Viread Adverse Reactions

The following adverse reactions are discussed in Precautions: Severe Acute Exacerbation of Hepatitis B in Patients with HBV Infection; New Onset or Worsening Renal Impairment; Immune Reconstitution Syndrome; Bone Loss and Mineralization Defects; Lactic Acidosis/Severe Hepatomegaly with Steatosis.
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 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 1,544 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.
Clinical Trials in Treatment-Naïve HIV-1 Infected Adult Subjects: In Trial 903, 600 antiretroviral-naïve subjects received VIREAD (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 13 provides the treatment-emergent adverse reactions (Grades 2-4) occuring in greater than or equal to 5% of subjects treated in any treatment group. (See Table 13.)

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Laboratory Abnormalities: Table 14 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 VIREAD group (19% and 1%) respectively, laboratory abnormalities observed in this trial occurred with similar frequency in the VIREAD and d4T treatment arms. (See Table 14.)

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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 VIREAD + 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 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 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 VIREAD 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 VIREAD 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 Precautions].
In Trial 934, 511 antiretroviral-naïve subjects received efavirenz (EFV) administered in combination with either emtricitabine (FTC) + VIREAD (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 15 provides the treatment-emergent adverse reactions (Grades 2−4) occurring in greater than or equal to 5% of subjects treated in any treatment group. (See Table 15.)

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Laboratory Abnormalities: Laboratory abnormalities observed in this trial were generally consistent with those seen in previous trials (Table 16). (See Table 16.)

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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 17 provides the treatment-emergent adverse reactions (Grades 2-4) occurring in greater than or equal to 3% of subjects treated in any treatment group. (See Table 17.)

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Laboratory Abnormalities: Table 18 provides a list of Grade 3-4 laboratory abnormalities observed in Trial 907. Laboratory abnormalities occurred with similar frequency in the VIREAD and placebo groups. (See Table 18.)

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Adverse Reactions from Clinical Trials Experience in HIV-1 Infected Pediatric Subjects 12 Years and Older: Assessment of adverse reactions is based on one randomized trial (Trial 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 [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions]. 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: 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 VIREAD group compared to the placebo 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. In the trial, skeletal growth (height) appeared to be unaffected for the duration of the clinical trial [see Precautions].
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 VIREAD during the 48-week double-blind period experienced nausea: 9% with VIREAD versus 2% with adefovir dipivoxil. 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.
In Trials 0102 and 0103, during the open-label phase of treatment with VIREAD (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 19 provides a list of Grade 3–4 laboratory abnormalities through Week 48. Grades 3–4 laboratory abnormalities were similar in subjects continuing VIREAD treatment for up to 384 weeks in these trials. (See Table 19.)

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The overall incidence of on-treatment ALT flares (defined as serum ALT greater than 2 x baseline and greater than 10 x ULN, with or without associated symptoms) was similar between VIREAD (2.6%) and adefovir dipivoxil (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 VIREAD 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 VIREAD or other antiviral drugs for up to 48 weeks [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions]. 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.
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 previously, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.