Intelence Side Effects

Generic Name: etravirine

Please note - some side effects for Intelence may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Intelence - for the Consumer

Intelence

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Intelence:

Mild burning, numbness, or tingling of the arms, hands, legs, or feet.

Seek medical attention right away if any of these SEVERE side effects occur when using Intelence:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the eyes, mouth, face, lips, throat, or tongue; unusual hoarseness); bloody vomit or vomit that looks like coffee grounds; blurred vision or other vision changes; change in amount of urine; chest, jaw, or left arm pain; dark urine; fainting; fever or general feeling of being unwell; irregular heartbeat; joint pain; loss of appetite; mood or mental changes (eg, anxiety, confusion, memory loss); muscle pain, tenderness, or weakness; pale stools; persistent burning, numbness, pain, or tingling of the arms, legs, hands, or feet; reddened, blistered, swollen, or peeling skin; seizures; severe or persistent dizziness, drowsiness, or headache; severe rash or rash with fever, mouth sores, or red and irritated eyes; severe stomach pain with or without nausea and vomiting; shortness of breath; unusual tiredness or weakness; yellowing of the skin or eyes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Intelence Side Effects - for the Professional

Intelence

The following adverse reactions are described in greater detail in other sections:

• Severe skin and hypersensitivity reactions [see Warnings and Precautions (5.1)].

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 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 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 < 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 1–2 weeks on continued therapy. The incidence of rash was higher in women compared to men in the Intelence® arm in the Phase 3 trials. 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 (≥ Grade 2) and reported in ≥ 2% of subjects treated with Intelence® and occurring at a higher rate compared to placebo (excess of 1%) are presented in Table 1. Laboratory abnormalities considered ADRs are included in Table 2.

Table 1: Treatment-Emergent Adverse Reactions* of at least Moderate Intensity† (Grades 2–4) in ≥ 2% of Adult Subjects in the Intelence® Treatment Groups and at a higher rate compared to placebo (excess of 1%)

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
* Includes adverse reactions at least possibly, probably, or very likely related to the drug. † Intensities are defined as follows: Moderate (discomfort enough to cause interference with usual activity); Severe (incapacitating with inability to work or do usual activity).
Nervous System Disorders
Peripheral neuropathy	4%	2%
Skin and Subcutaneous Tissue Disorders
Rash	10%	3%

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: 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: paraesthesia, 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 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 2.

Table 2: 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	7%	8%
Grade 3	> 2–5 × ULN	7%	8%
Grade 4	> 5 × ULN	2%	1%
Lipase
Grade 2	> 1.5–3 × ULN	4%	6%
Grade 3	> 3–5 × ULN	2%	2%
Grade 4	> 5×ULN	1%	< 1%
Creatinine
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%
HEMATOLOGY
Decreased hemoglobin
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 2	1,500–1,999/mm3	2%	3%
Grade 3	1,000–1,499/mm3	1%	4%
Grade 4	< 1,000/mm3	1%	< 1%
Neutrophils
Grade 2	750–999/mm3	5%	6%
Grade 3	500–749/mm3	4%	4%
Grade 4	< 500/mm3	2%	3%
Platelet count
Grade 2	50,000–99,999/mm3	3%	5%
Grade 3	25,000–49,999/mm3	1%	1%
Grade 4	< 25,000/mm3	< 1%	< 1%
LIPIDS AND GLUCOSE
Total cholesterol
Grade 2	> 6.20–7.77 mmol/L 240–300 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/L 160–190 mg/dL	13%	12%
Grade 3	> 4.9 mmol/L > 190 mg/dL	7%	7%
Triglycerides
Grade 2	5.65–8.48 mmol/L 500 –750 mg/dL	9%	7%
Grade 3	8.49–13.56 mmol/L 751 – 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/L 161–250 mg/dL	15%	13%
Grade 3	13.89–27.75 mmol/L 251 – 500 mg/dL	4%	2%
Grade 4	> 27.75 mmol/L > 500 mg/dL	0%	< 1%
HEPATIC PARAMETERS
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.

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.

Immune System Disorders: Severe hypersensitivity reactions including cases of hepatic failure have been reported [see Warnings and Precautions (5.1)].

Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis

Skin and Subcutaneous Tissue Disorders: Fatal cases of toxic epidermal necrolysis have been reported [see Warnings and Precautions (5.1)].

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Side Effects by Body System - for Healthcare Professionals

General

The safety report of etravirine is based on 599 HIV-1-infected, treatment-experienced patients receiving 200 mg twice daily in combination with background regimen (BR). The median exposure was 52.3 weeks. The most common side effects of moderate to severe intensity reported with etravirine and BR, regardless of causality, were peripheral neuropathy and rash. A total of 2.2% of HIV-1-infected patients in Phase 3 trials receiving etravirine discontinued due to rash.

Dermatologic

During clinical trials, rash generally was mild to moderate, occurred chiefly in the second week of therapy, and was infrequent after the fourth week. Rash usually resolved within 1 to 2 weeks on continued use of the drug. The incidence of rash was higher in women taking etravirine compared to men. Patients with a history of nonnucleoside reverse transcriptase inhibitor-related rash did not appear to be at increased risk.

Dermatologic side effects have included rash (16.9%, all intensities), regardless of causality. Side effects reported of at least moderate intensity have included rash (9.0%) and in less than 2% of patients, dry skin, face swelling, hyperhidrosis, lipohypertrophy, night sweats, and prurigo. Contact dermatitis, erythema, and pruritus have also been reported.

Gastrointestinal

Gastrointestinal side effects have included nausea (13.9%, all intensities), regardless of causality. Side effects reported of at least moderate intensity have included diarrhea (5.2%), nausea (4.7%), abdominal pain (3.0%), vomiting (2.3%), and in less than 2% of patients, abdominal distension, constipation, dry mouth, flatulence, gastritis, gastroesophageal reflux disease, hematemesis, pancreatitis, retching, and stomatitis.

Nervous system

Nervous system side effects of at least moderate intensity have included peripheral neuropathy (up to 4%), headache (2.7%), and in less than 2% of patients, amnesia, convulsion, disturbance in attention, hypersomnia, hypoesthesia, paresthesia, somnolence, syncope, tremor, and vertigo.

Hypersensitivity

Hypersensitivity side effects have included Stevens-Johnson syndrome, drug hypersensitivity reaction, and erythema multiforme in less than 0.1% of patients during clinical development. Erythema multiforme (no more than 0.5%, at least moderate intensity) has been reported in other trials. Severe hypersensitivity reactions (including cases of hepatic failure) and fatal cases of toxic epidermal necrolysis have been reported during postmarketing experience.

Cardiovascular

Cardiovascular side effects of at least moderate intensity have included hypertension (2.8%); in less than 2% of patients, angina pectoris, atrial fibrillation, and myocardial infarction; and in no more than 0.5%, angioneurotic edema and hemorrhagic stroke. Mild atrioventricular block has also been reported.

Metabolic

Metabolic side effects of at least moderate intensity have included anorexia, diabetes mellitus, and dyslipidemia in less than 2% of patients and acquired lipodystrophy in no more than 0.5%. Elevated pancreatic amylase (Grade 2: up to 7%, Grade 3: up to 7%, Grade 4: up to 2%), lipase (Grade 2: up to 4%, Grade 3: up to 2%, Grade 4: 1%), total cholesterol (Grade 2: up to 20%, Grade 3: up to 8%), low density lipoprotein (Grade 2: up to 13%, Grade 3: up to 7%), triglycerides (Grade 2: up to 9%, Grade 3: up to 6%, Grade 4: up to 4%), and glucose levels (Grade 2: up to 15%, Grade 3: up to 4%) have been reported.

Hepatic

Hepatic side effects of at least moderate intensity have included cytolytic hepatitis, hepatic steatosis, hepatitis, hepatic failure, and hepatomegaly in less than 2% of patients. Elevated alanine transaminase (ALT; Grade 2: up to 6%, Grade 3: up to 3%, Grade 4: up to 1%), and aspartate transaminase (AST; Grade 2: up to 6%, Grade 3: up to 3%, Grade 4: less than 1%) have been reported. Grade 2 or higher abnormalities representing a worsening from baseline of AST, ALT, and total bilirubin have been reported in 27.8%, 25%, and 7.1%, respectively, in patients coinfected with hepatitis B and/or C virus as compared to 6.7%, 7.5%, and 1.8% reported in non-coinfected patients.

Hematologic

Hematologic side effects of at least moderate intensity have included anemia and hemolytic anemia in less than 2% of patients. Decreased hemoglobin (Grade 2: up to 2%, Grade 3: up to 1%, Grade 4: less than 1%), white blood cell count (Grade 2: 2%, Grade 3: 1%, Grade 4: 1%), neutrophils (Grade 2: up to 5%, Grade 3: up to 4%, Grade 4: up to 2%), and platelet count (Grade 2: up to 3%, Grade 3: up to 1.2%, Grade 4: less than 1%) have been reported.

Renal

Renal side effects of at least moderate intensity have included acute renal failure in less than 2% of patients. Elevated creatinine (Grade 2: up to 6%, Grade 3: up to 2%) has been reported.

Other

Other side effects of at least moderate intensity have included fatigue (3.3%) and sluggishness (less than 2%). Pyrexia has been reported.

Immunologic

Immunologic side effects of at least moderate intensity have included drug hypersensitivity and immune reconstitution syndrome in less than 2% of patients.

Respiratory

Respiratory side effects of at least moderate intensity have included bronchospasm and exertional dyspnea in less than 2% of patients. Pneumonia and nasopharyngitis have also been reported.

Psychiatric

Psychiatric side effects of at least moderate intensity have included abnormal dreams, anxiety, confusional state, disorientation, insomnia, nervousness, nightmares, and sleep disorders in less than 2% of patients.

Endocrine

Endocrine side effects of at least moderate intensity have included gynecomastia in less than 2% of patients.

Ocular

Ocular side effects of at least moderate intensity have included blurred vision in less than 2% of patients.

Musculoskeletal

Musculoskeletal side effects have included at least one case of severe myopathy (including articular pain, muscular pain, weakness, stiffness, and increased creatine kinase). Rhabdomyolysis has been reported during postmarketing experience.

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