FDA label 88c4d937-d1e9-4d7f-b9d5-cb8a8d33b936

WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS, POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B, and RISK OF DRUG RESISTANCE WITH USE OF TRUVADA FOR PRE-EXPOSURE PROPHYLAXIS (PrEP) IN UNDIAGNOSED EARLY HIV-1 INFECTION Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD, a component of TRUVADA, in combination with other antiretrovirals [See Warnings and Precautions (5.1) ] . TRUVADA is not approved for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of TRUVADA 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 TRUVADA. Therefore, hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are infected with HBV and discontinue TRUVADA. If appropriate, initiation of anti-hepatitis B therapy may be warranted [See Warnings and Precautions (5.2) ] . TRUVADA used for a PrEP indication must only be prescribed to individuals confirmed to be HIV-negative immediately prior to initiating and periodically (at least every 3 months) during use. Drug-resistant HIV-1 variants have been identified with use of TRUVADA for a PrEP indication following undetected acute HIV-1 infection. Do not initiate TRUVADA for a PrEP indication if signs or symptoms of acute HIV-1 infection are present unless negative infection status is confirmed [See Warnings and Precautions (5.9) ] . WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS, POST-TREATMENT ACUTE EXACERBATION OF HEPATITIS B, and RISK OF DRUG RESISTANCE WITH USE OF TRUVADA FOR PrEP IN UNDIAGNOSED HIV-1 INFECTION 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 VIREAD, a component of TRUVADA. ( 5.1 ) • TRUVADA 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 HIV-1 and HBV who have discontinued TRUVADA. Therefore, hepatic function should be monitored closely in HBV-infected patients who discontinue TRUVADA. If appropriate, initiation of anti-hepatitis B therapy may be warranted. ( 5.2 ) • TRUVADA used for a PrEP indication must only be prescribed to individuals confirmed to be HIV-negative immediately prior to initial use and periodically during use. Drug-resistant HIV-1 variants have been identified with the use of TRUVADA for a PrEP indication following undetected acute HIV-1 infection. Do not initiate TRUVADA for a PrEP indication if signs or symptoms of acute HIV infection are present unless negative infection status is confirmed. ( 5.9 )

5 WARNINGS AND PRECAUTIONS • New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Assess creatinine clearance (CrCl) before initiating treatment with TRUVADA. Monitor CrCl and serum phosphorus in patients at risk. Avoid administering Truvada with concurrent or recent use of nephrotoxic drugs. ( 5.3 ) • Coadministration with Other Products: Do not use with drugs containing emtricitabine or tenofovir disoproxil fumarate including ATRIPLA, COMPLERA, EMTRIVA, VIREAD; or with drugs containing lamivudine. Do not administer in combination with HEPSERA. ( 5.4 ) • Decreases in bone mineral density (BMD): Consider assessment of BMD in patients with a history of pathologic fracture or other risk factors for osteoporosis or bone loss. ( 5.5 ) • Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy. ( 5.6 ) • Immune reconstitution syndrome: May necessitate further evaluation and treatment. ( 5.7 ) • Triple nucleoside-only regimens: Early virologic failure has been reported in HIV-infected patients. Monitor carefully and consider treatment modification. ( 5.8 ) • Comprehensive management to reduce the risk of acquiring HIV-1: Use as part of a comprehensive prevention strategy including other prevention measures; strictly adhere to dosing schedule. ( 5.9 ) • Management to reduce the risk of acquiring HIV-1 drug resistance: Prior to initiating TRUVADA for PrEP - if clinical symptoms consistent with acute viral infection are present and recent (<1 month) exposures are suspected, delay starting PrEP for at least one month and reconfirm negative HIV-1 status or use a test approved by the FDA as an aid in the diagnosis of HIV-1 infection, including acute or primary HIV-1 infection. While using TRUVADA for PrEP - HIV-1 screening tests should be repeated at least every 3 months. ( 5.9 ) 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 VIREAD, a component of TRUVADA, 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 or uninfected individual with known risk factors for liver disease; however, cases have also been reported in HIV-1 infected patients with no known risk factors. Treatment with TRUVADA should be suspended in any patient or uninfected individual 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 HBV Infection It is recommended that all individuals be tested for the presence of chronic hepatitis B virus (HBV) before initiating TRUVADA. TRUVADA is not approved for the treatment of chronic HBV infection and the safety and efficacy of TRUVADA have not been established in patients infected with HBV. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued TRUVADA. In some patients infected with HBV and treated with EMTRIVA, the exacerbations of hepatitis B were associated with liver decompensation and liver failure. Patients who are infected with HBV should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with TRUVADA. If appropriate, initiation of anti-hepatitis B therapy may be warranted. HBV -uninfected individuals should be offered vaccination. 5.3 New Onset or Worsening Renal Impairment Emtricitabine and tenofovir are 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 VIREAD [See Adverse Reactions (6.2) ] . It is recommended that creatinine clearance be calculated in all individuals prior to initiating therapy and as clinically appropriate during therapy with TRUVADA. Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in all individuals at risk for renal impairment, including individuals who have previously experienced renal events while receiving HEPSERA. TRUVADA should be avoided with concurrent or recent use of a nephrotoxic agent. Treatment of HIV-1 Infection Dosing interval adjustment of TRUVADA and close monitoring of renal function are recommended in all patients with creatinine clearance 30–49 mL/min, [See Dosage and Administration (2.3) ] . No safety or efficacy data are available in patients with renal impairment who received TRUVADA using these dosing guidelines, so the potential benefit of TRUVADA therapy should be assessed against the potential risk of renal toxicity. TRUVADA should not be administered to patients with creatinine clearance below 30 mL/min or patients requiring hemodialysis. Pre-exposure Prophylaxis TRUVADA for a PrEP indication should not be used if creatinine clearance is less than 60 mL/min. If a decrease in creatinine clearance is observed in uninfected individuals while using TRUVADA for PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use [See Dosage and Administration (2.3) ] . 5.4 Coadministration with Other Products TRUVADA is a fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate. Do not coadminister TRUVADA with ATRIPLA, COMPLERA, EMTRIVA, or VIREAD. Due to similarities between emtricitabine and lamivudine, do not coadminister TRUVADA with other drugs containing lamivudine, including Combivir (lamivudine/zidovudine), Epivir or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), or Trizivir (abacavir sulfate/lamivudine/zidovudine). Do not coadminister TRUVADA with HEPSERA ® (adefovir dipivoxil) . 5.5 Decreases in Bone Mineral Density Assessment of bone mineral density (BMD) should be considered for adults and in pediatric patients 12 years of age and older 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. If bone abnormalities are suspected then appropriate consultation should be obtained. Tenofovir Disoproxil Fumarate: In a 144-week trial of treatment-naive HIV-1 infected adult subjects, 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 VIREAD + 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 VIREAD-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 VIREAD group and 6 subjects in the comparator group. Tenofovir disoproxil fumarate 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 VIREAD. 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 VIREAD-treated group compared to the placebo group. Six VIREAD treated subjects and one placebo treated subject had significant (greater than 4%) lumbar spine BMD loss in 48 weeks. Among 28 subjects receiving 96 weeks of VIREAD, 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 VIREAD-treated pediatric subjects 12 years of age and older suggest increased bone turnover, consistent with the effects observed in adults. In clinical trials of HIV-1 uninfected individuals, decreases in BMD were observed. In the iPrEx trial, a substudy of 503 subjects found mean changes from baseline in BMD ranging from -0.4% to -1.0% across total hip, spine, femoral neck, and trochanter in the TRUVADA group compared with the placebo group, which returned toward baseline after discontinuation of treatment. Thirteen percent of subjects receiving TRUVADA vs. 6% of subjects receiving placebo lost at least 5% of BMD at the spine during treatment. Bone fractures were reported in 1.7% of the TRUVADA group compared with 1.4% in the placebo group. No correlation between BMD and fractures was noted [See Clinical Studies (14.2) ] . The Partners PrEP trial found similar fracture rates between treatment and placebo groups (0.8% and 0.6%, respectively). No BMD evaluations were conducted during this trial [See Clinical Studies (14.3) ] . The effects of VIREAD-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. For additional information, please 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 VIREAD [See Adverse Reactions (6.2) ] . 5.6 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 HIV-1 infected patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. 5.7 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in HIV-1 infected patients treated with combination antiretroviral therapy, including TRUVADA. During the initial phase of combination antiretroviral treatment, HIV-1 infected 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. 5.8 Early Virologic Failure Clinical trials in HIV-1 infected subjects have demonstrated that certain regimens that only contain three nucleoside reverse transcriptase inhibitors (NRTI) are generally less effective than triple drug regimens containing two NRTIs in combination with either a non-nucleoside reverse transcriptase inhibitor or a HIV-1 protease inhibitor. In particular, early virological failure and high rates of resistance substitutions have been reported. Triple nucleoside regimens should therefore be used with caution. Patients on a therapy utilizing a triple nucleoside-only regimen should be carefully monitored and considered for treatment modification. 5.9 Comprehensive Management to Reduce the Risk of Acquiring HIV-1 Use TRUVADA for pre-exposure prophylaxis only as part of a comprehensive prevention strategy that includes other prevention measures, such as safer sex practices, because TRUVADA is not always effective in preventing the acquisition of HIV-1 [See Clinical Studies (14.2 and 14.3) ] . • Counsel uninfected individuals about safer sex practices that include consistent and correct use of condoms, knowledge of their HIV-1 status and that of their partner(s), and regular testing for other sexually transmitted infections that can facilitate HIV-1 transmission (such as syphilis and gonorrhea). • Inform uninfected individuals about and support their efforts in reducing sexual risk behavior. Use TRUVADA to reduce the risk of acquiring HIV-1 only in individuals confirmed to be HIV-negative. HIV-1 resistance substitutions may emerge in individuals with undetected HIV-1 infection who are taking only TRUVADA, because TRUVADA alone does not constitute a complete treatment regimen for HIV-1 treatment [See Microbiology: Resistance (12.4) ] ; therefore, care should be taken to minimize drug exposure in HIV-infected individuals. • Many HIV-1 tests, such as rapid tests, detect anti-HIV antibodies and may not identify HIV-1 during the acute stage of infection. Prior to initiating TRUVADA for a PrEP indication, evaluate seronegative individuals for current or recent signs or symptoms consistent with acute viral infections (e.g., fever, fatigue, myalgia, skin rash, etc.) and ask about potential exposure events (e.g., unprotected, or condom broke during sex with an HIV-1 infected partner) that may have occurred within the last month. 1. If clinical symptoms consistent with acute viral infection are present and recent (<1 month) exposures are suspected, delay starting PrEP for at least one month and reconfirm HIV-1 status or use a test approved by the FDA as an aid in the diagnosis of HIV-1 infection, including acute or primary HIV-1 infection. • While using TRUVADA for a PrEP indication, HIV-1 screening tests should be repeated at least every 3 months. If symptoms consistent with acute HIV-1 infection develop following a potential exposure event, PrEP should be discontinued until negative infection status is confirmed using a test approved by the FDA as an aid in the diagnosis of HIV-1, including acute or primary HIV-1 infection. Counsel uninfected individuals to strictly adhere to the recommended TRUVADA dosing schedule. The effectiveness of TRUVADA in reducing the risk of acquiring HIV-1 is strongly correlated with adherence as demonstrated by measurable drug levels in clinical trials [See Clinical Studies (14.2 and 14.3) ] .

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: 1. Lactic Acidosis/Severe Hepatomegaly with Steatosis [See Boxed Warning , Warnings and Precautions (5.1) ] . 2. Severe Acute Exacerbations of hepatitis B [See Boxed Warning , Warnings and Precautions (5.2) ] . 3. New Onset or Worsening Renal Impairment [See Warnings and Precautions (5.3) ] . 4. Decreases in Bone Mineral Density [See Warnings and Precautions (5.5) ] . 5. Immune Reconstitution Syndrome [See Warnings and Precautions (5.7) ] . In HIV1 infected patients, the most common adverse reactions (incidence greater than or equal to 10%) are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. ( 6.1 ) In HIV-1 uninfected individuals in PrEP trials, adverse reactions that were reported by more than 2% of TRUVADA subjects and more frequently than by placebo subjects were headache, abdominal pain and weight decreased. ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-445-3235 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Adverse Reactions from Clinical Trials Experience in HIV-1 Infected Subjects 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 The most common adverse reactions (incidence greater than or equal to 10%, any severity) occurring in Study 934, an active-controlled clinical trial of efavirenz, emtricitabine, and tenofovir disoproxil fumarate, include diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. See also Table 2 for the frequency of treatment-emergent adverse reactions (Grade 2–4) occurring in greater than or equal to 5% of subjects treated in any treatment group in this trial. Skin discoloration, manifested by hyperpigmentation on the palms and/or soles, was generally mild and asymptomatic. The mechanism and clinical significance are unknown. Study 934 - Treatment Emergent Adverse Reactions: In Study 934, 511 antiretroviral-naive subjects received either VIREAD + EMTRIVA administered in combination with efavirenz (N=257) or zidovudine/lamivudine administered in combination with efavirenz (N=254) for 144 weeks. Subjects had a mean age of 40 years (range 20 to 73 years) and were predominantly male (88%). Overall, 65% were White, 17% were Black, and 13% were Hispanic. Adverse reactions observed in this trial were generally consistent with those seen in other trials in treatment-experienced or treatment-naive subjects receiving VIREAD and/or EMTRIVA (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 Any Treatment Group in Study 934 (0–144 Weeks) FTC + TDF + EFV From Weeks 96 to 144 of the trial, subjects received TRUVADA with efavirenz in place of VIREAD + EMTRIVA 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 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% Laboratory Abnormalities: Laboratory abnormalities observed in this trial were generally consistent with those seen in other trials of VIREAD and/or EMTRIVA (Table 3). Table 3 Significant Laboratory Abnormalities Reported in ≥1% of Subjects in Any Treatment Group in Study 934 (0–144 Weeks) FTC + TDF + EFV From Weeks 96 to 144 of the trial, subjects received TRUVADA with efavirenz in place of VIREAD + EMTRIVA 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% In addition to the events described above for Study 934, other adverse reactions that occurred in at least 5% of subjects receiving EMTRIVA or VIREAD with other antiretroviral agents in clinical trials include anxiety, arthralgia, increased cough, dyspepsia, fever, myalgia, pain, abdominal pain, back pain, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), pneumonia, and rhinitis. In addition to the laboratory abnormalities described above for Study 934, Grade 3/4 laboratory abnormalities of increased bilirubin (>2.5 × ULN), increased pancreatic amylase (>2.0 × ULN), increased or decreased serum glucose (<40 or >250 mg/dL), and increased serum lipase (>2.0 × ULN) occurred in up to 3% of subjects treated with EMTRIVA or VIREAD with other antiretroviral agents in clinical trials. Clinical Trials in Pediatric Subjects 12 Years of Age and Older 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 EMTRIVA 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 VIREAD were consistent with those observed in clinical trials of VIREAD in adults [See Warnings and Precautions (5.5) ]. 6.2 Adverse Reactions from Clinical Trial Experience in HIV-1 Uninfected Adult Subjects No new adverse reactions to TRUVADA were identified from two randomized placebo-controlled clinical trials (iPrEx, Partners PrEP) in which 2830 HIV-1 uninfected adults received TRUVADA once daily for pre-exposure prophylaxis. Subjects were followed for a median of 71 weeks and 87 weeks, respectively. These trials enrolled HIV-negative individuals ranging in age from 18 to 67 years. The iPrEx trial enrolled only males or transgender females of Hispanic/Latino (72%), White (18%), Black (9%) and Asian (5%) race. The Partners PrEP trial enrolled both males (61–64% across treatment groups) and females in Kenya and Uganda. Table 4 provides a list of all adverse events that occurred ≥2% of subjects in any treatment group in the iPrEx and Partners PrEP trials. Laboratory Abnormalities: Table 5 provides a list of laboratory abnormalities observed in both trials. Six subjects in the TDF-containing arms of the Partners PrEP trial discontinued participation in the study due to an increase in blood creatinine compared with no discontinuations in the placebo group. One subject in the TRUVADA arm of the iPrEx trial discontinued from the study due to an increase in blood creatinine and another due to low phosphorous. In addition to the laboratory abnormalities described above, Grade 1 proteinuria (1+) occurred in 6% of subjects receiving TRUVADA in the iPrEx trial. Grade 2–3 proteinuria (2–4+) and glycosuria (3+) occurred in less than 1% of subjects treated with TRUVADA in the iPrEx trial and Partners PrEP trial. Table 4 Selected Adverse Events (All Grades) Reported in ≥2% in Any Treatment Group in the iPrEx Trial and Partners PrEP Trial iPrEx Trial Partners PrEP Trial FTC/TDF (N=1251) Placebo (N=1248) FTC/TDF (N-1579) Placebo (N= 1584) Gastrointestinal Disorders Diarrhea 7% 8% 2% 3% Abdominal pain 4% 2% - not reported or reported below 2%. - Infections and Infestations Pharyngitis 13% 16% - - Urethritis 5% 7% - - Urinary tract infection 2% 2% 5% 7% Syphilis 6% 5% - - Secondary syphilis 6% 4% - - Anogenital warts 2% 3% - - Musculoskeletal and Connective Tissue Disorders Back pain 5% 5% - - Nervous System Disorders Headache 7% 6% - - Psychiatric Disorders Depression 6% 7% - - Anxiety 3% 3% - - Reproductive System and Breast Disorders Genital ulceration 2% 2% 2% 2% Investigations Weight decreased 3% 2% - - Table 5 Laboratory Abnormalities (Highest Toxicity Grade) Reported for Each Subject in the iPrEx Trial and Partners PrEP Trial iPrEx Trial Partners PrEP Trial Grade Grading is per DAIDS criteria. FTC/TDF N= 1251 Placebo N= 1248 FTC/TDF N=1579 Placebo N=1584 Creatinine 1 (1.1–1.3 × ULN) 27 (2%) 21 (2%) 18 (1%) 12 (<1%) 2–4 (> 1.4 × ULN) 5 (<1%) 3 (<1%) 2 (<1%) 1 (<1%) Phosphorus 1 (2.5 – <LLN mg/dL) 81 (7%) 110 (9%) NR Grade 1 phosphorus was not reported for the Partners PrEP trial. NR 2–4 (<2.0 mg/dL) 123 (10%) 101 (8%) 140 (9%) 136 (9%) AST 1 (1.25–<2.5 × ULN) 175 (14%) 175 (14%) 20 (1%) 25 (2%) 2–4 (> 2.6 × ULN) 57 (5%) 61 (5%) 10 (<1%) 4 (<1%) ALT 1 (1.25–<2.–5 × ULN) 178 (14%) 194 (16%) 21 (1%) 13 (<1%) 2–4 (> 2.6 × ULN) 84 (7%) 82 (7%) 4 (<1%) 6 (<1%) Hemoglobin 1 (8.5 – 10 mg/dL) 49 (4%) 62 (5%) 56 (4%) 39 (2%) 2–4 (<9.4 mg/dL) 13 (1%) 19 (2%) 28 (2%) 39 (2%) Neutrophils 1 (1000–1300/mm 3 ) 23 (2%) 25 (2%) 208 (13%) 163 (10%) 2–4 (<750/mm 3 ) 7 (<1%) 7 (<1%) 73 (5%) 56 (3%) 6.3 Postmarketing Experience The following adverse reactions have been identified during postapproval use of VIREAD. No additional adverse reactions have been identified during postapproval use of EMTRIVA. 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. 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 ID="_RefT2" width="100%"> <caption>Table 2 Selected Treatment-Emergent Adverse Reactions<footnote ID="_RefIDASXVPI">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 Any Treatment Group in Study 934 (0&#x2013;144 Weeks) </caption> <col width="19%"/> <col width="9%"/> <col width="12%"/> <thead> <tr styleCode="Toprule"> <th align="left" styleCode="Botrule Lrule " valign="top"/> <th align="center" styleCode="Botrule Lrule " valign="top"> <content styleCode="bold">FTC + TDF + EFV</content> <footnote ID="_RefIDAPYVPI">From Weeks 96 to 144 of the trial, subjects received TRUVADA with efavirenz in place of VIREAD + EMTRIVA with efavirenz.</footnote> </th> <th align="center" styleCode="Rrule Botrule Lrule " valign="top"> <content styleCode="bold">AZT/3TC + EFV</content> </th> </tr> <tr> <th align="left" styleCode="Lrule Botrule " valign="top"/> <th align="center" styleCode="Lrule Botrule " valign="top"> <content styleCode="bold">N=257</content> </th> <th align="center" styleCode="Rrule Lrule Botrule " valign="top"> <content styleCode="bold">N=254</content> </th> </tr> </thead> <tbody> <tr> <td> <paragraph>Gastrointestinal Disorder</paragraph> </td> <td styleCode="Lrule "/> <td styleCode="Rrule Lrule "/> </tr> <tr> <td> <paragraph> Diarrhea</paragraph> </td> <td styleCode="Lrule "> <paragraph>9%</paragraph> </td> <td styleCode="Rrule Lrule "> <paragraph>5%</paragraph> </td> </tr> <tr> <td> <paragraph> Nausea</paragraph> </td> <td styleCode="Lrule "> <paragraph>9%</paragraph> </td> <td styleCode="Rrule Lrule "> <paragraph>7%</paragraph> </td> </tr> <tr> <td> <paragraph> Vomiting</paragraph> </td> <td styleCode="Lrule "> <paragraph>2%</paragraph> </td> <td styleCode="Rrule Lrule "> <paragraph>5%</paragraph> </td> </tr> <tr> <td> <paragraph>General Disorders and Administration Site Condition</paragraph> </td> <td styleCode="Lrule "/> <td styleCode="Rrule Lrule "/> </tr> <tr> <td> <paragraph> Fatigue</paragraph> </td> <td styleCode="Lrule "> <paragraph>9%</paragraph> </td> <td styleCode="Rrule Lrule "> <paragraph>8%</paragraph> </td> </tr> <tr> <td> <paragraph>Infections and Infestations</paragraph> </td> <td styleCode="Lrule "/> <td styleCode="Rrule Lrule "/> </tr> <tr> <td> <paragraph> Sinusitis</paragraph> </td> <td styleCode="Lrule "> <paragraph>8%</paragraph> </td> <td styleCode="Rrule Lrule "> <paragraph>4%</paragraph> </td> </tr> <tr> <td> <paragraph> Upper respiratory tract infections</paragraph> </td> <td styleCode="Lrule "> <paragraph>8%</paragraph> </td> <td styleCode="Rrule Lrule "> <paragraph>5%</paragraph> </td> </tr> <tr> <td> <paragraph> Nasopharyngitis</paragraph> </td> <td styleCode="Lrule "> <paragraph>5%</paragraph> </td> <td styleCode="Rrule Lrule "> <paragraph>3%</paragraph> </td> </tr> <tr> <td> <paragraph>Nervous System Disorders</paragraph> </td> <td styleCode="Lrule "/> <td styleCode="Rrule Lrule "/> </tr> <tr> <td> <paragraph> Headache</paragraph> </td> <td styleCode="Lrule "> <paragraph>6%</paragraph> </td> <td styleCode="Rrule Lrule "> <paragraph>5%</paragraph> </td> </tr> <tr> <td> <paragraph> Dizziness</paragraph> </td> <td styleCode="Lrule "> <paragraph>8%</paragraph> </td> <td styleCode="Rrule Lrule "> <paragraph>7%</paragraph> </td> </tr> <tr> <td> <paragraph>Psychiatric Disorders</paragraph> </td> <td styleCode="Lrule "/> <td styleCode="Rrule Lrule "/> </tr> <tr> <td> <paragraph> Depression</paragraph> </td> <td styleCode="Lrule "> <paragraph>9%</paragraph> </td> <td styleCode="Rrule Lrule "> <paragraph>7%</paragraph> </td> </tr> <tr> <td> <paragraph> Insomnia</paragraph> </td> <td styleCode="Lrule "> <paragraph>5%</paragraph> </td> <td styleCode="Rrule Lrule "> <paragraph>7%</paragraph> </td> </tr> <tr> <td> <paragraph>Skin and Subcutaneous Tissue Disorders</paragraph> </td> <td styleCode="Lrule "/> <td styleCode="Rrule Lrule "/> </tr> <tr styleCode="Botrule"> <td> <paragraph> Rash event<footnote ID="_RefIDAVAWPI">Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and rash vesicular.</footnote> </paragraph> </td> <td styleCode="Lrule "> <paragraph>7%</paragraph> </td> <td styleCode="Rrule Lrule "> <paragraph>9%</paragraph> </td> </tr> </tbody> </table>

<table ID="_RefID71359A51F3934E9F8072D4C0FC38C295" width="100%"> <caption>Table 3 Significant Laboratory Abnormalities Reported in &#x2265;1% of Subjects in Any Treatment Group in Study 934 (0&#x2013;144 Weeks) </caption> <col width="16%"/> <col width="9%"/> <col width="12%"/> <thead> <tr styleCode="Toprule"> <th align="left" styleCode="Botrule Lrule " valign="top"/> <th align="center" styleCode="Botrule Lrule " valign="top"> <content styleCode="bold">FTC + TDF + EFV</content> <footnote ID="_RefIDAOCWPI">From Weeks 96 to 144 of the trial, subjects received TRUVADA with efavirenz in place of VIREAD + EMTRIVA with efavirenz.</footnote> </th> <th align="center" styleCode="Rrule Botrule Lrule " valign="top"> <content styleCode="bold">AZT/3TC + EFV</content> </th> </tr> <tr> <th align="left" styleCode="Lrule Botrule " valign="top"/> <th align="center" styleCode="Lrule Botrule " valign="top"> <content styleCode="bold">N=257</content> </th> <th align="center" styleCode="Rrule Lrule Botrule " valign="top"> <content styleCode="bold">N=254</content> </th> </tr> </thead> <tbody> <tr> <td styleCode="Lrule "> <paragraph>Any &#x2265; Grade 3 Laboratory Abnormality</paragraph> </td> <td styleCode="Lrule "> <paragraph>30%</paragraph> </td> <td styleCode="Rrule Lrule "> <paragraph>26%</paragraph> </td> </tr> <tr> <td styleCode="Lrule "> <paragraph>Fasting Cholesterol (&gt;240 mg/dL)</paragraph> </td> <td styleCode="Lrule "> <paragraph>22%</paragraph> </td> <td styleCode="Rrule Lrule "> <paragraph>24%</paragraph> </td> </tr> <tr> <td styleCode="Lrule "> <paragraph>Creatine Kinase (M: &gt;990 U/L) (F: &gt;845 U/L)</paragraph> </td> <td styleCode="Lrule "> <paragraph>9%</paragraph> </td> <td styleCode="Rrule Lrule "> <paragraph>7%</paragraph> </td> </tr> <tr> <td styleCode="Lrule "> <paragraph>Serum Amylase (&gt;175 U/L)</paragraph> </td> <td styleCode="Lrule "> <paragraph>8%</paragraph> </td> <td styleCode="Rrule Lrule "> <paragraph>4%</paragraph> </td> </tr> <tr> <td styleCode="Lrule "> <paragraph>Alkaline Phosphatase (&gt;550 U/L)</paragraph> </td> <td styleCode="Lrule "> <paragraph>1%</paragraph> </td> <td styleCode="Rrule Lrule "> <paragraph>0%</paragraph> </td> </tr> <tr> <td styleCode="Lrule "> <paragraph>AST (M: &gt;180 U/L) (F: &gt;170 U/L)</paragraph> </td> <td styleCode="Lrule "> <paragraph>3%</paragraph> </td> <td styleCode="Rrule Lrule "> <paragraph>3%</paragraph> </td> </tr> <tr> <td styleCode="Lrule "> <paragraph>ALT (M: &gt;215 U/L) (F: &gt;170 U/L)</paragraph> </td> <td styleCode="Lrule "> <paragraph>2%</paragraph> </td> <td styleCode="Rrule Lrule "> <paragraph>3%</paragraph> </td> </tr> <tr> <td styleCode="Lrule "> <paragraph>Hemoglobin (&lt;8.0 mg/dL)</paragraph> </td> <td styleCode="Lrule "> <paragraph>0%</paragraph> </td> <td styleCode="Rrule Lrule "> <paragraph>4%</paragraph> </td> </tr> <tr> <td styleCode="Lrule "> <paragraph>Hyperglycemia (&gt;250 mg/dL)</paragraph> </td> <td styleCode="Lrule "> <paragraph>2%</paragraph> </td> <td styleCode="Rrule Lrule "> <paragraph>1%</paragraph> </td> </tr> <tr> <td styleCode="Lrule "> <paragraph>Hematuria (&gt;75 RBC/HPF)</paragraph> </td> <td styleCode="Lrule "> <paragraph>3%</paragraph> </td> <td styleCode="Rrule Lrule "> <paragraph>2%</paragraph> </td> </tr> <tr> <td styleCode="Lrule "> <paragraph>Glycosuria (&#x2265;3+)</paragraph> </td> <td styleCode="Lrule "> <paragraph>&lt;1%</paragraph> </td> <td styleCode="Rrule Lrule "> <paragraph>1%</paragraph> </td> </tr> <tr> <td styleCode="Lrule "> <paragraph>Neutrophils (&lt;750/mm³)</paragraph> </td> <td styleCode="Lrule "> <paragraph>3%</paragraph> </td> <td styleCode="Rrule Lrule "> <paragraph>5%</paragraph> </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule "> <paragraph>Fasting Triglycerides (&gt;750 mg/dL)</paragraph> </td> <td styleCode="Lrule "> <paragraph>4%</paragraph> </td> <td styleCode="Rrule Lrule "> <paragraph>2%</paragraph> </td> </tr> </tbody> </table>

<table ID="_RefID6494B50F8DD74BF5A60A4941C7F3BA6E" width="100%"> <caption>Table 4 Selected Adverse Events (All Grades) Reported in &#x2265;2% in Any Treatment Group in the iPrEx Trial and Partners PrEP Trial </caption> <col width="17%"/> <col width="12%"/> <col width="14%"/> <col width="12%"/> <col width="14%"/> <thead> <tr> <th align="left" styleCode="Botrule Lrule Toprule " valign="top"/> <th align="center" colspan="2" styleCode="Botrule Lrule Toprule " valign="top"> <content styleCode="bold">iPrEx Trial</content> </th> <th align="center" colspan="2" styleCode="Botrule Lrule Toprule " valign="top"> <content styleCode="bold">Partners PrEP Trial</content> </th> </tr> <tr> <th align="left" styleCode="Lrule Botrule " valign="top"/> <th align="center" styleCode="Lrule Botrule " valign="top"> <content styleCode="bold">FTC/TDF</content> <content styleCode="bold">(N=1251)</content> </th> <th align="center" styleCode="Lrule Botrule " valign="top"> <content styleCode="bold">Placebo</content> <content styleCode="bold">(N=1248)</content> </th> <th align="center" styleCode="Lrule Botrule " valign="top"> <content styleCode="bold">FTC/TDF</content> <content styleCode="bold">(N-1579)</content> </th> <th align="center" styleCode="Lrule Botrule " valign="top"> <content styleCode="bold">Placebo</content> <content styleCode="bold">(N= 1584)</content> </th> </tr> </thead> <tbody> <tr> <td styleCode="Lrule Toprule "> <paragraph>Gastrointestinal Disorders</paragraph> </td> <td styleCode="Lrule Toprule "/> <td styleCode="Lrule Toprule "/> <td styleCode="Lrule Toprule "/> <td styleCode="Lrule Toprule "/> </tr> <tr> <td styleCode="Lrule "> <paragraph> Diarrhea</paragraph> </td> <td styleCode="Lrule "> <paragraph>7%</paragraph> </td> <td styleCode="Lrule "> <paragraph>8%</paragraph> </td> <td styleCode="Lrule "> <paragraph>2%</paragraph> </td> <td styleCode="Lrule "> <paragraph>3%</paragraph> </td> </tr> <tr> <td styleCode="Lrule "> <paragraph> Abdominal pain</paragraph> </td> <td styleCode="Lrule "> <paragraph>4%</paragraph> </td> <td styleCode="Lrule "> <paragraph>2%</paragraph> </td> <td styleCode="Lrule "> <paragraph>-<footnote ID="_RefIDAKRWPI">not reported or reported below 2%.</footnote> </paragraph> </td> <td styleCode="Lrule "> <paragraph>-</paragraph> </td> </tr> <tr> <td styleCode="Lrule "> <paragraph>Infections and Infestations</paragraph> </td> <td styleCode="Lrule "/> <td styleCode="Lrule "/> <td styleCode="Lrule "/> <td styleCode="Lrule "/> </tr> <tr> <td styleCode="Lrule "> <paragraph> Pharyngitis</paragraph> </td> <td styleCode="Lrule "> <paragraph>13%</paragraph> </td> <td styleCode="Lrule "> <paragraph>16%</paragraph> </td> <td styleCode="Lrule "> <paragraph>-</paragraph> </td> <td styleCode="Lrule "> <paragraph>-</paragraph> </td> </tr> <tr> <td styleCode="Lrule "> <paragraph> Urethritis</paragraph> </td> <td styleCode="Lrule "> <paragraph>5%</paragraph> </td> <td styleCode="Lrule "> <paragraph>7%</paragraph> </td> <td styleCode="Lrule "> <paragraph>-</paragraph> </td> <td styleCode="Lrule "> <paragraph>-</paragraph> </td> </tr> <tr> <td styleCode="Lrule "> <paragraph> Urinary tract infection</paragraph> </td> <td styleCode="Lrule "> <paragraph>2%</paragraph> </td> <td styleCode="Lrule "> <paragraph>2%</paragraph> </td> <td styleCode="Lrule "> <paragraph>5%</paragraph> </td> <td styleCode="Lrule "> <paragraph>7%</paragraph> </td> </tr> <tr> <td styleCode="Lrule "> <paragraph> Syphilis</paragraph> </td> <td styleCode="Lrule "> <paragraph>6%</paragraph> </td> <td styleCode="Lrule "> <paragraph>5%</paragraph> </td> <td styleCode="Lrule "> <paragraph>-</paragraph> </td> <td styleCode="Lrule "> <paragraph>-</paragraph> </td> </tr> <tr> <td styleCode="Lrule "> <paragraph> Secondary syphilis</paragraph> </td> <td styleCode="Lrule "> <paragraph>6%</paragraph> </td> <td styleCode="Lrule "> <paragraph>4%</paragraph> </td> <td styleCode="Lrule "> <paragraph>-</paragraph> </td> <td styleCode="Lrule "> <paragraph>-</paragraph> </td> </tr> <tr> <td styleCode="Lrule "> <paragraph> Anogenital warts</paragraph> </td> <td styleCode="Lrule "> <paragraph>2%</paragraph> </td> <td styleCode="Lrule "> <paragraph>3%</paragraph> </td> <td styleCode="Lrule "> <paragraph>-</paragraph> </td> <td styleCode="Lrule "> <paragraph>-</paragraph> </td> </tr> <tr> <td styleCode="Lrule "> <paragraph>Musculoskeletal and Connective Tissue Disorders</paragraph> </td> <td styleCode="Lrule "/> <td styleCode="Lrule "/> <td styleCode="Lrule "/> <td styleCode="Lrule "/> </tr> <tr> <td styleCode="Lrule "> <paragraph> Back pain</paragraph> </td> <td styleCode="Lrule "> <paragraph>5%</paragraph> </td> <td styleCode="Lrule "> <paragraph>5%</paragraph> </td> <td styleCode="Lrule "> <paragraph>-</paragraph> </td> <td styleCode="Lrule "> <paragraph>-</paragraph> </td> </tr> <tr> <td styleCode="Lrule "> <paragraph>Nervous System Disorders</paragraph> </td> <td styleCode="Lrule "/> <td styleCode="Lrule "/> <td styleCode="Lrule "/> <td styleCode="Lrule "/> </tr> <tr> <td styleCode="Lrule "> <paragraph> Headache</paragraph> </td> <td styleCode="Lrule "> <paragraph>7%</paragraph> </td> <td styleCode="Lrule "> <paragraph>6%</paragraph> </td> <td styleCode="Lrule "> <paragraph>-</paragraph> </td> <td styleCode="Lrule "> <paragraph>-</paragraph> </td> </tr> <tr> <td styleCode="Lrule "> <paragraph>Psychiatric Disorders</paragraph> </td> <td styleCode="Lrule "/> <td styleCode="Lrule "/> <td styleCode="Lrule "/> <td styleCode="Lrule "/> </tr> <tr> <td styleCode="Lrule "> <paragraph> Depression</paragraph> </td> <td styleCode="Lrule "> <paragraph>6%</paragraph> </td> <td styleCode="Lrule "> <paragraph>7%</paragraph> </td> <td styleCode="Lrule "> <paragraph>-</paragraph> </td> <td styleCode="Lrule "> <paragraph>-</paragraph> </td> </tr> <tr> <td styleCode="Lrule "> <paragraph> Anxiety</paragraph> </td> <td styleCode="Lrule "> <paragraph>3%</paragraph> </td> <td styleCode="Lrule "> <paragraph>3%</paragraph> </td> <td styleCode="Lrule "> <paragraph>-</paragraph> </td> <td styleCode="Lrule "> <paragraph>-</paragraph> </td> </tr> <tr> <td styleCode="Lrule "> <paragraph>Reproductive System and Breast Disorders</paragraph> </td> <td styleCode="Lrule "/> <td styleCode="Lrule "/> <td styleCode="Lrule "/> <td styleCode="Lrule "/> </tr> <tr> <td styleCode="Lrule "> <paragraph> Genital ulceration</paragraph> </td> <td styleCode="Lrule "> <paragraph>2%</paragraph> </td> <td styleCode="Lrule "> <paragraph>2%</paragraph> </td> <td styleCode="Lrule "> <paragraph>2%</paragraph> </td> <td styleCode="Lrule "> <paragraph>2%</paragraph> </td> </tr> <tr> <td styleCode="Lrule "> <paragraph>Investigations</paragraph> </td> <td styleCode="Lrule "/> <td styleCode="Lrule "/> <td styleCode="Lrule "/> <td styleCode="Lrule "/> </tr> <tr> <td styleCode="Botrule Lrule "> <paragraph> Weight decreased</paragraph> </td> <td styleCode="Botrule Lrule "> <paragraph>3%</paragraph> </td> <td styleCode="Botrule Lrule "> <paragraph>2%</paragraph> </td> <td styleCode="Botrule Lrule "> <paragraph>-</paragraph> </td> <td styleCode="Botrule Lrule "> <paragraph>-</paragraph> </td> </tr> </tbody> </table>