Tenofovir Disoproxil Fumarate Tablets

1 INDICATIONS AND USAGE Tenofovir disoproxil fumarate tablets are a nucleotide analog HIV-1 reverse transcriptase inhibitor and an HBV reverse transcriptase inhibitor and is indicated: in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 2 years of age and older weighing at least 10 kg. ( 1.1 ) for the treatment of chronic hepatitis B in adults and pediatric patients 2 years and older weighing at least 10 kg. ( 1.2 ) 1.1 HIV-1 Infection Tenofovir disoproxil fumarate tablets are indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and pediatric patients 2 years of age and older weighing at least 10 kg. 1.2 Chronic Hepatitis B Tenofovir disoproxil fumarate tablets are indicated for the treatment of chronic hepatitis B virus (HBV) in adults and pediatric patients 2 years of age and older weighing at least 10 kg.

2 DOSAGE AND ADMINISTRATION Testing: Prior to or when initiating tenofovir disoproxil fumarate tablets test for hepatitis B virus infection and HIV-1 infection. Prior to initiation and during use of Tenofovir disoproxil fumarate tablets, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorous. ( 2.1 ) Recommended tablet dosage in adults and pediatric patients weighing at least 35 kg: One tenofovir disoproxil fumarate 300 mg tablet once daily taken orally without regard to food. ( 2.2 ) Recommended dosage in pediatric patients at least 2 years of age and adults: Tablets: For patients weighing at least 17 kg who can swallow an intact tablet, one tenofovir disoproxil fumarate tablet (150 mg, 200 mg, 250 mg, or 300 mg based on body weight) once daily taken orally without regard to food. ( 2.2 ) Recommended dosage in renally impaired adult patients: Creatinine clearance (CrCL) 30 to 49 mL/min: 300 mg every 48 hours. ( 2.4 ) CrCL10 to 29 mL/min: 300 mg every 72 to 96 hours. ( 2.4 ) Hemodialysis: 300 mg every 7 days or after approximately 12 hours of dialysis. ( 2.4 ) 2.1 Testing Prior to Initiation of tenofovir disoproxil fumarate tablets for Treatment of HIV-1 Infection or Chronic Hepatitis B Prior to or when initiating tenofovir disoproxil fumarate tablets, test patients for HBV infection and HIV-1 infection. Tenofovir disoproxil fumarate tablets alone should not be used in patients with HIV-1 infection [see Warnings and Precautions ( 5.3 )]. Prior to initiation and during use of tenofovir disoproxil fumarate tablets, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus [see Warnings and Precautions ( 5.2 )]. 2.2 Recommended Tablet Dosage in Adults and Pediatric Patients 2 Years and Older Weighing at Least 17 kg The recommended dosage of tenofovir disoproxil fumarate tablet in adults and pediatric patients weighing at least 35 kg is one 300 mg tablet taken orally once daily without regard to food. The dosage for tenofovir disoproxil fumarate tablets is the same for both HIV and HBV indications. The recommended dosage of tenofovir disoproxil fumarate tablets tablet in adults and pediatric patients 2 years and older weighing at least 17 kg is 8 mg of tenofovir disoproxil fumarate (TDF) per kg of body weight (up to a maximum of 300 mg) once daily. Dosage for pediatric patients 2 years and older weighing between 17 kg and 35 kg and able to swallow an intact tablet is provided in Table 1. Weight should be monitored periodically and the tenofovir disoproxil fumarate tablets dose adjusted accordingly. Table 1 Recommended Dosing for Patients 2 Years and Older and Weighing at Least 17 kg Using Tenofovir Disoproxil Fumarate Tablets Body Weight (kg) Dosing of Tenofovir Disoproxil Fumarate T ablets 17 to less than 22 one 150 mg tablet once daily 22 to less than 28 one 200 mg tablet once daily 28 to less than 35 one 250 mg tablet once daily at least 35 one 300 mg tablet once daily 2.4 Dosage Adjustment in Patients with Renal Impairment Significant increase in drug exposures occurred when tenofovir disoproxil fumarate tablets were administered to subjects with moderate to severe renal impairment (creatinine clearance below 50 mL/min). Table 3 provides dosage interval adjustment for patients with renal impairment. No dosage adjustment of tenofovir disoproxil fumarate tablets 300 mg is necessary for patients with mild renal impairment (creatinine clearance 50 to 80 mL/min) [see Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.6 ), and Clinical Pharmacology ( 12.3 ) ] . Table 3 Dosage Interval Adjustment for Adult Patients with Altered Creatinine Clearance Creatinine Clearance (mL/min) a Hemodialysis Patients 50 or greater 30 to 49 10 to 29 Recommended 300 mg Dosing Interval Every 24 hours Every 48 hours Every 72 to 96 hours Every 7 days or after a total of approximately 12 hours of dialysis b a. Calculated using ideal (lean) body weight. b. Generally once weekly assuming 3 hemodialysis sessions a week of approximately 4 hours’ duration. Tenofovir disoproxil fumarate tablets should be administered following completion of dialysis. No data are available to make dosage recommendations in patients with creatinine clearance below 10 mL/min who are not on hemodialysis. No data are available to make dosage recommendations in pediatric patients with renal impairment.

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Severe Acute Exacerbation of Hepatitis B in Patients with HBV Infection [see Warnings and Precautions ( 5.1 )] . New Onset or Worsening Renal Impairment [see Warnings and Precautions ( 5.2 )] . Immune Reconstitution Syndrome [see Warnings and Precautions ( 5.4 )] . Bone Loss and Mineralization Defects [see Warnings and Precautions ( 5.5 )] . Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions ( 5.6 )] . In HIV-infected adult subjects: Most common adverse reactions (incidence greater than or equal to 10%, Grades 2 to 4) were rash, diarrhea, nausea, headache, pain, depression, and asthenia. ( 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 greater than or equal to 10%, all grades) were abdominal pain, nausea, insomnia, pruritus, vomiting, dizziness, and pyrexia. ( 6.1 ) In pediatric subjects: Adverse reactions in pediatric subjects were consistent with those observed in adults. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Chartwell RX, LLC. at 1-845-232-1683 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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. Adverse Reactions from Clinical Trials Experience in HIV-1 Infected Adults More than 12,000 subjects have been treated with tenofovir disoproxil fumarate 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 1,544 subjects have received tenofovir disoproxil fumarate tablets 300 mg once daily in clinical trials; over 11,000 subjects have received tenofovir disoproxil fumarate in expanded access programs. The most common adverse reactions (incidence greater than or equal to 10%, Grades 2 to 4) identified from any of the 3 large controlled clinical trials include rash, diarrhea, headache, pain, depression, asthenia, and nausea. Clinical Trials in Treatment-Naïve HIV-1 Infected Adult Subjects In Trial 903, 600 antiretroviral- naïve subjects received tenofovir disoproxil fumarate (N=299) or stavudine (d4T) (N=301) administered in combination with lamivudine (3TC) and efavirenz (EFV) for 144 weeks. The most common adverse reactions were mild to moderate gastrointestinal events and dizziness. Mild adverse reactions (Grade 1) were common with a similar incidence in both arms and included dizziness, diarrhea, and nausea. Table 4 provides the treatment-emergent adverse reactions (Grades 2−4) occurring in greater than or equal to 5% of subjects treated in any treatment group. Table 4 Selected Adverse Reactions a (Grades 2 to 4) Reported in ≥5% in Any Treatment Group in Trial 903 (0 to 144 Weeks) Tenofovir disoproxil fumarate + 3 T C+EFV d4T+3TC+EFV N=299 N=301 Rash event b 18% 12% Headache 14% 17% Pain 13% 12% Diarrhea 11% 13% Depression 11% 10% Back pain 9% 8% Nausea 8% 9% Fever 8% 7% Abdominal pain 7% 12% Asthenia 6% 7% Anxiety 6% 6% Vomiting 5% 9% Insomnia 5% 8% Arthralgia 5% 7% Pneumonia 5% 5% Dyspepsia 4% 5% Dizziness 3% 6% Myalgia 3% 5% Lipodystrophyc 1% 8% Peripheral neuropathy d 1% 5% a. Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. b. Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash. c. Lipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome. d. Peripheral neuropathy includes peripheral neuritis and neuropathy. La b o r a tory Abnormalities: Table 5 provides a list of laboratory abnormalities (Grades 3−4) observed in Trial 903. With the exception of fasting cholesterol and fasting triglyceride elevations that were more common in the d4T group (40% and 9%) compared with the tenofovir disoproxil fumarate group (19% and 1%), respectively, laboratory abnormalities observed in this trial occurred with similar frequency in the tenofovir disoproxil fumarate and d4T treatment arms. Table 5 Grades 3 to 4 Laboratory Abnormalities Reported in ≥1% of Tenofovir Disoproxil Fumarate-Treated Subjects in Trial 903 (0 to 144 Weeks) Tenofovir Disoproxil Fumarate + 3TC + EFV d 4T + 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% Changes in Bone Mineral Density: In HIV-1 infected adult subjects in Trial 903, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving tenofovir disoproxil fumarate + 3TC + EFV (-2.2% ± 3.9) compared with subjects receiving d4T + 3TC + EFV (-1.0% ± 4.6) through 144 weeks. Changes in BMD at the hip were similar between the two treatment groups (-2.8% ± 3.5 in the tenofovir disoproxil fumarate group vs. -2.4% ± 4.5 in the d4T group). In both groups, the majority of the reduction in BMD occurred in the first 24 to 48 weeks of the trial and this reduction was sustained through Week 144. Twenty-eight percent of tenofovir disoproxil fumarate-treated subjects vs. 21% of d4T-treated subjects lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 subjects in the tenofovir disoproxil fumarate group and 6 subjects in the d4T group. In addition, there were significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C telopeptide, and urinary N telopeptide) and higher serum parathyroid hormone levels and 1,25 Vitamin D levels in the tenofovir disoproxil fumarate group relative to the d4T group; however, except for bone-specific alkaline phosphatase, these changes resulted in values that remained within the normal range [see Warnings and Precautions ( 5.5 )] . In Trial 934, 511 antiretroviral-naïve subjects received efavirenz (EFV) administered in combination with either emtricitabine (FTC) + tenofovir disoproxil fumarate tablets (N=257) or zidovudine (AZT)/lamivudine (3TC) (N=254) for 144 weeks. The most common adverse reactions (incidence greater than or equal to 10%, all grades) included diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. Table 6 provides the treatment-emergent adverse reactions (Grades 2−4) occurring in greater than or equal to 5% of subjects treated in any treatment group. Table 6 Selected Adverse Reactions a (Grades 2 to 4) Reported in ≥5% in Any Treatment Group in Trial 934 (0 to 144 Weeks) Tenofovir disoproxil fumarate tablets b + FTC+EFV A ZT/3TC+EFV N=257 N=254 Fatigue 9% 8% Depression 9% 7% Nausea 9% 7% Diarrhea 9% 5% Dizziness 8% 7% Upper respiratory tract infections 8% 5% Sinusitis 8% 4% Rash eventc 7% 9% Headache 6% 5% Insomnia 5% 7% Nasopharyngitis 5% 3% Vomiting 2% 5% a. Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. b. From Weeks 96 to 144 of the trial, subjects received TRUVADA with EFV in place of tenofovir disoproxil fumarate + FTC with EFV. c. Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculopapular, rash pruritic, and rash vesicular. La b o r a tory Abnormalities: Laboratory abnormalities observed in this trial were generally consistent with those seen in previous trials (Table 7). Table 7 Significant Laboratory Abnormalities Reported in ≥1% of Subjects in AnyTreatment Group in Trial 934 (0 to 144 Weeks) Tenofovir Disoproxil Fumarate a + FTC + EFV A Z T / 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% a. From Weeks 96 to 144 of the trial, subjects received TRUVADA with EFV in place of tenofovir disoproxil fumarate + FTC with EFV. Clinical Trials in Treatment-Experienced HIV-1 Infected Adult Subjects In Trial 907, the adverse reactions seen in HIV-1 infected 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. Table 8 provides the treatment-emergent adverse reactions (Grades 2−4) occurring in greater than or equal to 3% of subjects treated in any treatment group. Table 8 Selected Adverse Reactions a (Grades 2 to 4) Reported in ≥3% in Any Treatment Group in Trial 907 (0 to 48 Weeks) Tenofovir Disoproxil Fumarate N=368 (Week 0 to 24) Placebo N=182 (Week 0 to 24) Tenofovir Disoproxil Fumarate N=368 (Week 0 to 48) Placebo Crossover to Tenofovir Disoproxil Fumarate N=170 (Week 24 to 48) Body as a Whole Asthenia Pain Headache Abdominal pain Back pain Chest pain Fever 7% 7% 5% 4% 3% 3% 2% 6% 7% 5% 3% 3% 1% 2% 11% 12% 8% 7% 4% 3% 4% 1% 4% 2% 6% 2% 2% 2% Digestive System Diarrhea Nausea Vomiting Anorexia Dyspepsia Flatulence 11% 8% 4% 3% 3% 3% 10% 5% 1% 2% 2% 1% 16% 11% 7% 4% 4% 4% 11% 7% 5% 1% 2% 1% Respiratory Pneumonia 2% 0% 3% 2% Nervous System Depression Insomnia Peripheral neuropathy b Dizziness 4% 3% 3% 1% 3% 2% 3% 3% 8% 4% 5% 3% 4% 4% 2% 1% Skin and Appendage Rash event c Sweating 5% 3% 4% 2% 7% 3% 1% 1% Musculoskeletal Myalgia 3% 3% 4% 1% Metabolic Weight loss 2% 1% 4% 2% a. Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. b. Peripheral neuropathy includes peripheral neuritis and neuropathy. c. Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash. La b o r a tory Abnormalities: Table 9 provides a list of Grade 3−4 laboratory abnormalities observed in Trial 907. Laboratory abnormalities occurred with similar frequency in the tenofovir disoproxil fumarate and placebo groups. Table 9 Grades 3 to 4 Laboratory Abnormalities Reported in ≥1% of Tenofovir Disoproxil Fumarate-Treated Subjects in Trial 907 (0 to 48 Weeks) Tenofovir Disoproxil Fumarate N=368 (Week 0 to 24) Placebo N=182 (Week 0 to 24) Tenofovir Disoproxil Fumarate N=368 (Week 0 to 48) Placebo Crossover to Tenofovir Disoproxil Fumarate N=170 (Week 24 to 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% Adverse Reactions from Clinical Trials Experience in HIV-1 Infected Pediatric Subjects 2 Years and Older Assessment of adverse reactions is based on two randomized trials (Trials 352 and 321) in 184 HIV-1 infected pediatric subjects (2 years to less than 18 years of age) who received treatment with tenofovir disoproxil fumarate (N=93) or placebo/active comparator (N=91) in combination with other antiretroviral agents for 48 weeks [see Clinical Studies ( 14.3 )]. The adverse reactions observed in subjects who received treatment with tenofovir disoproxil fumarate were consistent with those observed in the clinical trials in adults. In Trial 352, 89 pediatric subjects (2 years to less than 12 years of age) received tenofovir disoproxil fumarate for a median exposure of 104 weeks. Of these, 4 subjects discontinued from the trial due to adverse reactions consistent with proximal renal tubulopathy. Three of these 4 subjects presented with hypophosphatemia and also had decreases in total body or spine BMD Z-score [see Warnings and Precautions ( 5.5 )] . Changes in Bone Mineral Density: In Trial 321 (12 years to less than 18 years of age), the mean rate of BMD gain at Week 48 was less in the tenofovir disoproxil fumarate group compared to the placebo group. Six tenofovir disoproxil fumarate 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 tenofovir disoproxil fumarate for 96 weeks. In Trial 352 (2 years to less than 12 years of age), the mean rate of BMD gain in lumbar spine at Week 48 was similar between the tenofovir disoproxil fumarate and the d4T or AZT treatment groups. Total body BMD gain was less in the tenofovir disoproxil fumarate group compared to the d4T or AZT treatment group. One tenofovir disoproxil fumarate-treated subject and none of the d4T or AZT-treated subjects experienced significant (greater than 4%) lumbar spine BMD loss at Week 48. Changes from baseline in BMD Z scores were -0.012 for lumbar spine and -0.338 for total body in the 64 subjects who were treated with tenofovir disoproxil fumarate for 96 weeks. In both trials, skeletal growth (height) appeared to be unaffected for the duration of the clinical trials [see Warnings and Precautions ( 5.5 ) ] . Adverse Reactions from Clinical Trials Experience in HBV-Infected Adults Clinical Trials in Adult Subjects with Chronic Hepatitis B and Compensated Liver Disease In controlled clinical trials in 641 subjects with chronic hepatitis B (0102 and 0103), more subjects treated with tenofovir disoproxil fumarate during the 48-­week double-blind period experienced nausea: 9% with tenofovir disoproxil fumarate versus 2% with HEPSERA. Other treatment-emergent adverse reactions reported in more than 5% of subjects treated with tenofovir disoproxil fumarate included: abdominal pain, diarrhea, headache, dizziness, fatigue, nasopharyngitis, back pain, and skin rash. In Trials 0102 and 0103, during the open-label phase of treatment with tenofovir disoproxil fumarate (weeks 48 to 384), 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. La b o r a tory Abnormalities: Table 10 provides a list of Grades 3 to 4 laboratory abnormalities through Week 48. Grades 3 to 4 laboratory abnormalities were similar in subjects continuing tenofovir disoproxil fumarate treatment for up to 384 weeks in these trials. Table 10 Grades 3 to 4 Laboratory Abnormalities Reported in ≥1% of Tenofovir Disoproxil fumarate -Treated Subjects in Trials 0102 and 0103 (0 to 48 Weeks) Tenofovir Disoproxil Fumarate N = 426 HEPSE R A 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 tenofovir disoproxil fumarate (2.6%) and HEPSERA (2%). ALT flares generally occurred within the first 4 to 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 tenofovir disoproxil fumarate were consistent with those observed in other HBV clinical trials in adults. Clinical Trials in Adult Subjects with Chronic Hepatitis B and Decompensated Liver Disease In Trial 0108, a small randomized, double-blind, active-controlled trial, subjects with chronic HBV and decompensated liver disease received treatment with tenofovir disoproxil fumarate or other antiviral drugs for up to 48 weeks [see Clinical Studies ( 14.4 ) ] . Among the 45 subjects receiving tenofovir disoproxil fumarate, 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 tenofovir disoproxil fumarate and decompensated liver disease may have an impact on renal function, the contribution of tenofovir disoproxil fumarate 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. Adverse Reactions from Clinical Trials Experience in HBV-Infected Pediatric Subjects 12 Years and Older Assessment of adverse reactions in pediatric subjects infected with chronic HBV is based on one randomized trial: Trial GS-US-174-0115 in 106 subjects (12 years to less than 18 years of age) receiving treatment with tenofovir disoproxil fumarate (N=52) or placebo (N=54) for 72 weeks. The adverse reactions observed in pediatric subjects who received treatment with tenofovir disoproxil fumarate were consistent with those observed in clinical trials of tenofovir disoproxil fumarate in adults. In Trial 115 (12 years to less than 18 years of age) and Trial 144 (2 years to less than 12 years of age), both the tenofovir disoproxil fumarate and placebo treatment arms experienced an overall increase in mean lumbar spine and total body BMD over 72 weeks, as expected for a pediatric population (Table 11). In Trial 115, the mean percentage BMD gains from baseline to Week 72 in lumbar spine and total body BMD in tenofovir disoproxil fumarate-treated subjects were less than the mean percentage BMD gains observed in placebo-treated subjects (Table 11). Three subjects (6%) in the tenofovir disoproxil fumarate group and two subjects (4%) in the placebo group had significant (greater than or equal to 4%) lumbar spine BMD loss at Week 72. In Trial 144 (2 years to less than 12 years of age), mean percentage BMD gains from baseline to Week 48 in lumbar spine and total body BMD in tenofovir disoproxil fumarate-treated subjects were less than the mean percentage BMD gains observed in placebo-treated subjects. At Week 48, the cumulative percentage of subjects with greater than or equal to 4% decreases in spine or whole body BMD was numerically higher for subjects in the TDF group compared with the placebo group (Table 11). As observed in pediatric studies of HIV-infected subjects, normal skeletal growth (height) was not affected for the duration of the clinical trial [see Warnings and Precautions ( 5.5 )] . Table 11 Change in Bone Mineral Density from Baseline in Pediatric Subjects 2 Years to <12 Years of Age (Trials 115) T ria l 115 (Week 72) tenofovir disoproxil fumarate (N=52) Placebo (N=54) Mean percentage change in BMD Lumbar spine Total body +5% +3% +8% +5% Cumulative incidence of ≥4% decrease in BMD Lumbar spine 6% 4% Total body 0% 2% Baseline BMD Z-score (mean) Lumbar spine −0.43 −0.28 Total body −0.20 −0.26 Mean change in BMD Z-score Lumbar spine -0.05 +0.07 Total body -0.15 +0.06 The effects of tenofovir disoproxil fumarate tablets-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk in pediatric patients 2 years and older are unknown. The long-term effect of lower spine and total body BMD on skeletal growth in pediatric patients 2 years and older, and in particular, the effects of long-duration exposure in younger children is unknown [see Warnings and Precautions ( 5.5 )]. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of tenofovir disoproxil fumarate. 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 M e tabolism 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) S kin and Subcutaneous Tissue Disorders rash M u sculoskeletal 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.