Tenof Adverse Reactions

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.
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 studies. 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 >10%, Grades 2 to 4) identified from any of the 3 large controlled clinical trials include rash, diarrhea, headache, pain, depression, asthenia, and nausea.
Treatment-Naive Patients: Study 903 - Treatment-Emergent Adverse-Reactions: The most common adverse reactions seen in a double-blind comparative controlled study in which 600 treatment-naive subjects received tenofovir disoproxil fumarate (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 11. (See Table 11.)

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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 tenofovir disoproxil fumarate (19% and 1%) respectively, laboratory abnormalities observed in this study occurred with similar frequency in the tenofovir disoproxil fumarate and stavudine treatment arms. A summary of Grade 3 and 4 laboratory abnormalities is provided in Table 12. (See Table 12.)

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Study 934 - Treatment Emergent Adverse Reactions: In Study 934, 511 antiretroviral-naive subjects received either tenofovir disoproxil fumarate + EMTRIVA administered in combination with efavirenz (N=257) or zidovudine/lamivudine administered in combination with efavirenz (N=254). Adverse reactions observed in this study were generally consistent with those seen in previous studies in treatment-experienced or treatment-naive subjects (Table 13).
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 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 Precautions). (See Table 13.)

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Laboratory Abnormalities: Laboratory abnormalities observed in this study were generally consistent with those seen in previous studies. (See Table 14.)

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Treatment-Experienced Patients: Treatment-Emergent Adverse Reactions: The adverse reactions seen in treatment experienced subjects were generally consistent with those seen in treatment naive subjects including mild to moderate gastrointestinal events, such as nausea, diarrhea, vomiting, and flatulence. Less than 1% of subjects discontinued participation in the clinical studies 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 15. (See Table 15.)

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Laboratory Abnormalities: Laboratory abnormalities observed in this study occurred with similar frequency in the tenofovir disoproxil fumarate and placebo-treated groups. A summary of Grade 3 and 4 laboratory abnormalities is provided in Table 16. (See Table 16.)

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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 <18 years of age) who received treatment with tenofovir disoproxil fumarate (N=45) or placebo/active comparator (N=42) in combination with other antiretroviral agents for 48 weeks. The adverse reactions observed in subjects who received treatment with tenofovir disoproxil fumarate 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 tenofovir disoproxil fumarate compared to the placebo treatment 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. Skeletal growth (height) appeared to be unaffected. (See Precautions.)
Clinical Trials in Adult Subjects with Chronic Hepatitis B and Compensated Liver Disease: Treatment-Emergent Adverse Reactions: In controlled clinical trials in 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 >5% of subjects treated with tenofovir disoproxil fumarate included: abdominal pain, diarrhea, headache, dizziness, fatigue, nasopharyngitis, back pain and skin rash.
During the open-label phase of treatment with TENOFOVIR DISOPROXIL FUMARATE (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 Grade 3 and 4 laboratory abnormalities through Week 48 is provided in Table 8. Grade 3/4 laboratory abnormalities were similar in subjects continuing tenofovir disoproxil fumarate treatment for up to 384 weeks in these studies. (See Table 17.)

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The overall incidence of on-treatment ALT flares (defined as serum ALT >2 × baseline and >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 hepatitis B clinical trials in adults.
Clinical Trial 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 tenofovir disoproxil fumarate or other antiviral drugs for up to 48 weeks (see Pharmacology: Clinical Studies under Actions). 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 study 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 < 2 mg/dL through Week 48). Three of these subjects (each of whom had a Child-Pugh score 10 and MELD score ≥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 study.
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 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 this study, both the tenofovir disoproxil fumarate 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 tenofovir disoproxil fumarate-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 tenofovir disoproxil fumarate 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 tenofovir disoproxil fumarate 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 tenofovir disoproxil fumarate 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.
Post Marketing 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.
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 mentioned may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.