Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate for HIV

INDICATIONS AND USAGE Efavirenz, lamivudine and tenofovir disoproxil fumarate tablets are indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adult and pediatric patients weighing at least 40 kg. Efavirenz, lamivudine and tenofovir disoproxil fumarate tablets are three-drug combination of efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor, and lamivudine (3TC) and tenofovir disoproxil fumarate (TDF), both nucleo(t)side reverse transcriptase inhibitors and are indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adult and pediatric patients weighing at least 40 kg. ( 1 )

DOSAGE AND ADMINISTRATION Testing: Prior to initiation and during treatment with efavirenz, lamivudine and tenofovir disoproxil fumarate tablets, patients should be tested for hepatitis B virus infection, and estimated creatinine clearance, urine glucose, and urine protein should be obtained. ( 2.1 ) Recommended dose: One tablet taken orally once daily on an empty stomach, preferably at bedtime. ( 2.2 ) Renal Impairment: Not recommended in patients with CrCL less than 50 mL/min or patients with end-stage renal disease requiring hemodialysis. ( 2.3 ) Hepatic Impairment: Not recommended for patients with moderate or severe hepatic impairment. Use caution in patients with mild hepatic impairment. ( 2.4 ) 2.1 Testing Prior to Initiation and During Treatment with Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate Tablets Prior to initiation of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets, test patients for hepatitis B virus infection [see Warnings and Precautions (5.1) ] . It is recommended that serum creatinine, serum phosphorus, estimated creatinine clearance, urine glucose, and urine protein be assessed before initiating efavirenz, lamivudine and tenofovir disoproxil fumarate tablets and during therapy in all patients as clinically appropriate [see Warnings and Precautions (5.4) ]. Monitor hepatic function prior to and during treatment with efavirenz, lamivudine and tenofovir disoproxil fumarate tablets [see Warnings and Precautions (5.9) ] . 2.2 Recommended Dosage for Adult and Pediatric Patients Weighing at Least 40 kg Efavirenz, lamivudine and tenofovir disoproxil fumarate tablets are a three-drug fixed-dose combination product containing 600 mg of efavirenz (EFV), 300 mg of lamivudine (3TC), and 300 mg of tenofovir disoproxil fumarate (TDF). The recommended dosage of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets in HIV-1-infected adults and pediatric patients who weigh at least 40 kg, and can swallow a solid tablet, is one tablet taken orally once daily. Efavirenz, lamivudine and tenofovir disoproxil fumarate tablets should be taken on an empty stomach, preferably at bedtime. Dosing at bedtime may improve the tolerability of nervous system symptoms [see Warnings and Precautions (5.6) a nd Adverse Reactions (6.1)]. 2.3 Not Recommended in Renal Impairment Because efavirenz, lamivudine and tenofovir disoproxil fumarate tablets are a fixed-dose combination tablet and cannot be dose adjusted, they are not recommended for patients with impaired renal function (creatinine clearance less than 50 mL/min) or patients with end-stage renal disease (ESRD) requiring hemodialysis [see Use in Specific Populations (8.6) ] . 2.4 Not Recommended in Moderate to Severe Hepatic Impairment Efavirenz, lamivudine and tenofovir disoproxil fumarate tablets are not recommended in patients with moderate or severe hepatic impairment (Child-Pugh B or C) [see Warnings and Precautions (5.9) and Use in Specific Populations (8.7)] .

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 [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. I mportant 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 3 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during 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

DRUG INTERACTIONS Efavirenz, lamivudine and tenofovir disoproxil fumarate should not be administered with other antiretroviral medications for the treatment of HIV-1 infection. ( 7.1 ) Coadministration of efavirenz, lamivudine and tenofovir disoproxil fumarate can alter the concentrations of other drugs and other drugs may alter the concentration of efavirenz, lamivudine and tenofovir disoproxil fumarate. The potential for drug-drug interactions should be considered before and during therapy. ( 5.3 , 7 ) 7.1 Not Recommended with Other Antiretroviral Medications Efavirenz, lamivudine and tenofovir disoproxil fumarate is a complete regimen for the treatment of HIV-1 infection; therefore, it should not be administered with other antiretroviral medications for treatment of HIV-1 infection. 7.2 QT Prolonging Drugs There is limited information available on the potential for a pharmacodynamic interaction between EFV and drugs that prolong the QTc interval. QTc prolongation has been observed with the use of EFV [see Clinical Pharmacology (12.2) ] . Consider alternatives to EFV when coadministered with a drug with a known risk of Torsade de Pointes. 7.3 Drugs Affecting Renal Function Tenofovir is primarily eliminated by the kidneys [see Clinical Pharmacology (12.3) ]. Coadministration of EFV/3TC/TDF with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the coadministered drug. Some examples include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.4) ] . Drugs that decrease renal function may increase concentrations of tenofovir. 7.4 Cannabinoid Test Interaction EFV does not bind to cannabinoid receptors. False-positive urine cannabinoid test results have been reported with some screening assays in uninfected and HIV-infected subjects receiving EFV. Confirmation of positive screening tests for cannabinoids by a more specific method is recommended. 7.5 Established and Other Potentially Significant Interactions EFV has been shown in vivo to induce CYP3A and CYP2B6. Other compounds that are substrates of CYP3A or CYP2B6 may have decreased plasma concentrations when coadministered with EFV. Drugs that induce CYP3A activity (e.g., phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of EFV resulting in lowered plasma concentrations. No drug interaction studies have been conducted using efavirenz, lamivudine and tenofovir disoproxil fumarate tablets. However, drug interaction studies have been conducted with the individual components of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets (EFV, 3TC, and TDF) [see Clinical Pharmacology (12.3) ] . Drug interactions with EFV are summarized in Table 3 [for pharmacokinetics data see Clinical Pharmacology (12.3 , Tables 6 and 7) ]. This table includes potentially significant interactions, but is not all inclusive. Table 3. Established and Other Potentially Significant Drug Interactions with EFV: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction * The interaction between EFV and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. Concomitant Drug Class: Drug Name Effect Clinical Comment Anticoagulant: Warfarin ↑or ↓warfarin Monitor INR and adjust warfarin dosage if necessary. Anticonvulsants: Carbamazepine ↓carbamazepine* ↓EFV* There are insufficient data to make a dose recommendation for EFV. Alternative anticonvulsant treatment should be used. Phenytoin Phenobarbital ↓anticonvulsant ↓EFV Monitor anticonvulsant plasma levels periodically because of potential for reduction in anticonvulsant and/or EFV plasma levels. Antidepressants: Bupropion Sertraline ↓bupropion* ↓sertraline* Increases in bupropion dosage should be guided by clinical response. Bupropion dose should not exceed the maximum recommended dose. Increases in sertraline dosage should be guided by clinical response. Antifungals: Itraconazole Ketoconazole Posaconazole ↓itraconazole* ↓hydroxyitraconazole* ↓ketoconazole ↓posaconazole* Consider alternative antifungal treatment because no dose recommendation for itraconazole or ketoconazole can be made. Avoid concomitant use unless the benefit outweighs the risks. Anti-infective: Clarithromycin ↓clarithromycin* ­↑14-OH metabolite* Consider alternatives to macrolide antibiotics because of the risk of QT interval prolongation. Antimycobacterial: Rifabutin Rifampin ↓rifabutin* ↓EFV* Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week. Increase EFV total daily dose to 800 mg once daily when coadministered with rifampin to patients weighing 50 kg or more. Antimalarials: Artemether/lumefantrine Atovaquone/proguanil ↓artemether* ↓dihydroartemisinin* ↓lumefantrine* ↓atovaquone ↓proguanil Consider alternatives to artemether/lumefantrine because of the risk of QT interval prolongation [see Warnings and Precautions (5.16) ] . Concomitant administration is not recommended. Calcium channel blockers: Diltiazem Others (e.g., felodipine, nicardipine, nifedipine, verapamil) ↓diltiazem* ↓desacetyl diltiazem* ↓N-monodesmethyldiltiazem* ↓calcium channel blocker Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). When coadministered with EFV, dosage adjustment of calcium channel blocker may be needed and should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker). HMG-CoA reductase inhibitors: Atorvastatin Pravastatin Simvastatin ↓atorvastatin* ↓pravastatin* ↓simvastatin* Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose. Hepatitis C antiviral agents: Boceprevir Elbasvir/Grazoprevir Pibrentasvir/Glecaprevir Simeprevir Velpatasvir/Sofosbuvir Velpatasvir/Sofosbuvir/ Voxilaprevir Ledipasvir/Sofosbuvir ↓boceprevir* ↓elbasvir ↓grazoprevir ↓pibrentasvir ↓glecaprevir ↓simeprevir* ↔EFV ↓velpatasvir ↓velpatasvir ↓voxilaprevir ↑TDF Concomitant administration of boceprevir is not recommended. Coadministration of EFV with elbasvir/grazoprevir is contraindicated [see Contraindications (4) ] because it may lead to loss of virologic response to elbasvir/grazoprevir. Coadministration of EFV is not recommended because it may lead to reduced therapeutic effect of pibrentasvir/glecaprevir. Concomitant administration of simeprevir is not recommended. Coadministration of EFV and sofosbuvir/velpatasvir is not recommended because it may result in loss of therapeutic effect of sofosbuvir/velpatasvir. Coadministration of EFV and sofosbuvir/velpatasvir/voxilaprevir is not recommended because it may result in loss of therapeutic effect of sofosbuvir/velpatasvir/voxilaprevir. Monitor for adverse reactions associated with TDF. Hepatitis B antiviral agents Adefovir dipivoxil Concomitant administration of adefovir dipivoxil is not recommended. Hormonal contraceptives: Oral Ethinyl estradiol/ Norgestimate Implant Etonogestrel ↓active metabolites of norgestimate* ↓etonogestrel A reliable method of barrier contraception should be used in addition to hormonal contraceptives. A reliable method of barrier contraception should be used in addition to hormonal contraceptives. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in EFV-exposed patients. Immunosuppressants: Cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A ↓immunosuppressant Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are

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 are impaired concentration, abnormal dreams, headache, nausea, malaise and fatigue, nasal signs and symptoms, diarrhea, rash, dizziness, insomnia, pain, depression, asthenia, and cough. ( 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-naїve 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 (Grade 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% Laboratory Abnormalities: Table 2 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 2. 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% 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 D