FDA label 4ab93fb4-72b5-e0f2-e063-6294a90aa511

WARNING: POSTTREATMENT EXACERBATION OF HEPATITIS Severe acute exacerbations of hepatitis have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including VIREAD. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy, including VIREAD. If appropriate, resumption of anti-hepatitis B therapy may be warranted [See Warnings and Precautions (5.1) ] . WARNING: POSTTREATMENT EXACERBATION OF HEPATITIS See full prescribing information for complete boxed warning. Severe acute exacerbations of hepatitis have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including VIREAD. Hepatic function should be monitored closely in these patients. If appropriate, resumption of anti-hepatitis B therapy may be warranted. ( 5.1 )

5 WARNINGS AND PRECAUTIONS New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Assess estimated creatinine clearance before initiating treatment with VIREAD. In patients at risk for renal dysfunction, assess estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein before initiating treatment with VIREAD and periodically during treatment. Avoid administering VIREAD with concurrent or recent use of nephrotoxic drugs. ( 5.2 ) Lactic acidosis/severe hepatomegaly with steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. ( 5.3 ) Coadministration with other products: Do not use with other tenofovir-containing products (e.g., ATRIPLA, BIKTARVY, COMPLERA, DESCOVY, GENVOYA, ODEFSEY, STRIBILD, TRUVADA, or VEMLIDY). Do not administer in combination with HEPSERA. ( 5.4 ) HIV testing: HIV antibody testing should be offered to all HBV-infected patients before initiating therapy with VIREAD. VIREAD should only be used as part of an appropriate antiretroviral combination regimen in HIV-infected patients with or without HBV coinfection. ( 5.5 ) 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. ( 5.6 ) Immune reconstitution syndrome: Observed in HIV-infected patients. 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 Exacerbation of Hepatitis after Discontinuation of Treatment Discontinuation of anti-HBV therapy, including VIREAD, may be associated with severe acute exacerbations of hepatitis. Patients infected with HBV who discontinue VIREAD 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. 5.2 New Onset or Worsening Renal Impairment Tenofovir 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 VIREAD [See Adverse Reactions (6.2) ] . It is recommended that estimated creatinine clearance be assessed in all patients prior to initiating therapy and as clinically appropriate during therapy with VIREAD. In patients at risk of renal dysfunction, including patients who have previously experienced renal events while receiving HEPSERA™, it is recommended that estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein be assessed prior to initiation of VIREAD, and periodically during VIREAD therapy. Dosing interval adjustment of VIREAD and close monitoring of renal function are recommended in all patients with creatinine clearance below 50 mL/min [See Dosage and Administration (2.2) ] . No safety or efficacy data are available in patients with renal impairment who received VIREAD using these dosing guidelines, so the potential benefit of VIREAD therapy should be assessed against the potential risk of renal toxicity. VIREAD should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs)) [See Drug Interactions (7.1) ] . 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 tenofovir DF. 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 at-risk patients. 5.3 Lactic Acidosis/Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir DF, alone or in combination with other antiretrovirals. Treatment with VIREAD 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). 5.4 Coadministration with Other Products VIREAD should not be used in combination with other drugs containing tenofovir DF or tenofovir alafenamide, including ATRIPLA, BIKTARVY, COMPLERA, DESCOVY, GENVOYA, ODEFSEY, STRIBILD, TRUVADA or VEMLIDY. VIREAD should not be administered in combination with HEPSERA (adefovir dipivoxil) VIREAD should not be administered in combination with HEPSERA (adefovir dipivoxil) [See Drug Interactions (7.2) ]. 5.5 Patients Coinfected with HIV-1 and HBV Due to the risk of development of HIV-1 resistance, VIREAD should only be used in HIV-1 and HBV coinfected patients as part of an appropriate antiretroviral combination regimen. HIV-1 antibody testing should be offered to all HBV-infected patients before initiating therapy with VIREAD. It is also recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B before initiating treatment with VIREAD. 5.6 Bone Effects Bone Mineral Density: In clinical trials in HIV-1 infected adults, VIREAD was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving VIREAD [See Adverse Reactions (6.1) ] . Clinical trials evaluating VIREAD in pediatric and adolescent subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1 infected subjects aged 2 years to less than 18 years, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the VIREAD-treated HIV-1 infected pediatric subjects as compared to the control groups. Similar trends were observed in chronic hepatitis B infected adolescent subjects aged 12 years to less than 18 years. In all pediatric trials, skeletal growth (height) appeared to be unaffected. [See Adverse Reactions (6.1) ] . The effects of VIREAD-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for adults and 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 for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained. Mineralization Defects: Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of VIREAD [See Adverse Reactions (6.2) ] . Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing tenofovir DF [See Warnings and Precautions (5.2) ]. 5.7 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including VIREAD. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment. 5.8 Early Virologic Failure Clinical trials 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: Severe Acute Exacerbation of Hepatitis [See Boxed Warning , Warnings and Precautions (5.1) ] . New Onset or Worsening Renal Impairment [See Warnings and Precautions (5.2) ] . Lactic Acidosis/Severe Hepatomegaly with Steatosis [See Warnings and Precautions (5.3) ] . Bone Effects [See Warnings and Precautions (5.6) ] . Immune Reconstitution Syndrome [See Warnings and Precautions (5.7) ] . In HIV-infected subjects: Most common adverse reactions (incidence ≥10%, Grades 2 – 4) are rash, diarrhea, headache, pain, depression, asthenia, and nausea. ( 6.1 ) In HBV-infected subjects with compensated liver disease: Most common adverse reaction (all grades) was nausea (9%). ( 6.1 ) In HBV-infected subjects with decompensated liver disease: Most common adverse reactions (incidence ≥10%, all grades) were abdominal pain, nausea, insomnia, pruritus, vomiting, dizziness, and pyrexia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at safety_fc@gilead.com or the US FDA at 1-800-FDA-1088 or at 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. Clinical Trials in Adult Patients with HIV-1 Infection More than 12,000 subjects have been treated with VIREAD alone or in combination with other antiretroviral medicinal products for periods of 28 days to 215 weeks in clinical trials and expanded access programs. A total of 1544 subjects have received VIREAD 300 mg once daily in clinical trials; over 11,000 subjects have received VIREAD in expanded access programs. The most common adverse reactions (incidence greater than or equal to 10%, Grades 2–4) identified from any of the 3 large controlled clinical trials include rash, diarrhea, headache, pain, depression, asthenia, and nausea. Treatment-Naïve Patients Study 903 –Treatment-Emergent Adverse Reactions: The most common adverse reactions seen in a double-blind comparative controlled trial in which 600 treatment-naïve subjects received VIREAD (N=299) or stavudine (N=301) in combination with lamivudine and efavirenz for 144 weeks (Study 903) 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. Selected treatment-emergent moderate to severe adverse reactions are summarized in 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 903 (0–144 Weeks) VIREAD+3TC+ EFV d4T+3TC+EFV N=299 N=301 Body as a Whole Headache 14% 17% Pain 13% 12% Fever 8% 7% Abdominal pain 7% 12% Back pain 9% 8% Asthenia 6% 7% Digestive System Diarrhea 11% 13% Nausea 8% 9% Dyspepsia 4% 5% Vomiting 5% 9% Metabolic Disorders Lipodystrophy Lipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome. 1% 8% Musculoskeletal Arthralgia 5% 7% Myalgia 3% 5% Nervous System Depression 11% 10% Insomnia 5% 8% Dizziness 3% 6% Peripheral neuropathy Peripheral neuropathy includes peripheral neuritis and neuropathy. 1% 5% Anxiety 6% 6% Respiratory Pneumonia 5% 5% Skin and Appendages Rash event Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash. 18% 12% Laboratory Abnormalities: With the exception of fasting cholesterol and fasting triglyceride elevations that were more common in the stavudine group (40% and 9%) compared with VIREAD (19% and 1%), respectively, laboratory abnormalities observed in this trial occurred with similar frequency in the VIREAD and stavudine treatment arms. A summary of Grades 3–4 laboratory abnormalities is provided in Table 3. Table 3 Grades 3–4 Laboratory Abnormalities Reported in ≥1% of VIREAD-Treated Subjects in Study 903 (0–144 Weeks) VIREAD+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% Study 934 – Treatment -Emergent Adverse Reactions: In Study 934, 511 antiretroviral-naïve 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 trial were generally consistent with those seen in previous studies in treatment-experienced or treatment-naïve subjects (Table 4). Changes in Bone Mineral Density: In HIV-1 infected adult subjects in Study 903, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving VIREAD + lamivudine + efavirenz ( – 2.2% ± 3.9) compared with subjects receiving stavudine + lamivudine + efavirenz ( – 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 VIREAD group vs. – 2.4% ± 4.5 in the stavudine group). 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 Week 144. Twenty-eight percent of VIREAD-treated subjects vs. 21% of the stavudine-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 VIREAD group and 6 subjects in the stavudine 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 VIREAD group relative to the stavudine group; however, except for bone-specific alkaline phosphatase, these changes resulted in values that remained within the normal range [See Warnings and Precautions (5.6) ] . Table 4 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) VIREAD From Weeks 96 to 144 of the trial, subjects received TRUVADA with efavirenz in place of VIREAD + EMTRIVA with efavirenz. +FTC+EFV 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 maculopapular, rash pruritic, and rash vesicular. 7% 9% Laboratory Abnormalities: Laboratory abnormalities observed in this trial were generally consistent with those seen in previous trials (Table 5). Table 5 Significant Laboratory Abnormalities Reported in ≥1% of Subjects in Any Treatment Group in Study 934 (0–144 Weeks) VIREAD From Weeks 96 to 144 of the trial, subjects received TRUVADA with efavirenz in place of VIREAD + EMTRIVA with efavirenz. +FTC+EFV 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% Treatment-Experienced Patients Treatment-Emergent Adverse Reactions: The adverse reactions seen in treatment -experienced subjects were generally consistent with those seen in treatment -naïve subjects including mild to moderate gastrointestinal events, such as nausea, diarrhea, vomiting, and flatulence. Less than 1% of subjects discontinued participation in the clinical trials due to gastrointestinal adverse reactions (Study 907). A summary of moderate to severe treatment-emergent adverse reactions that occurred during the first 48 weeks of Study 907 is provided in Table 6. Table 6 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 ≥3% in Any Treatment Group in Study 907 (0– 48 Weeks) VIREAD (N=368) (Week 0 – 24) Placebo (N=182) (Week 0–24) VIREAD (N=368) (Week 0 – 48) Placebo Crossover to VIREAD (N=170) (Week 24 – 48) Body as a Whole Asthenia 7% 6% 11% 1% Pain 7% 7% 12% 4% Headache 5% 5% 8% 2% Abdominal pain 4% 3% 7% 6% Back pain 3% 3% 4% 2% Chest pain 3% 1% 3% 2% Fever 2% 2% 4% 2% Digestive System Diarrhea 11% 10% 16% 11% Nausea 8% 5% 11% 7% Vomiting 4% 1% 7% 5% Anorexia 3% 2% 4% 1% Dyspepsia 3% 2% 4% 2% Flatulence 3% 1% 4% 1% Respiratory Pneumonia 2% 0% 3% 2% Nervous System Depression 4% 3% 8% 4% Insomnia 3% 2% 4% 4% Peripheral neuropathy Peripheral neuropathy includes peripheral neuritis and neuropathy. 3% 3% 5% 2% Dizziness 1% 3% 3% 1% Skin and Appendage Rash event Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash. 5% 4% 7% 1% Sweating 3% 2% 3% 1% Musculoskeletal Myalgia 3% 3% 4% 1% Metabolic Weight loss 2% 1% 4% 2% Laboratory Abnormalities: Laboratory abnormalities observed in this trial occurred with similar frequency in the VIREAD and placebo-treated groups. A summary of Grades 3 – 4 laboratory abnormalities is provided in Table 7. Table 7 Grades 3 – 4 Laboratory Abnormalities Reported in ≥1% of VIREAD-Treated Subjects in Study 907 (0 – 48 Weeks) VIREAD (N=368) (Week 0 – 24) Placebo (N=182) (Week 0 – 24) VIREAD (N=368) (Week 0 – 48) Placebo Crossover to VIREAD (N=170) (Week 24 – 48) Any ≥ Grade 3 Laboratory Abnormality 25% 38% 35% 34% Triglycerides (>750 mg/dL) 8% 13% 11% 9% Creatine Kinase (M: >990 U/L; F: >845 U/L) 7% 14% 12% 12% Serum Amylase (>175 U/L) 6% 7% 7% 6% Glycosuria (≥3+) 3% 3% 3% 2% AST (M: >180 U/L; F: >170 U/L) 3% 3% 4% 5% ALT (M: >215 U/L; F: >170 U/L) 2% 2% 4% 5% Serum Glucose (>250 U/L) 2% 4% 3% 3% Neutrophils (<750/mm 3 ) 1% 1% 2% 1% Clinical Trials in Pediatric Subjects 12 Years of Age and Older with HIV-1 Infection Assessment of adverse reactions is based on one randomized trial (Study 321) in 87 HIV-1 infected pediatric subjects (12 to less than 18 years of age) who received treatment with VIREAD (N=45) or placebo (N=42) in combination with other antiretroviral agents for 48 weeks. The adverse reactions observed in subjects who received treatment with VIREAD were consistent with those observed in clinical trials in adults. Changes in Bone Mineral Density: Clinical trials in HIV-1 infected children and adolescents evaluated BMD changes. In Study 321 (12 to less than 18 years), the mean rate of BMD gain at Week 48 was less in the VIREAD compared to the placebo treatment group. Six VIREAD-treated subjects and one placebo-treated subject had significant (greater than 4%) lumbar spine BMD loss at Week 48. Changes from baseline BMD Z-scores were – 0.341 for lumbar spine and – 0.458 for total body in the 28 subjects who were treated with VIREAD for 96 weeks, skeletal growth (height) appeared to be unaffected. [See Warnings and Precautions (5.6) ] . Clinical Trials in Adult Subjects with Chronic Hepatitis B and Compensated Liver Disease Treatment-Emergent Adverse Reactions: In controlled clinical trials in 641 subjects with chronic hepatitis B (0102 and 0103), more subjects treated with VIREAD during the 48-week double-blind period experienced nausea: 9% with VIREAD versus 2% with HEPSERA. Other treatment-emergent adverse reactions reported in more than 5% of subjects treated with VIREAD included: abdominal pain, diarrhea, headache, dizziness, fatigue, nasopharyngitis, back pain, and skin rash. During the open-label phase of treatment with VIREAD (weeks 48–384) in Studies 0102 and 0103, 2% of subjects (13/585) experienced a confirmed increase in serum creatinine of 0.5 mg/dL from baseline. No significant change in the tolerability profile was observed with continued treatment for up to 384 weeks. Laboratory Abnormalities: A summary of Grades 3 – 4 laboratory abnormalities through Week 48 is provided in Table 8. Grades 3 – 4 laboratory abnormalities were similar in subjects continuing VIREAD treatment for up to 384 weeks in these trials. Table 8 Grades 3–4 Laboratory Abnormalities Reported in ≥1% of VIREAD-Treated Subjects in Studies 0102 and 0103 (0–48 Weeks) VIREAD (N=426) HEPSERA (N=215) Any ≥ Grade 3 Laboratory Abnormality 19% 13% Creatine Kinase (M: >990 U/L; F: >845 U/L) 2% 3% Serum Amylase (>175 U/L) 4% 1% Glycosuria (≥3+) 3% <1% AST (M: >180 U/L; F: >170 U/L) 4% 4% ALT (M: >215 U/L; F: >170 U/L) 10% 6% The overall incidence of on-treatment ALT flares (defined as serum ALT greater than 2 × baseline and greater than 10 × ULN, with or without associated symptoms) was similar between VIREAD (2.6%) and HEPSERA (2%). ALT flares generally occurred within the first 4 – 8 weeks of treatment and were accompanied by decreases in HBV DNA levels. No subject had evidence of decompensation. ALT flares typically resolved within 4 to 8 weeks without changes in study medication. The adverse reactions observed in subjects with chronic hepatitis B and lamivudine resistance who received treatment with VIREAD were consistent with those observed in other hepatitis B clinical trials in adults. Clinical Trials in Adult Subjects with Chronic Hepatitis B and Decompensated Liver Disease In a small randomized, double-blind, active-controlled trial (0108), subjects with CHB and decompensated liver disease received treatment with VIREAD or other antiviral drugs for up to 48 weeks [See Clinical Studies (14.2) ] . Among the 45 subjects receiving VIREAD, the most frequently reported treatment-emergent adverse reactions of any severity were abdominal pain (22%), nausea (20%), insomnia (18%), pruritus (16%), vomiting (13%), dizziness (13%), and pyrexia (11%). Two of 45 (4%) subjects died through Week 48 of the trial due to progression of liver disease. Three of 45 (7%) subjects discontinued treatment due to an adverse event. Four of 45 (9%) subjects experienced a confirmed increase in serum creatinine of 0.5 mg/dL (1 subject also had a confirmed serum phosphorus less than 2 mg/dL through Week 48). Three of these subjects (each of whom had a Child-Pugh score greater than or equal to 10 and MELD score greater than or equal to 14 at entry) developed renal failure. Because both VIREAD and decompensated liver disease may have an impact on renal function, the contribution of VIREAD to renal impairment in this population is difficult to ascertain. One of 45 subjects experienced an on-treatment hepatic flare during the 48 week trial. Clinical Trials in Pediatric Subjects 12 Years of Age and Older with Chronic Hepatitis B Assessment of adverse reactions is based on one randomized study (Study GS-US-174-0115) in 106 pediatric subjects (12 to less than 18 years of age) infected with chronic hepatitis B receiving treatment with VIREAD (N = 52) or placebo (N = 54) for 72 weeks. The adverse reactions observed in pediatric subjects who received treatment with VIREAD were consistent with those observed in clinical trials of VIREAD in adults. In this study, both the VIREAD and placebo treatment arms experienced an overall increase in mean lumbar spine BMD over 72 weeks, as expected for an adolescent population. The BMD gains from baseline to Week 72 in lumbar spine and total body BMD in VIREAD-treated subjects (+5% and +3%, respectively) were less than the BMD gains observed in placebo-treated subjects (+8% and +5%, respectively). Three subjects in the VIREAD group and two subjects in the placebo group had significant (greater than 4%) lumbar spine BMD loss at Week 72. At baseline, mean BMD Z-scores in subjects randomized to VIREAD were −0.43 for lumbar spine and −0.20 for total body, and mean BMD Z-scores in subjects randomized to placebo were −0.28 for lumbar spine and −0.26 for total body. In subjects receiving VIREAD for 72 weeks, the mean change in BMD Z-score was −0.05 for lumbar spine and −0.15 for total body compared to +0.07 and +0.06, respectively, in subjects receiving placebo. As observed in pediatric studies of HIV-infected patients, skeletal growth (height) appeared to be unaffected [See Warnings and Precautions (5.6) ] . 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of VIREAD. 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 width="60%"><caption>Table 2 Selected Treatment-Emergent Adverse Reactions <footnote ID="K1634">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 903 (0&#x2013;144 Weeks) </caption><col width="33%" align="left" valign="top"/><col width="34%" align="center" valign="top"/><col width="33%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule"/><th styleCode="Botrule Rrule">VIREAD+3TC+ EFV</th><th styleCode="Botrule Rrule">d4T+3TC+EFV</th></tr><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule">N=299</th><th styleCode="Rrule">N=301</th></tr></thead><tbody><tr><td styleCode="Lrule Rrule">Body as a Whole</td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule"> Headache</td><td styleCode="Lrule Rrule">14%</td><td styleCode="Rrule">17%</td></tr><tr><td styleCode="Lrule Rrule"> Pain</td><td styleCode="Rrule">13%</td><td styleCode="Rrule">12%</td></tr><tr><td styleCode="Lrule Rrule"> Fever</td><td styleCode="Rrule">8%</td><td styleCode="Rrule">7%</td></tr><tr><td styleCode="Lrule Rrule"> Abdominal pain</td><td styleCode="Rrule">7%</td><td styleCode="Rrule">12%</td></tr><tr><td styleCode="Lrule Rrule"> Back pain</td><td styleCode="Rrule">9%</td><td styleCode="Rrule">8%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Asthenia</td><td styleCode="Rrule">6%</td><td styleCode="Rrule">7%</td></tr><tr><td styleCode="Lrule Rrule">Digestive System</td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule"> Diarrhea</td><td styleCode="Rrule">11%</td><td styleCode="Rrule">13%</td></tr><tr><td styleCode="Lrule Rrule"> Nausea</td><td styleCode="Rrule">8%</td><td styleCode="Rrule">9%</td></tr><tr><td styleCode="Lrule Rrule"> Dyspepsia</td><td styleCode="Rrule">4%</td><td styleCode="Rrule">5%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Vomiting</td><td styleCode="Rrule">5%</td><td styleCode="Rrule">9%</td></tr><tr><td styleCode="Lrule Rrule">Metabolic Disorders</td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Lipodystrophy <footnote ID="K1800">Lipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome.</footnote></td><td styleCode="Rrule">1%</td><td styleCode="Rrule">8%</td></tr><tr><td styleCode="Lrule Rrule">Musculoskeletal</td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule"> Arthralgia</td><td styleCode="Rrule">5%</td><td styleCode="Rrule">7%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Myalgia</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">5%</td></tr><tr><td styleCode="Lrule Rrule">Nervous System</td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule"> Depression</td><td styleCode="Rrule">11%</td><td styleCode="Rrule">10%</td></tr><tr><td styleCode="Lrule Rrule"> Insomnia</td><td styleCode="Rrule">5%</td><td styleCode="Rrule">8%</td></tr><tr><td styleCode="Lrule Rrule"> Dizziness</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">6%</td></tr><tr><td styleCode="Lrule Rrule"> Peripheral neuropathy <footnote ID="K1879">Peripheral neuropathy includes peripheral neuritis and neuropathy.</footnote></td><td styleCode="Rrule">1%</td><td styleCode="Rrule">5%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Anxiety</td><td styleCode="Rrule">6%</td><td styleCode="Rrule">6%</td></tr><tr><td styleCode="Lrule Rrule">Respiratory</td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pneumonia</td><td styleCode="Rrule">5%</td><td styleCode="Rrule">5%</td></tr><tr><td styleCode="Lrule Rrule">Skin and Appendages</td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule"> Rash event <footnote ID="K1929">Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash.</footnote></td><td styleCode="Rrule">18%</td><td styleCode="Rrule">12%</td></tr></tbody></table>

<table width="75%"><caption>Table 3 Grades 3&#x2013;4 Laboratory Abnormalities Reported in &#x2265;1% of VIREAD-Treated Subjects in Study 903 (0&#x2013;144 Weeks)</caption><col width="48%" align="left" valign="middle"/><col width="26%" align="center" valign="middle"/><col width="26%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule"/><th styleCode="Botrule Rrule">VIREAD+3TC+EFV</th><th styleCode="Botrule Rrule">d4T+3TC+EFV</th></tr><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule">N=299</th><th styleCode="Rrule">N=301</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Any &#x2265; Grade 3 Laboratory Abnormality</td><td styleCode="Rrule">36%</td><td styleCode="Rrule">42%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Fasting Cholesterol (&gt;240 mg/dL)</td><td styleCode="Rrule">19%</td><td styleCode="Rrule">40%</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">12%</td><td styleCode="Rrule">12%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Serum Amylase (&gt;175 U/L)</td><td styleCode="Rrule">9%</td><td styleCode="Rrule">8%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">AST (M: &gt;180 U/L; F: &gt;170 U/L)</td><td styleCode="Rrule">5%</td><td styleCode="Rrule">7%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">ALT (M: &gt;215 U/L; F: &gt;170 U/L)</td><td styleCode="Rrule">4%</td><td styleCode="Rrule">5%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hematuria (&gt;100 RBC/HPF)</td><td styleCode="Rrule">7%</td><td styleCode="Rrule">7%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Neutrophils (&lt;750/mm ³) </td><td styleCode="Rrule">3%</td><td styleCode="Rrule">1%</td></tr><tr><td styleCode="Lrule Rrule">Fasting Triglycerides (&gt;750 mg/dL)</td><td styleCode="Rrule">1%</td><td styleCode="Rrule">9%</td></tr></tbody></table>

<table width="75%"><caption>Table 4 Selected Treatment-Emergent Adverse Reactions <footnote ID="K2151">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="40%" align="left" valign="top"/><col width="30%" align="center" valign="top"/><col width="30%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule"/><th styleCode="Botrule Rrule">VIREAD <footnote ID="K2173">From Weeks 96 to 144 of the trial, subjects received TRUVADA with efavirenz in place of VIREAD + EMTRIVA with efavirenz.</footnote>+FTC+EFV </th><th styleCode="Botrule Rrule">AZT/3TC+EFV</th></tr><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule">N=257</th><th styleCode="Rrule">N=254</th></tr></thead><tbody><tr><td styleCode="Lrule Rrule">Gastrointestinal Disorder</td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule"> Diarrhea</td><td styleCode="Rrule">9%</td><td styleCode="Rrule">5%</td></tr><tr><td styleCode="Lrule Rrule"> Nausea</td><td styleCode="Rrule">9%</td><td styleCode="Rrule">7%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule"> 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 Rrule"> Fatigue</td><td styleCode="Rrule">9%</td><td styleCode="Rrule">8%</td></tr><tr><td styleCode="Lrule Rrule">Infections and Infestations</td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule"> Sinusitis</td><td styleCode="Rrule">8%</td><td styleCode="Rrule">4%</td></tr><tr><td styleCode="Lrule Rrule"> Upper respiratory tract infections</td><td styleCode="Rrule">8%</td><td styleCode="Rrule">5%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Nasopharyngitis</td><td styleCode="Rrule">5%</td><td styleCode="Rrule">3%</td></tr><tr><td styleCode="Lrule Rrule">Nervous System Disorders</td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule"> Headache</td><td styleCode="Rrule">6%</td><td styleCode="Rrule">5%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dizziness</td><td styleCode="Rrule">8%</td><td styleCode="Rrule">7%</td></tr><tr><td styleCode="Lrule Rrule">Psychiatric Disorders</td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule"> Depression</td><td styleCode="Rrule">9%</td><td styleCode="Rrule">7%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Insomnia</td><td styleCode="Rrule">5%</td><td styleCode="Rrule">7%</td></tr><tr><td styleCode="Lrule Rrule">Skin and Subcutaneous Tissue Disorders</td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule"> Rash event <footnote ID="K2356">Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculopapular, rash pruritic, and rash vesicular.</footnote></td><td styleCode="Rrule">7%</td><td styleCode="Rrule">9%</td></tr></tbody></table>