ADVERSE REACTIONS
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.
The safety assessment is based on all data from 1203 subjects in the ongoing 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 b.i.d.). In these pooled trials, the median exposure for subjects in the INTELENCE™ arm and placebo arm was 30.0 and 29.1 weeks, respectively.
The most commonly (> 10%) reported adverse events of all intensities and regardless of causality that occurred at a higher rate in INTELENCE™-treated subjects as compared to placebo-treated subjects are presented in Table 1.
Table 1: Adverse Events of All Intensities and Regardless of Causality at a Higher Rate Compared to Placebo in > 10% of Adult Subjects in the INTELENCE™ Treatment Groups | Pooled TMC125-C206 and TMC125-C216 Trials |
System Organ Class, Preferred Term,
% | INTELENCE™ + BR
N=599 | Placebo + BR
N=604 |
| N=total number of subjects per treatment group, BR=background regimen |
| Gastrointestinal Disorders | |
| Nausea | 13.9% | 11.1% |
| Skin and Subcutaneous Tissue Disorders | |
| Rash (any type) | 16.9% | 9.3% |
The most frequently reported adverse drug reaction (ADR) at least Grade 2 in severity was rash (9.0%). Stevens-Johnson syndrome, hypersensitivity reaction, and erythema multiforme were reported in < 0.1% of subjects during clinical development with INTELENCE™. A total of 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 1-2 weeks on continued therapy [ see Warnings and Precautions ]. The incidence of rash was higher in women compared to men in the INTELENCE™ arm. 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
ADRs of moderate intensity or greater (≥ Grade 2) and reported in ≥ 2% of subjects treated with INTELENCE™ are presented in Table 2. Laboratory abnormalities considered ADRs are included in Table 3.
Table 2: Treatment-Emergent Adverse ReactionsIncludes adverse reactions at least possibly, probably, or very likely related to the drug. of at least Moderate IntensityIntensities are defined as follows: Moderate (discomfort enough to cause interference with usual activity); Severe (incapacitating with inability to work or do usual activity). (Grades 2-4) in ≥ 2% of Adult Subjects in the INTELENCE™ Treatment Groups System Organ Class, Preferred Term,
% | Pooled TMC125-C206 and TMC125-C216 Trials |
INTELENCE™ + BR
N=599 | Placebo + BR
N=604 |
| N=total number of subjects per treatment group, BR=background regimen |
| Gastrointestinal Disorders | |
| Diarrhea | 5.2% | 9.6% |
| Nausea | 4.7% | 3.5% |
| Abdominal pain | 3.0% | 2.5% |
| Vomiting | 2.3% | 2.0% |
| General Disorders and Administration Site Conditions | |
| Fatigue | 3.3% | 4.0% |
| Nervous System Disorders | |
| Peripheral neuropathy | 2.8% | 1.8% |
| Headache | 2.7% | 4.1% |
| Skin and Subcutaneous Tissue Disorders | |
| Rash | 9.0% | 3.1% |
| Vascular Disorders | |
| Hypertension | 2.8% | 2.2% |
Less Common Adverse Reactions
Treatment-emergent ADRs occurring in less than 2% of subjects (n=599) receiving INTELENCE™ and of at least moderate intensity (≥ 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: anemia, hemolytic anemia
Hepatobiliary Disorders: cytolytic hepatitis, hepatic steatosis, hepatitis, hepatomegaly
Immune System Disorders: drug hypersensitivity, immune reconstitution syndrome
Metabolism and Nutrition Disorders: diabetes mellitus, dyslipidemia, anorexia
Nervous System Disorders: paraesthesia, somnolence, convulsion, hypoesthesia, syncope, amnesia, hypersomnia, tremor
Psychiatric Disorders: insomnia, anxiety, sleep disorders, abnormal dreams, confusional state, disorientation, nervousness, nightmares
Renal and Urinary Disorders: renal failure
Reproductive System and Breast Disorders: gynecomastia
Respiratory,Thoracic and Mediastinal Disorders: exertional dyspnea, bronchospasm
Skin and Subcutaneous Tissue Disorders: night sweats, hyperhidrosis, prurigo, dry skin, lipohypertrophy, swelling face
Additional ADRs of at least moderate intensity observed in other trials were acquired lipodystrophy, angioneurotic edema, erythema multiforme and haemorrhagic 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.
Table 3: Selected Grade 2 to 4 Laboratory Abnormalities Observed in Treatment-Experienced Subjects | | Pooled TMC125-C206 and TMC125-C216 Trials |
Laboratory Parameter Preferred Term,
% | DAIDS Toxicity Range | INTELENCE™ + BR
N=599 | Placebo + BR
N=604 |
| ULN=Upper Limit of Normal, BR=background regimen |
| GENERAL BIOCHEMISTRY | | | |
| Pancreatic amylase | | | |
| Grade 2 | > 1.5-2 — ULN | 5.9% | 7.3% |
| Grade 3 | > 2-5 — ULN | 6.3% | 7.0% |
| Grade 4 | > 5 — ULN | 1.2% | 1.0% |
| Lipase | | | |
| Grade 2 | > 1.5-3 — ULN | 3.4% | 4.8% |
| Grade 3 | > 3-5 — ULN | 1.7% | 1.2% |
| Grade 4 | > 5—ULN | 1.0% | 0.5% |
| Creatinine | | | |
| Grade 2 | > 1.4-1.8 — ULN | 4.7% | 4.0% |
| Grade 3 | > 1.9-3.4 — ULN | 1.9% | 1.2% |
| Grade 4 | > 3.4 — ULN | 0% | 0.2% |
| HEMATOLOGY | | | |
| Decreased hemoglobin | | | |
| Grade 2 | 90-99 g/L | 1.9% | 3.5% |
| Grade 3 | 70-89 g/L | 1.0% | 0.7% |
| Grade 4 | < 70 g/L | 0.7% | 0.7% |
| Neutrophils | | | |
| Grade 2 | 750-999/mm3 | 4.4% | 5.3% |
| Grade 3 | 500-749/mm3 | 2.7% | 3.5% |
| Grade 4 | < 500/mm3 | 1.0% | 2.8% |
| Platelet count | | | |
| Grade 2 | 50,000-99,999/mm3 | 2.9% | 4.5% |
| Grade 3 | 25,000-49,999/mm3 | 1.2% | 0.8% |
| Grade 4 | < 25,000/mm3 | 0.2% | 0.2% |
| LIPIDS AND GLUCOSE | | | |
| Total cholesterol | | | |
| Grade 2 | > 6.20-7.77 mmol/L
240-300 mg/dL | 18.0% | 12.6% |
| Grade 3 | > 7.77 mmol/L
> 300 mg/dL | 5.8% | 4.1% |
| Low density lipoprotein | | | |
| Grade 2 | 4.13-4.9 mmol/L
160-190 mg/dL | 11.5% | 9.1% |
| Grade 3 | > 4.9 mmol/L
> 190 mg/dL | 5.2% | 5.4% |
| Triglycerides | | | |
| Grade 2 | 5.65-8.48 mmol/L
500 —750 mg/dL | 7.1% | 6.5% |
| Grade 3 | 8.49-13.56 mmol/L
751 - 1200 mg/dL | 4.1% | 3.0% |
| Grade 4 | > 13.56 mmol/L
> 1200 mg/dL | 2.9% | 1.3% |
| Elevated glucose levels | | | |
| Grade 2 | 6.95-13.88 mmol/L
161-250 mg/dL | 13.1% | 10.8% |
| Grade 3 | 13.89-27.75 mmol/L
251 — 500 mg/dL | 2.5% | 1.8% |
| Grade 4 | > 27.75 mmol/L
> 500 mg/dL | 0% | 0.2% |
| HEPATIC PARAMETERS | | | |
| Alanine amino transferase | | | |
| Grade 2 | 2.6-5 — ULN | 5.4% | 4.0% |
| Grade 3 | 5.1-10 — ULN | 1.9% | 1.3% |
| Grade 4 | > 10 — ULN | 0.7% | 0.3% |
| Aspartate amino transferase | | | |
| Grade 2 | 2.6-5 — ULN | 5.1% | 6.5% |
| Grade 3 | 5.1-10 — ULN | 2.0% | 1.3% |
| Grade 4 | > 10 — ULN | 0.5% | 0.3% |
Patients co-infected with hepatitis B and/or hepatitis C virus
In Phase 3 trials TMC125-C206 and TMC125-C216, 140 subjects (12.4%) with chronic hepatitis B and/or hepatitis C virus co-infection out of 1130 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 22.8%, 21.4% and 5.7% respectively, of INTELENCE™-treated co-infected subjects as compared to 5.5%, 6.1% and 1.2% 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.
Postmarketing Experience
The following events have been identified during postmarketing use of INTELENCE™. Because these events are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Fatal cases of toxic epidermal necrolysis have been reported. Severe hypersensitivity reactions including cases of hepatic failure have been reported [ see Warnings and Precautions ].
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