The following adverse reactions are described in greater detail in other sections:
- Severe skin and hypersensitivity reactions [see Warnings and Precautions (5.1)].
- Immune reconstitution syndrome [see Warnings and Precautions (5.3)].
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.
Clinical Trials Experience in Adults
The safety assessment is based on all data from 1203 subjects in the Phase 3 placebo-controlled trials, TMC125-C206 and TMC125-C216, conducted in antiretroviral treatment-experienced HIV-1-infected adult subjects, 599 of whom received INTELENCE (200 mg twice daily). In these pooled trials, the median exposure for subjects in the INTELENCE arm and placebo arm was 52.3 and 51.0 weeks, respectively. Discontinuations due to adverse drug reactions (ADRs) were 5.2% in the INTELENCE arm and 2.6% in the placebo arm.
The most frequently reported ADR at least Grade 2 in severity was rash (10.0%). Stevens-Johnson syndrome, drug hypersensitivity reaction and erythema multiforme were reported in less than 0.1% of subjects during clinical development with INTELENCE [see Warnings and Precautions (5.1)]. A total of 2.2% of HIV-1-infected subjects in Phase 3 trials receiving INTELENCE discontinued due to rash. In general, in clinical trials, rash was mild to moderate, occurred primarily in the second week of therapy, and was infrequent after Week 4. Rash generally resolved within 1 to 2 weeks on continued therapy. The incidence of rash was higher in women compared to men in the INTELENCE arm in the Phase 3 trials (rash ≥ Grade 2 was reported in 9/60 [15.0%] women versus 51/539 [9.5%] men; discontinuations due to rash were reported in 3/60 [5.0%] women versus 10/539 [1.9%] men) [see Warnings and Precautions (5.1)]. Patients with a history of NNRTI-related rash did not appear to be at increased risk for the development of INTELENCE-related rash compared to patients without a history of NNRTI-related rash.
Common Adverse Reactions
Clinical ADRs of moderate intensity or greater (greater than or equal to Grade 2) and reported in at least 2% of subjects treated with INTELENCE and occurring at a higher rate compared to placebo (excess of 1%) are presented in Table 2. Laboratory abnormalities considered ADRs are included in Table 3.
|Preferred Term||INTELENCE + BRN=599%||Placebo + BRN=604%|
|N=total number of subjects per treatment group; BR=background regimen|
Less Common Adverse Reactions
Treatment-emergent ADRs occurring in less than 2% of subjects (599 subjects) receiving INTELENCE and of at least moderate intensity (greater than or equal to Grade 2) are listed below by body system:
Cardiac Disorders: myocardial infarction, angina pectoris, atrial fibrillation
Ear and Labyrinth Disorders: vertigo
Eye Disorders: blurred vision
Gastrointestinal Disorders: gastroesophageal reflux disease, flatulence, gastritis, abdominal distension, pancreatitis, constipation, dry mouth, hematemesis, retching, stomatitis
General Disorders and Administration Site Conditions: sluggishness
Hematologic Disorders: hemolytic anemia
Hepatobiliary Disorders: hepatic failure, hepatomegaly, cytolytic hepatitis, hepatic steatosis, hepatitis
Immune System Disorders: drug hypersensitivity, immune reconstitution syndrome
Metabolism and Nutrition Disorders: diabetes mellitus, anorexia, dyslipidemia
Nervous System Disorders: paresthesia, somnolence, convulsion, hypoesthesia, amnesia, syncope, disturbance in attention, hypersomnia, tremor
Psychiatric Disorders: anxiety, sleep disorders, abnormal dreams, confusional state, disorientation, nervousness, nightmares
Renal and Urinary Disorders: acute renal failure
Reproductive System and Breast Disorders: gynecomastia
Respiratory, Thoracic and Mediastinal Disorders: exertional dyspnea, bronchospasm
Skin and Subcutaneous Tissue Disorders: night sweats, lipohypertrophy, prurigo, hyperhidrosis, dry skin, swelling face
Additional ADRs of at least moderate intensity observed in other trials were acquired lipodystrophy, angioneurotic edema, erythema multiforme and hemorrhagic stroke, each reported in no more than 0.5% of subjects.
Laboratory Abnormalities in Treatment-Experienced Patients
Selected Grade 2 to Grade 4 laboratory abnormalities that represent a worsening from baseline observed in adult subjects treated with INTELENCE are presented in Table 3.
|Laboratory Parameter||DAIDS Toxicity Range||INTELENCE + BRN=599%||Placebo + BRN=604%|
|ULN=Upper Limit of Normal; BR=background regimen|
|Grade 2||> 1.5–2 × ULN||7%||8%|
|Grade 3||> 2–5 × ULN||7%||8%|
|Grade 4||> 5 × ULN||2%||1%|
|Grade 2||> 1.5–3 × ULN||4%||6%|
|Grade 3||> 3–5 × ULN||2%||2%|
|Grade 4||> 5 × ULN||1%||< 1%|
|Grade 2||> 1.4–1.8 × ULN||6%||5%|
|Grade 3||> 1.9–3.4 × ULN||2%||1%|
|Grade 4||> 3.4 × ULN||0%||< 1%|
|Grade 2||90–99 g/L||2%||4%|
|Grade 3||70–89 g/L||< 1%||< 1%|
|Grade 4||< 70 g/L||< 1%||< 1%|
|White blood cell count|
|Grade 4||< 1,000/mm3||1%||< 1%|
|Grade 4||< 500/mm3||2%||3%|
|Grade 4||< 25,000/mm3||< 1%||< 1%|
|LIPIDS AND GLUCOSE|
|Grade 2||> 6.20–7.77 mmol/L240–300 mg/dL||20%||17%|
|Grade 3||> 7.77 mmol/L> 300 mg/dL||8%||5%|
|Low density lipoprotein|
|Grade 2||4.13–4.9 mmol/L160–190 mg/dL||13%||12%|
|Grade 3||> 4.9 mmol/L> 190 mg/dL||7%||7%|
|Grade 2||5.65–8.48 mmol/L500–750 mg/dL||9%||7%|
|Grade 3||8.49–13.56 mmol/L751–1200 mg/dL||6%||4%|
|Grade 4||> 13.56 mmol/L> 1200 mg/dL||4%||2%|
|Elevated glucose levels|
|Grade 2||6.95–13.88 mmol/L161–250 mg/dL||15%||13%|
|Grade 3||13.89–27.75 mmol/L251–500 mg/dL||4%||2%|
|Grade 4||> 27.75 mmol/L> 500 mg/dL||0%||< 1%|
|Alanine amino transferase|
|Grade 2||2.6–5 × ULN||6%||5%|
|Grade 3||5.1–10 × ULN||3%||2%|
|Grade 4||> 10 × ULN||1%||< 1%|
|Aspartate amino transferase|
|Grade 2||2.6–5 × ULN||6%||8%|
|Grade 3||5.1–10 × ULN||3%||2%|
|Grade 4||> 10 × ULN||< 1%||< 1%|
Patients Co-Infected With Hepatitis B and/or Hepatitis C Virus
In Phase 3 trials TMC125-C206 and TMC125-C216, 139 subjects (12.3%) with chronic hepatitis B and/or hepatitis C virus co-infection out of 1129 subjects were permitted to enroll. AST and ALT abnormalities occurred more frequently in hepatitis B and/or hepatitis C virus co-infected subjects for both treatment groups. Grade 2 or higher laboratory abnormalities that represent a worsening from baseline of AST, ALT or total bilirubin occurred in 27.8%, 25.0% and 7.1% respectively, of INTELENCE-treated co-infected subjects as compared to 6.7%, 7.5% and 1.8% of non-co-infected INTELENCE-treated subjects. In general, adverse events reported by INTELENCE-treated subjects with hepatitis B and/or hepatitis C virus co-infection were similar to INTELENCE-treated subjects without hepatitis B and/or hepatitis C virus co-infection.
Clinical Trials Experience in Pediatric Subjects (2 Years to Less Than 18 years of age)
The safety assessment in pediatric subjects is based on two single-arm trials. TMC125-C213 is a Phase 2 trial in which 101 antiretroviral treatment-experienced HIV-1 infected pediatric subjects 6 years to less than 18 years of age received INTELENCE in combination with other antiretroviral agents (Week 24 analysis). TMC125-C234/IMPAACT P1090 is a Phase 1/2 trial in which 20 antiretroviral treatment-experienced HIV-1 infected pediatric subjects 2 years to less than 6 years of age received INTELENCE in combination with other antiretroviral agents (Week 24 analysis) [see Clinical Studies (14.2)].
In TMC125-C213, the frequency, type and severity of adverse drug reactions in pediatric subjects 6 years to less than 18 years of age were comparable to those observed in adult subjects, except for rash which was observed more frequently in pediatric subjects. The most common adverse drug reactions in at least 2% of pediatric subjects were rash and diarrhea. Rash was reported more frequently in female subjects than in male subjects (rash ≥ Grade 2 was reported in 13/64 [20.3%] females versus 2/37 [5.4%] males; discontinuations due to rash were reported in 4/64 [6.3%] females versus 0/37 [0%] males). Rash (greater than or equal to Grade 2) occurred in 15% of pediatric subjects from 6 years to less than 18 years of age. In the majority of cases, rash was mild to moderate, of macular/papular type, and occurred in the second week of therapy. Rash was self-limiting and generally resolved within 1 week on continued therapy. The safety profile for subjects who completed 48 weeks of treatment was similar to the safety profile for subjects who completed 24 weeks of treatment.
In TMC125-C234/IMPAACT P1090, the frequency, type and severity of adverse drug reactions in pediatric subjects 2 years to less than 6 years of age through Week 24 were comparable to those observed in adults. The most common adverse drug reactions (any grade) of pediatric subjects were rash (50% [10/20]) and diarrhea (25% [5/20]). In this age group, no subjects had Grade 3 or Grade 4 rash and no subjects discontinued prematurely due to rash. One subject discontinued etravirine due to asymptomatic lipase elevation.
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