TENOFOVIR DISOPROXIL FUMARATE (Page 2 of 10)

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 tenofovir disoproxil fumarate [see Adverse Reactions (6.2)].

Prior to initiation and during use of tenofovir disoproxil fumarate, 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.

Dosing interval adjustment of tenofovir disoproxil fumarate and close monitoring of renal function are recommended in all patients with creatinine clearance below 50 ml/min [See Dosage and Administration (2.4)]. No safety or efficacy data are available in patients with renal impairment who received tenofovir disoproxil fumarate using these dosing guidelines, so the potential benefit of tenofovir disoproxil fumarate therapy should be assessed against the potential risk of renal toxicity.

Tenofovir disoproxil fumarate 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 TDF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction.

Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in patients at risk of renal dysfunction.

5.3 Patients Coinfected with HIV-1 and HBV

Due to the risk of development of HIV-1 resistance, tenofovir disoproxil fumarate 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 tenofovir disoproxil fumarate. It is also recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B before initiating treatment with tenofovir disoproxil fumarate.

5.4 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in HIV-1 infected patients treated with combination antiretroviral therapy, including tenofovir disoproxil fumarate. 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-Barre 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.

5.5 Bone Loss and Mineralization Defects

Bone Mineral Density

In clinical trials in HIV-1 infected adults, tenofovir disoproxil fumarate 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 [See Adverse Reactions (6.1)]. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving tenofovir disoproxil fumarate.

Clinical trials evaluating tenofovir disoproxil fumarate in pediatric subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1 infected subjects 2 years to less than 18 years of age, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the tenofovir disoproxil fumarate-treated HIV-1 infected pediatric subjects as compared to the control groups. Similar trends were observed in chronic HBV-infected pediatric subjects 12 years to less than 18 years of age. In all pediatric trials, normal skeletal growth (height) was not affected for the duration of the clinical trials [See Adverse Reactions (6.1)].

The effects of tenofovir disoproxil fumarate -associated changes in BMD and biochemical markers on long-term bone health and future fracture risk in adults and pediatric subjects 2 years and older are unknown. The long-term effect of lower spine and total body BMD on skeletal growth in pediatric patients, and in particular, the effects of long-duration exposure in younger children is unknown.

Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial. Assessment of BMD should be considered for adult and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. If bone abnormalities are suspected, 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 tenofovir disoproxil fumarate use [See Adverse Reactions (6.2)]. Arthralgia 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 TDF-containing products [See Warnings and Precautions (5.2)].

Pediatric use information is approved for Gilead Sciences, Inc.’s VIREAD® (tenofovir disoproxil fumarate) tablets. However, due to Gilead Sciences, Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

5.6 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 TDF, alone or in combination with other antiretrovirals. Treatment with tenofovir disoproxil fumarate 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).

5.7 Risk of Adverse Reactions Due to Drug Interactions

The concomitant use of tenofovir disoproxil fumarate and other drugs may result in known or potentially significant drug interactions, some of which may lead to possible clinically significant adverse reactions from greater exposures of concomitant drugs [see Drug Interactions (7.2)].

See Table 12 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during therapy with tenofovir disoproxil fumarate; review concomitant medications during therapy with tenofovir disoproxil fumarate; and monitor for adverse reactions associated with the concomitant drugs.

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)].

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 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 2-4) 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 2–4) Reported in ≥5% in Any Treatment Group in Trial 903 (0–144 Weeks)

a. Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug.

b. Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash.

c. Lipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome.

d. Peripheral neuropathy includes peripheral neuritis and neuropathy.

Tenofovir disoproxil fumarate +3TC+EFV d4T+3TC+EFV
N=299 N=301
Rash event b 18% 12%
Headache 14% 17%
Pain 13% 12%
Diarrhea 11% 13%
Depression 11% 10%
Back pain 9% 8%
Nausea 8% 9%
Fever 8% 7%
Abdominal pain 7% 12%
Asthenia 6% 7%
Anxiety 6% 6%
Vomiting 5% 9%
Insomnia 5% 8%
Arthralgia 5% 7%
Pneumonia 5% 5%
Dyspepsia 4% 5%
Dizziness 3% 6%
Myalgia 3% 5%
Lipodystrophy c 1% 8%
Peripheral neuropathy d 1% 5%

Laboratory Abnormalities: Table 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 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 3-4 Laboratory Abnormalities Reported in ≥1% of Tenofovir Disoproxil Fumarate-Treated Subjects in Trial 903 (0–144 Weeks)

Tenofovir disoproxil fumarate + 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%

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 + 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 tenofovir disoproxil fumarate 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 tenofovir disoproxil fumarate-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 tenofovir disoproxil fumarate 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 tenofovir disoproxil fumarate 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 (5.5)].

In Trial 934, 511 antiretroviral-naïve subjects received efavirenz (EFV) administered in combination with either emtricitabine (FTC) + tenofovir disoproxil fumarate (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 2–4) Reported in ≥5% in Any Treatment Group in Trial 934 (0–144 Weeks)

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 efavirenz in place of tenofovir disoproxil fumarate + EMTRIVA with efavirenz.

c. Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculopapular, rash pruritic, and rash vesicular.

Tenofovir disoproxil fumarate b +FTC+EFV AZT/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 event c 7% 9%
Headache 6% 5%
Insomnia Nasopharyngitis 5% 7%
5% 3%
Vomiting 2% 5%

Laboratory 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 Any Treatment Group in Trial 934 (0–144 Weeks)

a From Weeks 96 to 144 of the trial, subjects received TRUVADA with efavirenz in place of tenofovir disoproxil fumarate + EMTRIVA with efavirenz.

Tenofovir disoproxil fumarate a + FTC + EFV a 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%

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 2–4) Reported in 3% in Any Treatment Group in Trial 907 (0–48 Weeks)

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.

Tenofovir disoproxil fumarate (N=368) (Week 0–24) Placebo (N=182) (Week 0–24) Tenofovir disoproxil fumarate (N=368) (Week 0–48) Placebo Crossover to Tenofovir disoproxil fumarate (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 b 3% 3% 5% 2%
Dizziness 1% 3% 3% 1%
Skin and Appendage
Rash event c 5% 4% 7% 1%
Sweating 3% 2% 3% 1%
Musculoskeletal
Myalgia 3% 3% 4% 1%
Metabolic
Weight loss 2% 1% 4% 2%

Laboratory 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 Grade 3-4 Laboratory Abnormalities Reported in ≥1% of Tenofovir Disoproxil Fumarate-Treated Subjects in Trial 907 (0–48 Weeks)

Tenofovir disoproxil fumarate (N=368) (Week 0–24) Placebo (N=182) (Week 0–24) Tenofovir disoproxil fumarate (N=368) (Week 0–48) Placebo Crossover to tenofovir disoproxil fumarate (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%

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 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 d4Tor AZT treatment groups. Total body BMD gain was less in the tenofovir disoproxil fumarate group compared to the d4T or AZT treatment groups. 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 tenoforvir disoproxil fumarate (weeks 48–384), 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.

Laboratory Abnormalities: Table 10 provides a list of Grade 3–4 laboratory abnormalities through Week 48. Grade 3-4 laboratory abnormalities were similar in subjects continuing tenofovir disoproxil fumarate treatment for up to 384 weeks in these trials.

Table 10 Grades 3-4 Laboratory Abnormalities Reported in ≥1% of Tenofovir Disoproxil Fumarate–Treated Subjects in Trials 0102 and 0103 (0-48 Weeks)

TENOFOVIR DISOPROXIL FUMARATE 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 tenofovir disoproxil fumarate (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 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 2mg/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 trials: 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), 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.

Table 11 Change in Bone Mineral Density from Baseline in Pediatric Subjects 2 Years to <12 Years of Age (Trials 115)

Trial 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 -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)].

Pediatric use information is approved for Gilead Sciences, Inc.’s VIREAD® (tenofovir disoproxil fumarate) tablets. However, due to Gilead Sciences, Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

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