events: In Study 934, 19 subjects treated with efavirenz, emtricitabine, and tenofovir DF and 20 subjects treated with efavirenz and fixed-dose zidovudine/lamivudine were hepatitis B surface antigen or hepatitis C antibody positive. Among these coinfected subjects, one subject (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 subjects (2/20) had elevations in transaminases to greater than five times ULN through 144 weeks. No HBV and/or HCV coinfected subject discontinued from the trial due to hepatobiliary disorders [See Warnings and Precautions (5.10) ]. 6.3 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, vertigo 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. A few of the postmarketing reports of hepatic failure, including cases in patients with no pre-existing hepatic disease or other identifiable risk factors, were characterized by a fulminant course, progressing in some cases to transplantation or death. Immune System Disorders Allergic reactions Metabolism and Nutrition Disorders Redistribution/accumulation of body fat [See Warnings and Precautions (5.14) ] , hypercholesterolemia, hypertriglyceridemia Musculoskeletal and Connective Tissue Disorders Arthralgia, myalgia, myopathy Nervous System Disorders Abnormal coordination, ataxia, cerebellar coordination and balance disturbances, 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, photoallergic dermatitis, Stevens-Johnson syndrome Emtricitabine: No postmarketing adverse reactions have been identified for inclusion in this section. Tenofovir Disoproxil Fumarate: Immune System Disorders Allergic reaction, including angioedema Metabolism and Nutrition Disorders Lactic acidosis, hypokalemia, hypophosphatemia Respiratory, Thoracic, and Mediastinal Disorders Dyspnea Gastrointestinal Disorders Pancreatitis, increased amylase, abdominal pain Hepatobiliary Disorders Hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT, gamma GT) Skin and Subcutaneous Tissue Disorders Rash Musculoskeletal and Connective Tissue Disorders Rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy Renal and Urinary Disorders Acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria General Disorders and Administration Site Conditions Asthenia The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.

<table width="100%" ID="table2"> <caption>Table 2 Selected Treatment-Emergent Adverse Reactions<footnote>Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug.</footnote> (Grades 2&#x2013;4) Reported in &#x2265;5% in Either Treatment Group in Study 934 (0&#x2013;144 Weeks)</caption> <col width="40%" align="left" valign="top"/> <col width="30%" align="center" valign="top"/> <col width="30%" align="center" valign="top"/> <thead> <tr> <th styleCode="Lrule Rrule"/> <th styleCode="Botrule Rrule">FTC + TDF + EFV<footnote>From Weeks 96 to 144 of the trial, subjects received emtricitabine/tenofovir DF administered in combination with efavirenz in place of emtricitabine + tenofovir DF with efavirenz.</footnote> </th> <th styleCode="Botrule Rrule">AZT/3TC + EFV</th> </tr> <tr> <th styleCode="Lrule Rrule"/> <th styleCode="Rrule">N=257</th> <th styleCode="Rrule">N=254</th> </tr> </thead> <tbody> <tr> <td styleCode="Lrule Rrule">Gastrointestinal Disorder</td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule"> Diarrhea</td> <td styleCode="Rrule">9%</td> <td styleCode="Rrule">5%</td> </tr> <tr> <td styleCode="Lrule Rrule"> Nausea</td> <td styleCode="Rrule">9%</td> <td styleCode="Rrule">7%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Vomiting</td> <td styleCode="Rrule">2%</td> <td styleCode="Rrule">5%</td> </tr> <tr> <td styleCode="Lrule Rrule">General Disorders and Administration Site Condition</td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Fatigue</td> <td styleCode="Rrule">9%</td> <td styleCode="Rrule">8%</td> </tr> <tr> <td styleCode="Lrule Rrule">Infections and Infestations</td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule"> Sinusitis</td> <td styleCode="Rrule">8%</td> <td styleCode="Rrule">4%</td> </tr> <tr> <td styleCode="Lrule Rrule"> Upper respiratory tract infections</td> <td styleCode="Rrule">8%</td> <td styleCode="Rrule">5%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Nasopharyngitis</td> <td styleCode="Rrule">5%</td> <td styleCode="Rrule">3%</td> </tr> <tr> <td styleCode="Lrule Rrule">Nervous System Disorders</td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule"> Headache</td> <td styleCode="Rrule">6%</td> <td styleCode="Rrule">5%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Dizziness</td> <td styleCode="Rrule">8%</td> <td styleCode="Rrule">7%</td> </tr> <tr> <td styleCode="Lrule Rrule">Psychiatric Disorders</td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule"> Anxiety</td> <td styleCode="Rrule">5%</td> <td styleCode="Rrule">4%</td> </tr> <tr> <td styleCode="Lrule Rrule"> Depression</td> <td styleCode="Rrule">9%</td> <td styleCode="Rrule">7%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Insomnia</td> <td styleCode="Rrule">5%</td> <td styleCode="Rrule">7%</td> </tr> <tr> <td styleCode="Lrule Rrule">Skin and Subcutaneous Tissue Disorders</td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule"> Rash Event<footnote>Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and rash vesicular.</footnote> </td> <td styleCode="Rrule">7%</td> <td styleCode="Rrule">9%</td> </tr> </tbody> </table>

<table width="100%" ID="table3"> <caption>Table 3 Significant Laboratory Abnormalities Reported in &#x2265;1% of Subjects in Either Treatment Group in Study 934 (0&#x2013;144 Weeks)</caption> <col width="40%" align="left" valign="top"/> <col width="30%" align="center" valign="middle"/> <col width="30%" align="center" valign="middle"/> <thead> <tr> <th styleCode="Lrule Rrule"/> <th styleCode="Botrule Rrule">FTC + TDF + EFV<footnote>From Weeks 96 to 144 of the trial, subjects received emtricitabine/tenofovir DF administered in combination with efavirenz in place of emtricitabine + tenofovir DF with efavirenz.</footnote> </th> <th styleCode="Botrule Rrule">AZT/3TC + EFV</th> </tr> <tr> <th styleCode="Lrule Rrule"/> <th styleCode="Rrule">N=257</th> <th styleCode="Rrule">N=254</th> </tr> </thead> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Any &#x2265; Grade 3 Laboratory Abnormality</td> <td styleCode="Rrule">30%</td> <td styleCode="Rrule">26%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Fasting Cholesterol (&gt;240 mg/dL)</td> <td styleCode="Rrule">22%</td> <td styleCode="Rrule">24%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Creatine Kinase (M: &gt;990 U/L) (F: &gt;845 U/L)</td> <td styleCode="Rrule">9%</td> <td styleCode="Rrule">7%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Serum Amylase (&gt;175 U/L)</td> <td styleCode="Rrule">8%</td> <td styleCode="Rrule">4%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Alkaline Phosphatase (&gt;550 U/L)</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">0%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">AST (M: &gt;180 U/L) (F: &gt;170 U/L)</td> <td styleCode="Rrule">3%</td> <td styleCode="Rrule">3%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">ALT (M: &gt;215 U/L) (F: &gt;170 U/L)</td> <td styleCode="Rrule">2%</td> <td styleCode="Rrule">3%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Hemoglobin (&lt;8.0 mg/dL)</td> <td styleCode="Rrule">0%</td> <td styleCode="Rrule">4%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Hyperglycemia (&gt;250 mg/dL)</td> <td styleCode="Rrule">2%</td> <td styleCode="Rrule">1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Hematuria (&gt;75 RBC/HPF)</td> <td styleCode="Rrule">3%</td> <td styleCode="Rrule">2%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Glycosuria (&#x2265;3+)</td> <td styleCode="Rrule">&lt;1%</td> <td styleCode="Rrule">1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Neutrophils (&lt;750/mm³)</td> <td styleCode="Rrule">3%</td> <td styleCode="Rrule">5%</td> </tr> <tr> <td styleCode="Lrule Rrule">Fasting Triglycerides (&gt;750 mg/dL)</td> <td styleCode="Rrule">4%</td> <td styleCode="Rrule">2%</td> </tr> </tbody> </table>