Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate

WARNING: POST TREATMENT ACUTE EXACERBATIONS OF HEPATITIS B Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine or tenofovir disoproxil fumarate, two components of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis B treatment [see Warnings and Precautions (5.1) ]. WARNING: POST TREATMENT ACUTE EXACERBATIONS OF HEPATITIS B See full prescribing information for complete boxed warning. • Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with HBV and human immunodeficiency virus (HIV-1) and have discontinued lamivudine and tenofovir disoproxil fumarate. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis B treatment. ( 5.1 )

5 WARNINGS AND PRECAUTIONS Lactic Acidosis/Severe Hepatomegaly with Steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. ( 5.2 ) New Onset or Worsening Renal Impairment: Can include acute renal failure and Fanconi syndrome. Avoid administering efavirenz, lamivudine and tenofovir disoproxil fumarate tablets with concurrent or recent use of nephrotoxic drugs. ( 5.4 ) Serious Psychiatric Symptoms: Immediate medical evaluation is recommended for serious psychiatric symptoms such as severe depression or suicidal ideation. ( 5.5 ) Nervous System Symptoms (NSS): NSS are frequent, usually begin 1 to 2 days after initiating therapy and resolve in 2 to 4 weeks. Dosing at bedtime may improve tolerability. NSS are not predictive of onset of psychiatric symptoms. ( 5.6 ) Rash: Rash usually begins within 1 to 2 weeks after initiating therapy and resolves within 4 weeks. Discontinue if severe rash develops. ( 5.8 ) 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. ( 5.9 , 8.7 ) Pancreatitis: Use with caution in pediatric patients with a history of pancreatitis or other significant risk factors for pancreatitis. Discontinue efavirenz, lamivudine and tenofovir disoproxil fumarate as clinically appropriate. ( 5.10 ) Convulsions: Use caution in patients with a history of seizures. ( 5.11 ) Lipids: Total cholesterol and triglyceride elevations. Monitor before therapy and periodically thereafter. ( 5.12 ) Decreases in Bone Mineral Density (BMD): Observed in HIV-infected patients. Consider assessment of BMD in patients with a history of pathologic fracture or other risk factors for osteoporosis or bone loss. ( 5.13 ) Immune Reconstitution Syndrome: Observed in HIV-infected patients. May necessitate further evaluation and treatment. ( 5.14 ) Redistribution/Accumulation of Body Fat: Observed in HIV-infected patients receiving antiretroviral combination therapy. ( 5.15 ) 5.1 Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV Posttreatment Exacerbations of Hepatitis: All patients with HIV-1 should be tested for the presence of chronic hepatitis B virus (HBV) before initiating antiretroviral therapy therapy [see Dosage and Administration (2.1) ] . Discontinuation of anti-HBV therapy, including 3TC and TDF, may be associated with severe acute exacerbations of hepatitis B. Patients infected with HBV who discontinue efavirenz, lamivudine and tenofovir disoproxil fumarate should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption of anti-hepatitis B therapy may be warranted. Important Differences Among Lamivudine-Containing Products: Efavirenz, lamivudine and tenofovir disoproxil fumarate tablets contain a higher dose of the same active ingredient, 3TC, than EPIVIR-HBV ® tablets. EPIVIR-HBV was developed for patients with chronic hepatitis B. The formulation and dosage of 3TC in EPIVIR- HBV are not appropriate for patients co-infected with HIV-1 and HBV. Safety and efficacy of 3TC have not been established for treatment of chronic hepatitis B in patients co-infected with HIV-1 and HBV. If treatment with EPIVIR-HBV, TDF, or a tenofovir alafenamide (TAF)-containing product is prescribed for chronic hepatitis B for a patient with unrecognized or untreated HIV-1 infection, rapid emergence of HIV-1 resistance is likely to result because of the subtherapeutic dose and the inappropriateness of monotherapy HIV-1 treatment. 5.2 Lactic Acidosis and Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs and other antiretrovirals. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. Treatment 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 . 5.3 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions The concomitant use of efavirenz, lamivudine and tenofovir disoproxil fumarate and other drugs may result in known or potentially significant drug interactions, some of which may lead to [see Contraindications (4) and Drug Interactions (7.5)]: •Loss of therapeutic effect of efavirenz, lamivudine and tenofovir disoproxil fumarate and possible development of resistance. •Possible clinically significant adverse reactions from greater exposures of concomitant drugs. See Table 5 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 therapy with efavirenz, lamivudine and tenofovir disoproxil fumarate; review concomitant medications during therapy with efavirenz, lamivudine and tenofovir disoproxil fumarate; and monitor for the adverse reactions associated with the concomitant drugs. 5.4 New Onset or Worsening Renal Impairment TDF, a component of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets is principally eliminated by the kidney. 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 [see Adverse Reactions (6.2) ] . Prior to initiation and during use of efavirenz, lamivudine and tenofovir disoproxil fumarate, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. Avoid efavirenz, lamivudine and tenofovir disoproxil fumarate with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs [NSAIDs]) [see Drug Interactions (7.3) ] . 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. 5.5 Psychiatric Symptoms Serious psychiatric adverse experiences have been reported in patients treated with EFV, a component of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets. In controlled trials of 1,008 patients treated with regimens containing EFV for a mean of 2.1 years and 635 patients treated with control regimens for a mean of 1.5 years, the frequency (regardless of causality) of specific serious psychiatric events among patients 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 a study using EFV 600 mg, 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 study entry; similar associations were observed in both the EFV and control treatment groups. In a study using EFV 600 mg, onset of new serious psychiatric symptoms occurred throughout the study for both EFV-treated and control-treated patients. One percent of EFV-treated patients discontinued or interrupted treatment because of one or more of these selected psychiatric symptoms. In the ENCORE1 (Evaluation of Novel Concepts in Optimization of antiRetroviral Efficacy) study, at Week 48 the frequency (regardless of causality) of the most common (occurring in > 1% patients) psychiatric events among patients who received EFV 400 mg (N = 321) or EFV 600 mg (N = 309) regimens, respectively, were: abnormal dreams (8.7%, 11.3%), insomnia (6.2%, 6.5%), somnolence (3.1%, 3.9%), depression (3.1%, 1.6%), nightmare (1.9%, 2.6%), sleep disorder (2.2%, 1.3%), and anxiety (1.2%, 1.3%). There have also been occasional postmarketing reports of death by suicide, delusions, psychosis-like behavior, although a causal relationship to the use of EFV cannot be determined from these reports [see Adverse Reactions (6.2) ] . Postmarketing cases of catatonia have also been reported and may be associated with increased efavirenz 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. 5.6 Nervous System Symptoms Fifty-three percent (531/1,008) of patients receiving EFV, a component of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets, in controlled trials reported central nervous system symptoms (any grade, regardless of causality) compared to 25% (156/635) of patients receiving control regimens. These symptoms included, but were not limited to, dizziness (28.1% of the 1,008 patients), insomnia (16.3%), impaired concentration (8.3%), somnolence (7.0%), abnormal dreams (6.2%), and hallucinations (1.2%). These symptoms were severe in 2.0% of patients and 2.1% of patients discontinued therapy as a result. These symptoms usually begin during the first or second day of therapy and generally resolve after the first 2 to 4 weeks of therapy. After 4 weeks of therapy, the prevalence of nervous system symptoms of at least moderate severity ranged from 5% to 9% in patients treated with regimens containing EFV and from 3% to 5% in patients treated with a control regimen. Inform patients 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) ] . In the ENCORE1 study, at Week 48, 40% of EFV 400 mg recipients and 48% of EFV 600 mg recipients reported central nervous system disorders. The most common symptoms (> 10%) were dizziness (27% vs. 35%) and headache (11% vs. 11%). Late-onset neurotoxicity, including ataxia and encephalopathy (impaired consciousness, confusion, psychomotor slowing, psychosis, delirium), may occur months to years after beginning efavirenz therapy. Some events of late-onset neurotoxicity have occurred in patients with CYP2B6 genetic polymorphisms which are associated with increased efavirenz levels despite daily dosages of 600 mg of efavirenz. 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 efavirenz use, and whether discontinuation of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets is warranted. 5.7 Embryo-Fetal Toxicity EFV, a component of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets, may cause fetal harm when administered during the first trimester to a pregnant woman. Advise females of reproductive potential who are receiving EFV to avoid pregnancy [see Use in Specific Populations (8.1 , 8.3) ]. 5.8 Skin and Systemic Hypersensitivity Reaction In controlled clinical trials, 26% (266/1,008) of patients treated with 600 mg EFV experienced new-onset skin rash compared with 17% (111/635) of patients treated in control groups. Rash associated with blistering, moist desquamation, or ulceration occurred in 0.9% (9/1,008) of patients treated with EFV. The incidence of Grade 4 rash (e.g., erythema multiforme, Stevens- Johnson syndrome) in patients treated with EFV in all studies and expanded access was 0.1%. Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 2 weeks of initiating therapy with EFV (median time to onset of rash in adults was 11 days) and, in most patients continuing therapy with EFV, rash resolves within 1 month (median duration, 16 days). The discontinuation rate for rash in clinical trials was 1.7% (17/1,008). EFV can generally be reinitiated in patients interrupting therapy because of rash. EFV 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), alternate therapy should be considered [see Contraindications (4) ] . In the ENCORE1 study at Week 48, different types of rash (such as rash, rash papular, rash maculopapular and rash pruritic) occurred in 32% of EFV 600 mg recipients and 26% of EFV 400 mg recipients. Grade 3 to 4 rash was reported in 3% of EFV 600 mg recipients and 1% of EFV 400 mg recipients. The discontinuation rate for rash in the ENCORE1 study was 3% of EFV 600 mg recipients and 1% of EFV 400 mg recipients. 5.9 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. 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. EFV, a component of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets, is not recommended for patients with moderate or severe hepatic impairment. Careful monitoring is recommended for patients with mild hepatic impairment receiving EFV [see Adverse Reactions (6.1) 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 efavirenz, lamivudine and tenofovir disoproxil fumarate in patients with persistent elevations of serum transaminases to greater than five times the upper limit of the normal range. Discontinue efavirenz, lamivudine and tenofovir disoproxil fumarate if elevation of serum transaminases is accompanied by clinical signs or symptoms of hepatitis or hepatic decompensation. 5.10 Pancreatitis In pediatric patients with a history of prior antiretroviral nucleoside exposure, a history of pancreatitis, or other significant risk factors for the development of pancreatitis, 3TC, a component of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets, should be used with caution. Treatment with efavirenz, lamivudine and tenofovir disoproxil fumarate should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur [see Adverse Reactions (6.1) ] . 5.11 Convulsions Convulsions have been observed in patients receiving EFV, generally in the presence of known medical history of seizures [see Nonclinical Toxicology (13.2) ] . Caution should 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 (7.5) ] . 5.12 Lipid Elevations Treatment with EFV has resulted in increases in the concentration of total cholesterol and triglycerides. Cholesterol and triglyceride testing should be performed before initiating EFV therapy and at periodic intervals during therapy. 5.13 Bone Loss and Mineralization Effects Bone Mineral Density (BMD): In clinical trials in HIV-1-infected adults, TDF was associated with slightly greater decreases in BMD and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators [see Adverse Reactions (6.1) ] . Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving TDF. The effects of TDF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk in adults and pediatric subjects 2 years and older are unknown. The long-term effect of lower spine and total body BMD on skeletal growth in pediatric patients, and in particular, the effects of long-duration exposure in younger children is unknown. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all. Assessment of BMD should be considered for adult and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. If bone abnormalities are suspected then appropriate consultation should be obtained. Mineralization Defects: Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with TDF use [see Adverse Reactions (6.2) ] . Arthralgia and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving TDF-containing products [see Warnings and Precautions (5.4) ]. 5.14 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including EFV, 3TC, and TDF. 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-Barre 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. 5.15 Fat Redistribution In HIV-infected patients, 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 combination antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. 5.16 QTc Prolongation QTc prolongation has been observed with the use of EFV [see Drug Interactions (7.2 , 7.5 ) and Clinical Pharmacology (12.2) ] . Consider alternatives to products containing EFV 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.

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Exacerbations of Hepatitis B [see Boxed Warning , Warnings and Precautions (5.1) ] . Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions (5.2) ] . New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.4) ] . Psychiatric Symptoms [see Warnings and Precautions (5.5) ] . Nervous System Symptoms [see Warnings and Precautions (5.6) ] . Skin and Systemic Hypersensitivity Reaction [see Warnings and Precautions (5.8) ] . Hepatotoxicity [see Warnings and Precautions (5.9) ]. Pancreatitis [see Warnings and Precautions (5.10) ] . Bone Loss and Mineralization Effects [see Warnings and Precautions (5.13) ] . Immune Reconstitution Syndrome [see Warnings and Precautions (5.14) ] . Fat Redistribution [see Warnings and Precautions (5.15) ] . Most common adverse reactions (>5% with efavirenz, lamivudine and tenofovir disoproxil fumarate) are rash and dizziness. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Laurus Generics Inc. at 1-833-3-LAURUS (1-833-352-8787) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, the adverse reaction rates observed in 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. Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate Clinical Trials in Treatment-Naïve HIV-1 Infected Adult Subjects In Trial 903, 600 antiretroviral-naïve subjects received TDF (N = 299) or stavudine (d4T) (N = 301) administered in combination with 3TC and EFV for 144 weeks. The most common adverse reactions were mild to moderate gastrointestinal events and dizziness. Mild adverse reactions (Grade 1) were common with a similar incidence in both arms and included dizziness, diarrhea, and nausea. Table 1 provides the treatment-emergent adverse reactions (Grades 2 to 4) occurring in greater than or equal to 5% of subjects treated in any treatment group. Table 1. Selected Adverse Reactions a (Grades 2 to 4) Reported in ≥ 5% in Any Treatment Group in Trial 903 (0 to 144 Weeks) a Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. b Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash. c Lipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome. d Peripheral neuropathy includes peripheral neuritis and neuropathy. TDF + 3TC + EFV d4T + 3TC + EFV N = 299 N = 301 Rash event b 18% 12% Headache 14% 17% Pain 13% 12% Diarrhea 11% 13% Depression 11% 10% Back pain 9% 8% Nausea 8% 9% Fever 8% 7% Abdominal pain 7% 12% Asthenia 6% 7% Anxiety 6% 6% Vomiting 5% 9% Insomnia 5% 8% Arthralgia 5% 7% Pneumonia 5% 5% Dyspepsia 4% 5% Dizziness 3% 6% Myalgia 3% 5% Lipodystrophy c 1% 8% Peripheral neuropathy d 1% 5% ENCORE1 Study - Adverse Reactions: The most common adverse reactions seen in a double-blind comparative controlled study in which 630 treatment-naïve subjects received EFV 400 mg (N = 321) or EFV 600 mg (N = 309) in combination with fixed-dose emtricitabine (FTC)/TDF for 48 weeks were mild to moderate gastrointestinal events, dizziness, abnormal dreams, and rash. Selected clinical adverse reactions of moderate or severe intensity reported in ≥ 2% of treatment-naive patients receiving combination therapy including EFV 400 mg and EFV 600 mg are presented in Table 2. Table 2. Selected Adverse Reactions a (Grades 2 to 4) Reported in ≥ 2% in Either Treatment Group in the ENCORE1 Study through Week 48 a Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. b Rash events include dermatitis allergic, drug hypersensitivity, pruritus generalized, eosinophilic pustular folliculitis, rash, rash erythematous, rash generalized, rash macular, rash maculopapular, rash morbilliform, rash papular, rash pruritic, rash vesicular, and urticaria. EFV 400 mg + FTC/TDF EFV 600 mg + FTC/TDF N = 321 N = 309 Rash event b 9% 13% Dizziness 6% 9% Insomnia 3% 4% Abnormal dreams 2% 2% Headache 1% 3% Diarrhea 2% 3% Vomiting 1% 2% Pyrexia 2% 1% Upper respiratory tract infection 3% 1% Nasopharyngitis 3% 2% Herpes zoster 3% 1% Gastroenteritis 2% 2% Laboratory Abnormalities: Table 3 provides a list of laboratory abnormalities (Grades 3 to 4) observed in Trial 903. With the exception of fasting cholesterol and fasting triglyceride elevations that were more common in the d4T group (40% and 9%) compared with the TDF group (19% and 1%) respectively, laboratory abnormalities observed in this trial occurred with similar frequency in the TDF and d4T treatment arms. Table 3. Grade 3 to 4 Laboratory Abnormalities Reported in ≥ 1% of Patients Randomized to Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate in Study 903 (0 to 144 Weeks) TDF + 3TC + EFV d4T + 3TC + EFV N = 299 N = 301 Any ≥ Grade 3 Laboratory Abnormality 36% 42% Fasting Cholesterol (> 240 mg/dL) 19% 40% Creatine Kinase (M: > 990 U/L; F: > 845 U/L) 12% 12% Serum Amylase (> 175 U/L) 9% 8% AST (M: > 180 U/L; F: > 170 U/L) 5% 7% ALT (M: > 215 U/L; F: > 170 U/L) 4% 5% Hematuria (> 100 RBC/HPF) 7% 7% Neutrophils (< 750/mm 3 ) 3% 1% Fasting Triglycerides (> 750 mg/dL) 1% 9% In ENCORE1 study, a summary of Grade 3 and 4 laboratory abnormalities is provided in Table 4. Table 4. Grades 3 to 4 Laboratory Abnormalities in ≥ 2% in Either Treatment Group Through Week 48 Laboratory Parameter EFV 400 mg + FTC + TDF EFV 600 mg + FTC + TDF N = 321 N = 309 ALT 5% 3% AST 2% 2% Total bilirubin 0.3% 3% Cholesterol 2% 5% Neutrophils 2% 3% Phosphorus 2% 3% Pancreatitis: Pancreatitis, which has been fatal in some cases, has been observed in antiretroviral nucleoside-experienced pediatric subjects receiving 3TC alone or in combination with other antiretroviral agents [see Warnings and Precautions (5.10) ]. Changes in Bone Mineral Density: In HIV-1-infected adult subjects in Trial 903, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving TDF + 3TC + EFV (-2.2% ± 3.9) compared with subjects receiving d4T + 3TC + EFV (-1.0% ± 4.6) through 144 weeks. Changes in BMD at the hip were similar between the two treatment groups (-2.8% ± 3.5 in the TDF group vs. -2.4% ± 4.5 in the d4T group). In both groups, the majority of the reduction in BMD occurred in the first 24 to 48 weeks of the trial and this reduction was sustained through Week 144. Twenty-eight percent of TDF-treated subjects vs. 21% of the d4T-treated 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 TDF group and 6 subjects in the d4T group. In addition, there were significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C telopeptide, and urinary N telopeptide) and higher serum parathyroid hormone levels and 1,25 Vitamin D levels in the TDF group relative to the d4T group; however, except for bone-specific alkaline phosphatase, these changes resulted in values that remained within the normal range [see Warnings and Precautions (5.13) ] . 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use for each of the individual components of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets (EFV, 3TC, and TDF). Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to EFV, 3TC, and TDF. Efavirenz Body as a Whole: allergic reactions, asthenia, redistribution/accumulation of body fat [see Warnings and Precautions (5.15) ]. Central and Peripheral Nervous System: abnormal coordination, ataxia, encephalopathy, cerebellar coordination and balance disturbances, convulsions, hypoesthesia, paresthesia, neuropathy, tremor, vertigo. Endocrine: gynecomastia. Gastrointestinal: constipation, malabsorption. Cardiovascular: flushing, palpitations. Liver and Biliary System: hepatic enzyme increase, hepatic failure, hepatitis. Metabolic and Nutritional: hypercholesterolemia, hypertriglyceridemia. Musculoskeletal: arthralgia, myalgia, myopathy. Psychiatric: aggressive reactions, agitation, delusions, emotional lability, mania, neurosis, paranoia, psychosis, suicide, catatonia. Respiratory: dyspnea. Skin and Appendages: erythema multiforme, photoallergic dermatitis, Stevens-Johnson syndrome. Special Senses: abnormal vision, tinnitus. Lamivudine Body as a Whole: redistribution/accumulation of body fat [see Warnings and Precautions (5.15) ]. Endocrine and Metabolic: hyperglycemia. General: weakness. Hemic and Lymphatic: anemia (including pure red cell aplasia and severe anemias progressing on therapy). Hepatic and Pancreatic: lactic acidosis and hepatic steatosis, posttreatment exacerbation of hepatitis B [see Boxed Warning, Warnings and Precautions (5.1 , 5.2) ] . Hypersensitivity: anaphylaxis, urticaria. Musculoskeletal: muscle weakness, CPK elevation, rhabdomyolysis. Skin: Alopecia, pruritus. 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. Renal and Urinary Disorders: renal insufficiency, 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 [see Warnings and Precautions (5.4) ] . 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. 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 cellspacing="0" cellpadding="0" border="0" width="100%"><caption>Table 1. Selected Adverse Reactions^a (Grades 2 to 4) Reported in &#x2265; 5% in Any Treatment Group in Trial 903 (0 to 144 Weeks) </caption><colgroup><col width="37.62%"/><col width="36.64%"/><col width="25.74%"/></colgroup><tfoot><tr><td colspan="3" align="justify">^a Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. ^b Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash. ^c Lipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome. ^d Peripheral neuropathy includes peripheral neuritis and neuropathy. </td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" rowspan="2" valign="top"> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">TDF + 3TC + EFV</content> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">d4T + 3TC + EFV</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="middle"><content styleCode="bold">N = 299</content> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">N = 301</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Rash event^b </td><td styleCode="Rrule" align="center" valign="middle">18% </td><td styleCode="Rrule" align="center" valign="middle">12% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Headache </td><td styleCode="Rrule" align="center" valign="middle">14% </td><td styleCode="Rrule" align="center" valign="middle">17% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Pain </td><td styleCode="Rrule" align="center" valign="middle">13% </td><td styleCode="Rrule" align="center" valign="middle">12% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Diarrhea </td><td styleCode="Rrule" align="center" valign="middle">11% </td><td styleCode="Rrule" align="center" valign="middle">13% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Depression </td><td styleCode="Rrule" align="center" valign="middle">11% </td><td styleCode="Rrule" align="center" valign="middle">10% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Back pain </td><td styleCode="Rrule" align="center" valign="middle">9% </td><td styleCode="Rrule" align="center" valign="middle">8% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Nausea </td><td styleCode="Rrule" align="center" valign="middle">8% </td><td styleCode="Rrule" align="center" valign="middle">9% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Fever </td><td styleCode="Rrule" align="center" valign="middle">8% </td><td styleCode="Rrule" align="center" valign="middle">7% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Abdominal pain </td><td styleCode="Rrule" align="center" valign="middle">7% </td><td styleCode="Rrule" align="center" valign="middle">12% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Asthenia </td><td styleCode="Rrule" align="center" valign="middle">6% </td><td styleCode="Rrule" align="center" valign="middle">7% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Anxiety </td><td styleCode="Rrule" align="center" valign="middle">6% </td><td styleCode="Rrule" align="center" valign="middle">6% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Vomiting </td><td styleCode="Rrule" align="center" valign="middle">5% </td><td styleCode="Rrule" align="center" valign="middle">9% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Insomnia </td><td styleCode="Rrule" align="center" valign="middle">5% </td><td styleCode="Rrule" align="center" valign="middle">8% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Arthralgia </td><td styleCode="Rrule" align="center" valign="middle">5% </td><td styleCode="Rrule" align="center" valign="middle">7% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Pneumonia </td><td styleCode="Rrule" align="center" valign="middle">5% </td><td styleCode="Rrule" align="center" valign="middle">5% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Dyspepsia </td><td styleCode="Rrule" align="center" valign="middle">4% </td><td styleCode="Rrule" align="center" valign="middle">5% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Dizziness </td><td styleCode="Rrule" align="center" valign="middle">3% </td><td styleCode="Rrule" align="center" valign="middle">6% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Myalgia </td><td styleCode="Rrule" align="center" valign="middle">3% </td><td styleCode="Rrule" align="center" valign="middle">5% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Lipodystrophy^c </td><td styleCode="Rrule" align="center" valign="middle">1% </td><td styleCode="Rrule" align="center" valign="middle">8% </td></tr><tr><td styleCode="Lrule Rrule" valign="middle">Peripheral neuropathy^d </td><td styleCode="Rrule" align="center" valign="middle">1% </td><td styleCode="Rrule" align="center" valign="middle">5% </td></tr></tbody></table>

<table cellspacing="0" cellpadding="0" border="0" width="100%"><caption>Table 2. Selected Adverse Reactions^a (Grades 2 to 4) Reported in &#x2265; 2% in Either Treatment Group in the ENCORE1 Study through Week 48 </caption><colgroup><col width="44.24%"/><col width="28.84%"/><col width="26.92%"/></colgroup><tfoot><tr><td colspan="3" align="justify">^aFrequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. ^bRash events include dermatitis allergic, drug hypersensitivity, pruritus generalized, eosinophilic pustular folliculitis, rash, rash erythematous, rash generalized, rash macular, rash maculopapular, rash morbilliform, rash papular, rash pruritic, rash vesicular, and urticaria. </td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">EFV 400 mg + FTC/TDF</content> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">EFV 600 mg + FTC/TDF</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">N = 321</content> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">N = 309</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Rash event^b </td><td styleCode="Rrule" align="center" valign="middle">9% </td><td styleCode="Rrule" align="center" valign="middle">13% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Dizziness </td><td styleCode="Rrule" align="center" valign="middle">6% </td><td styleCode="Rrule" align="center" valign="middle">9% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Insomnia </td><td styleCode="Rrule" align="center" valign="middle">3% </td><td styleCode="Rrule" align="center" valign="middle">4% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Abnormal dreams </td><td styleCode="Rrule" align="center" valign="middle">2% </td><td styleCode="Rrule" align="center" valign="middle">2% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Headache </td><td styleCode="Rrule" align="center" valign="middle">1% </td><td styleCode="Rrule" align="center" valign="middle">3% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Diarrhea </td><td styleCode="Rrule" align="center" valign="middle">2% </td><td styleCode="Rrule" align="center" valign="middle">3% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Vomiting </td><td styleCode="Rrule" align="center" valign="middle">1% </td><td styleCode="Rrule" align="center" valign="middle">2% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Pyrexia </td><td styleCode="Rrule" align="center" valign="middle">2% </td><td styleCode="Rrule" align="center" valign="middle">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Upper respiratory tract infection </td><td styleCode="Rrule" align="center" valign="middle">3% </td><td styleCode="Rrule" align="center" valign="middle">1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Nasopharyngitis </td><td styleCode="Rrule" align="center" valign="middle">3% </td><td styleCode="Rrule" align="center" valign="middle">2% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Herpes zoster </td><td styleCode="Rrule" align="center" valign="middle">3% </td><td styleCode="Rrule" align="center" valign="middle">1% </td></tr><tr><td styleCode="Lrule Rrule" valign="middle">Gastroenteritis </td><td styleCode="Rrule" align="center" valign="middle">2% </td><td styleCode="Rrule" align="center" valign="middle">2% </td></tr></tbody></table>

<table cellspacing="0" cellpadding="0" border="0" width="100%"><caption>Table 3. Grade 3 to 4 Laboratory Abnormalities Reported in &#x2265; 1% of Patients Randomized to Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate in Study 903 (0 to 144 Weeks) </caption><colgroup><col width="47.28%"/><col width="27.58%"/><col width="25.12%"/></colgroup><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">TDF + 3TC + EFV</content> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">d4T + 3TC + EFV</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">N = 299</content> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">N = 301</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Any &#x2265; Grade 3 Laboratory Abnormality </td><td styleCode="Rrule" align="center" valign="middle">36% </td><td styleCode="Rrule" align="center" valign="middle">42% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Fasting Cholesterol (&gt; 240 mg/dL) </td><td styleCode="Rrule" align="center" valign="middle">19% </td><td styleCode="Rrule" align="center" valign="middle">40% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Creatine Kinase (M: &gt; 990 U/L; F: &gt; 845 U/L) </td><td styleCode="Rrule" align="center" valign="middle">12% </td><td styleCode="Rrule" align="center" valign="middle">12% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Serum Amylase (&gt; 175 U/L) </td><td styleCode="Rrule" align="center" valign="middle">9% </td><td styleCode="Rrule" align="center" valign="middle">8% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">AST (M: &gt; 180 U/L; F: &gt; 170 U/L) </td><td styleCode="Rrule" align="center" valign="middle">5% </td><td styleCode="Rrule" align="center" valign="middle">7% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">ALT (M: &gt; 215 U/L; F: &gt; 170 U/L) </td><td styleCode="Rrule" align="center" valign="middle">4% </td><td styleCode="Rrule" align="center" valign="middle">5% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Hematuria (&gt; 100 RBC/HPF) </td><td styleCode="Rrule" align="center" valign="middle">7% </td><td styleCode="Rrule" align="center" valign="middle">7% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Neutrophils (&lt; 750/mm³) </td><td styleCode="Rrule" align="center" valign="middle">3% </td><td styleCode="Rrule" align="center" valign="middle">1% </td></tr><tr><td styleCode="Lrule Rrule" valign="middle">Fasting Triglycerides (&gt; 750 mg/dL) </td><td styleCode="Rrule" align="center" valign="middle">1% </td><td styleCode="Rrule" align="center" valign="middle">9% </td></tr></tbody></table>