FDA label 877e3186-0c6f-47e4-b946-2fe53d80ef12

WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B 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. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue TRUVADA. If appropriate, initiation of anti-hepatitis B therapy may be warranted [See Warnings and Precautions (5.2) ] . WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B See full prescribing information for complete boxed warning. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including 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. Hepatic function should be monitored closely in these patients. If appropriate, initiation of anti-hepatitis B therapy may be warranted. ( 5.2 )

5 WARNINGS AND PRECAUTIONS 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, EMTRIVA, VIREAD; or with drugs containing lamivudine. Do not administer in combination with HEPSERA. ( 5.4 ) Decreases in bone mineral density (BMD): Consider monitoring BMD in patients with a history of pathologic fracture or who are at risk for osteopenia. ( 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 ) 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 with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with TRUVADA should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). 5.2 Patients Coinfected with HIV-1 and HBV It is recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B virus (HBV) before initiating antiretroviral therapy. TRUVADA is not approved for the treatment of chronic 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. 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 coinfected with HIV-1 and HBV should be closely monitored with both clinical and laboratory follow up for at least several months after stopping treatment with Truvada. If appropriate, initiation of anti-hepatitis B therapy may be warranted. 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 patients 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 patients at risk for renal impairment, including patients who have previously experienced renal events while receiving HEPSERA. 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 (2.2) ] . 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 <30 mL/min or patients requiring hemodialysis. TRUVADA should be avoided with concurrent or recent use of a nephrotoxic agent. 5.4 Coadministration with Other Products TRUVADA is a fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate. TRUVADA should not be coadministered with ATRIPLA, EMTRIVA, or VIREAD. Due to similarities between emtricitabine and lamivudine, TRUVADA should not be coadministered with other drugs containing lamivudine, including Combivir (lamivudine/zidovudine), Epivir or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), or Trizivir (abacavir sulfate/lamivudine/zidovudine). TRUVADA should not be administered with HEPSERA ® (adefovir dipivoxil). 5.5 Decreases in Bone Mineral Density Bone mineral density (BMD) monitoring should be considered for HIV-1 infected patients who have a history of pathologic bone fracture or are at risk for osteopenia. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained. Tenofovir Disoproxil Fumarate: In a 144-week study of treatment-naive subjects, decreases in BMD were seen at the lumbar spine and hip in both arms of the study. 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 study 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. 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 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 patients treated with combination antiretroviral therapy, including TRUVADA. 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. 5.8 Early Virologic Failure Clinical studies in HIV-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.

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Lactic Acidosis/Severe Hepatomegaly with Steatosis [See Boxed Warning , Warnings and Precautions (5.1) ] . Severe Acute Exacerbations of hepatitis B [See Boxed Warning , Warnings and Precautions (5.2) ] . New Onset or Worsening Renal Impairment [See Warnings and Precautions (5.3) ] . Decreases in Bone Mineral Density [See Warnings and Precautions (5.5) ] . Immune Reconstitution Syndrome [See Warnings and Precautions (5.7) ] . Most common adverse reactions (incidence ≥10%) are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Adverse Reactions from Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions (incidence ≥10%, any severity) occurring in Study 934, an active-controlled clinical study 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 ≥5% of subjects treated with efavirenz, emtricitabine, and tenofovir disoproxil fumarate in this study. 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). Adverse reactions observed in this study were generally consistent with those seen in other studies 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 study, 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 study were generally consistent with those seen in other studies 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 study, 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 elevations of bilirubin (>2.5 × ULN), pancreatic amylase (>2.0 × ULN), serum glucose (<40 or >250 mg/dL), and serum lipase (>2.0 × ULN) occurred in up to 3% of subjects treated with EMTRIVA or VIREAD with other antiretroviral agents in clinical trials. 6.2 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="table2" width="80%"> <caption>Table 2 Selected Treatment-Emergent Adverse Reactions<footnote>Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug.</footnote> (Grades 2&#x2013;4) Reported in &#x2265;5% in Any Treatment Group in Study 934 (0&#x2013;144 Weeks)</caption> <col align="left" valign="top" width="40%"/> <col align="center" valign="top" width="30%"/> <col align="center" valign="top" width="30%"/> <thead> <tr> <th styleCode="Lrule Rrule"/> <th styleCode="Rrule Botrule">FTC + TDF + EFV<footnote>From Weeks 96 to 144 of the study, subjects received TRUVADA with efavirenz in place of VIREAD + EMTRIVA with efavirenz.</footnote> </th> <th styleCode="Rrule Botrule">AZT/3TC + EFV</th> </tr> <tr> <th styleCode="Lrule Rrule"/> <th styleCode="Rrule">N=257</th> <th styleCode="Rrule">N=254</th> </tr> </thead> <tbody> <tr> <td styleCode="Lrule">Gastrointestinal Disorder</td> <td styleCode="Lrule Rrule"/> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule"> Diarrhea</td> <td styleCode="Lrule Rrule">9%</td> <td styleCode="Rrule">5%</td> </tr> <tr> <td styleCode="Lrule"> Nausea</td> <td styleCode="Lrule Rrule">9%</td> <td styleCode="Rrule">7%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule"> Vomiting</td> <td styleCode="Lrule Rrule">2%</td> <td styleCode="Rrule">5%</td> </tr> <tr> <td styleCode="Lrule">General Disorders and Administration Site Condition</td> <td styleCode="Lrule Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule"> Fatigue</td> <td styleCode="Lrule Rrule">9%</td> <td styleCode="Rrule">8%</td> </tr> <tr> <td styleCode="Lrule">Infections and Infestations</td> <td styleCode="Lrule Rrule"/> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule"> Sinusitis</td> <td styleCode="Lrule Rrule">8%</td> <td styleCode="Rrule">4%</td> </tr> <tr> <td styleCode="Lrule"> Upper respiratory tract infections</td> <td styleCode="Lrule Rrule">8%</td> <td styleCode="Rrule">5%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule"> Nasopharyngitis</td> <td styleCode="Lrule Rrule">5%</td> <td styleCode="Rrule">3%</td> </tr> <tr> <td styleCode="Lrule">Nervous System Disorders</td> <td styleCode="Lrule Rrule"/> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule"> Headache</td> <td styleCode="Lrule Rrule">6%</td> <td styleCode="Rrule">5%</td> </tr> <tr> <td styleCode="Lrule"> Dizziness</td> <td styleCode="Lrule Rrule">8%</td> <td styleCode="Rrule">7%</td> </tr> <tr> <td styleCode="Lrule Toprule">Psychiatric Disorders</td> <td styleCode="Lrule Rrule Toprule"/> <td styleCode="Rrule Toprule"/> </tr> <tr> <td styleCode="Lrule"> Depression</td> <td styleCode="Lrule Rrule">9%</td> <td styleCode="Rrule">7%</td> </tr> <tr> <td styleCode="Lrule"> Insomnia</td> <td styleCode="Lrule Rrule">5%</td> <td styleCode="Rrule">7%</td> </tr> <tr> <td styleCode="Lrule Toprule">Skin and Subcutaneous Tissue Disorders</td> <td styleCode="Lrule Rrule Toprule"/> <td styleCode="Rrule Toprule"/> </tr> <tr> <td styleCode="Lrule"> Rash event<footnote>Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and rash vesicular.</footnote> </td> <td styleCode="Lrule Rrule">7%</td> <td styleCode="Rrule">9%</td> </tr> </tbody> </table>

<table ID="table3" width="80%"> <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 align="left" valign="middle" width="40%"/> <col align="center" valign="middle" width="30%"/> <col align="center" valign="middle" width="30%"/> <thead> <tr> <th styleCode="Lrule Rrule"/> <th styleCode="Rrule Botrule">FTC + TDF + EFV<footnote>From Weeks 96 to 144 of the study, subjects received TRUVADA with efavirenz in place of VIREAD + EMTRIVA with efavirenz.</footnote> </th> <th styleCode="Rrule Botrule">AZT/3TC + EFV</th> </tr> <tr> <th styleCode="Lrule Rrule"/> <th styleCode="Rrule">N=257</th> <th styleCode="Rrule">N=254</th> </tr> </thead> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Any &#x2265; Grade 3 Laboratory Abnormality</td> <td styleCode="Rrule">30%</td> <td styleCode="Rrule">26%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Fasting Cholesterol (&gt;240 mg/dL)</td> <td styleCode="Rrule">22%</td> <td styleCode="Rrule">24%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Creatine Kinase (M: &gt;990 U/L) (F: &gt;845 U/L)</td> <td styleCode="Rrule">9%</td> <td styleCode="Rrule">7%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Serum Amylase (&gt;175 U/L)</td> <td styleCode="Rrule">8%</td> <td styleCode="Rrule">4%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Alkaline Phosphatase (&gt;550 U/L)</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">0%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">AST (M: &gt;180 U/L) (F: &gt;170 U/L)</td> <td styleCode="Rrule">3%</td> <td styleCode="Rrule">3%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">ALT (M: &gt;215 U/L) (F: &gt;170 U/L)</td> <td styleCode="Rrule">2%</td> <td styleCode="Rrule">3%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Hemoglobin (&lt;8.0 mg/dL)</td> <td styleCode="Rrule">0%</td> <td styleCode="Rrule">4%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Hyperglycemia (&gt;250 mg/dL)</td> <td styleCode="Rrule">2%</td> <td styleCode="Rrule">1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Hematuria (&gt;75 RBC/HPF)</td> <td styleCode="Rrule">3%</td> <td styleCode="Rrule">2%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Glycosuria (&#x2265;3+)</td> <td styleCode="Rrule">&lt;1%</td> <td styleCode="Rrule">1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Neutrophils (&lt;750/mm³)</td> <td styleCode="Rrule">3%</td> <td styleCode="Rrule">5%</td> </tr> <tr> <td styleCode="Lrule Rrule">Fasting Triglycerides (&gt;750 mg/dL)</td> <td styleCode="Rrule">4%</td> <td styleCode="Rrule">2%</td> </tr> </tbody> </table>