ADVERSE REACTIONS
Clinical Trials
More than 12,000 patients have been treated with VIREAD alone or in combination with other antiretroviral medicinal products for periods of 28 days to 215 weeks in Phase I-III clinical trials and expanded access studies. A total of 1,544 patients have received VIREAD 300 mg once daily in Phase I–III clinical trials; over 11,000 patients have received VIREAD in expanded access studies.
Treatment-Naïve Patients
Study 903 - Treatment-Emergent Adverse Events
The most common adverse reactions seen in a double-blind comparative controlled study in which 600 treatment-naïve patients 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 events (Grade 1) were common with a similar incidence in both arms, and included dizziness, diarrhea, and nausea. Selected treatment-emergent moderate to severe adverse events are summarized in Table 9.
Table 9 Selected Treatment-Emergent Adverse Events (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 | | |
| LipodystrophyLipodystrophy 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 neuropathyPeripheral neuropathy includes peripheral neuritis and neuropathy. | 1% | 5% |
| Anxiety | 6% | 6% |
| Respiratory | | |
| Pneumonia | 5% | 5% |
| Skin and Appendages | | |
| Rash eventRash 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 study occurred with similar frequency in the VIREAD and stavudine treatment arms. A summary of Grade 3 and 4 laboratory abnormalities is provided in Table 10.
Table 10 Grade 3/4 Laboratory Abnormalities Reported in ≥1% of VIREAD-Treated Patients 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/mm3) | 3% | 1% |
| Fasting Triglycerides (>750 mg/dL) | 1% | 9% |
Study 934 - Treatment Emergent Adverse Events
In Study 934, 511 antiretroviral-naïve patients received either VIREAD + EMTRIVA administered in combination with efavirenz (N=257) or zidovudine/lamivudine administered in combination with efavirenz (N=254). Adverse events observed in this study were generally consistent with those seen in previous studies in treatment-experienced or treatment-naïve patients (Table 11).
Table 11 Selected Treatment-Emergent Adverse Events (Grades 2–4) Reported in ≥3% in Any Treatment Group in Study 934 (0–48 Weeks) | VIREAD + FTC + EFV | AZT/3TC + EFV |
|---|
| N=257 | N=254 |
|---|
| Gastrointestinal Disorder | | |
| Diarrhea | 7% | 4% |
| Nausea | 8% | 6% |
| Vomiting | 1% | 4% |
| General Disorders and Administration Site Condition | | |
| Fatigue | 7% | 6% |
| Infections and Infestations | | |
| Sinusitis | 4% | 2% |
| Upper respiratory tract infections | 3% | 3% |
| Nasopharyngitis | 3% | 1% |
| Nervous System Disorders | | |
| Somnolence | 3% | 2% |
| Headache | 5% | 4% |
| Dizziness | 8% | 7% |
| Psychiatric Disorders | | |
| Depression | 4% | 7% |
| Insomnia | 4% | 5% |
| Abnormal dreams | 4% | 3% |
| Skin and Subcutaneous Tissue Disorders | | |
| Rash | 5% | 4% |
Laboratory Abnormalities
Laboratory abnormalities observed in this study were generally consistent with those seen in previous studies (Table 12).
Table 12 Significant Laboratory Abnormalities Reported in ≥1% of Patients in Any Treatment Group in Study 934 (0–48 Weeks) | VIREAD + FTC + EFV | AZT/3TC + EFV |
|---|
| N=257 | N=254 |
|---|
| Any ≥ Grade 3 Laboratory Abnormality | 25% | 22% |
| Fasting Cholesterol (>240 mg/dL) | 15% | 17% |
Creatine Kinase
(M: >990 U/L)
(F: >845 U/L) | 7% | 6% |
| Serum Amylase (>175 U/L) | 7% | 3% |
| Alkaline Phosphatase (>550 U/L) | 1% | 0% |
AST
(M: >180 U/L)
(F: >170 U/L) | 3% | 2% |
ALT
(M: >215 U/L)
(F: >170 U/L) | 2% | 2% |
| Hemoglobin (<8.0 mg/dL) | 0% | 3% |
| Hyperglycemia (>250 mg/dL) | 1% | 1% |
| Hematuria (>75 RBC/HPF) | 2% | 2% |
| Neutrophils (<750/mm3) | 3% | 4% |
| Fasting Triglycerides (>750 mg/dL) | 4% | 2% |
Treatment-Experienced Patients
Treatment-Emergent Adverse Events
The adverse reactions seen in treatment experienced patients were generally consistent with those seen in treatment naïve patients including mild to moderate gastrointestinal events, such as nausea, diarrhea, vomiting, and flatulence. Less than 1% of patients discontinued participation in the clinical studies due to gastrointestinal adverse events (Study 907).
A summary of moderate to severe, treatment-emergent adverse events that occurred during the first 48 weeks of Study 907 is provided in Table 13.
Table 13 Selected Treatment-Emergent Adverse Events (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 neuropathyPeripheral neuropathy includes peripheral neuritis and neuropathy. | 3% | 3% | 5% | 2% |
| Dizziness | 1% | 3% | 3% | 1% |
| Skin and Appendage | | | | |
| Rash eventRash 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 study occurred with similar frequency in the VIREAD and placebo-treated groups. A summary of Grade 3 and 4 laboratory abnormalities is provided in Table 14.
Table 14 Grade 3/4 Laboratory Abnormalities Reported in ≥1% of VIREAD-Treated Patients 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: >990U/L)
(F: >845 U/L) | 7% | 14% | 12% | 12% |
| Serum Amylase (>175 U/L) | 6% | 7% | 7% | 6% |
| Urine Glucose (≥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/mm3) | 1% | 1% | 2% | 1% |
Post Marketing Experience
The following events have been identified during post-approval use of VIREAD. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting or potential causal connection to VIREAD.
IMMUNE SYSTEM DISORDERS
Allergic reaction
METABOLISM AND NUTRITION DISORDERS
Hypophosphatemia, Lactic acidosis
RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS
Dyspnea
GASTROINTESTINAL DISORDERS
Abdominal pain, Increased amylase, Pancreatitis
HEPATOBILIARY DISORDERS
Increased liver enzymes, Hepatitis
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
Rash
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
Myopathy, Osteomalacia (both associated with proximal renal tubulopathy)
RENAL AND URINARY DISORDERS
Renal insufficiency, Renal failure, Acute renal failure, Fanconi syndrome, Proximal tubulopathy, Proteinuria, Increased creatinine, Acute tubular necrosis, Nephrogenic diabetes insipidus, Polyuria, Interstitial nephritis (including acute cases).
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
Asthenia
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