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Overview
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Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Indications
INTELENCE®1, in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-experienced patients ages 6 years and older, who have evidence of viral replication and HIV-1 strains resistant to a non-nucleoside reverse transcriptase inhibitor (NNRTI) and other antiretroviral agents.
The indication for adult use is based on Week 48 analyses from 2 randomized, double-blind, placebo-controlled trials of INTELENCE®. Both studies were conducted in clinically advanced, 3-class antiretroviral (NNRTI, N[t]RTI, PI) treatment-experienced adults. The indication for pediatric use is based on 24-week analyses of a single-arm, Phase 2 trial in antiretroviral treatment-experienced pediatric subjects 6 years to less than 18 years of age.
In treatment-experienced adult and pediatric patients, the following points should be considered when initiating therapy with INTELENCE®:
Treatment history and resistance testing should guide the use of INTELENCE® due to concerns for potential cross-resistance .
In patients who have experienced virologic failure on an NNRTI-containing regimen, do not use INTELENCE® in combination with only N[t]RTIs .
The use of other active antiretroviral agents with INTELENCE® is associated with an increased likelihood of treatment response.
The safety and efficacy of INTELENCE® have not been established in treatment-naïve adult patients.
Dosage
The recommended oral dose of INTELENCE® tablets is 200 mg (one 200 mg tablet or two 100 mg tablets) taken twice daily following a meal. The type of food does not affect the exposure to etravirine.
DOSAGE FORMS AND STRENGTHS
INTELENCE® 25 mg Tablets
INTELENCE® 25 mg tablets are supplied as white to off-white, oval, scored tablets debossed with "TMC" on one side.
INTELENCE® 100 mg Tablets
INTELENCE® 100 mg tablets are supplied as white to off-white oval tablets debossed with "TMC125" on one side and "100" on the other side.
INTELENCE® 200 mg Tablets
INTELENCE® 200 mg tablets are supplied as white to off-white, biconvex, oblong tablets debossed with "T200" on one side.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Etravirine in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Etravirine in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Indications
INTELENCE®1, in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-experienced patients ages 6 years and older, who have evidence of viral replication and HIV-1 strains resistant to a non-nucleoside reverse transcriptase inhibitor (NNRTI) and other antiretroviral agents.
The indication for adult use is based on Week 48 analyses from 2 randomized, double-blind, placebo-controlled trials of INTELENCE®. Both studies were conducted in clinically advanced, 3-class antiretroviral (NNRTI, N[t]RTI, PI) treatment-experienced adults. The indication for pediatric use is based on 24-week analyses of a single-arm, Phase 2 trial in antiretroviral treatment-experienced pediatric subjects 6 years to less than 18 years of age.
In treatment-experienced pediatric patients, the following points should be considered when initiating therapy with INTELENCE®:
Treatment history and resistance testing should guide the use of INTELENCE® due to concerns for potential cross-resistance .
In patients who have experienced virologic failure on an NNRTI-containing regimen, do not use INTELENCE® in combination with only N[t]RTIs .
The use of other active antiretroviral agents with INTELENCE® is associated with an increased likelihood of treatment response.
The safety and efficacy of INTELENCE® have not been established in treatment-naïve adult patients.
Dosage
Pediatric Patients (6 years to less than 18 years of age)
The recommended dose of INTELENCE® for pediatric patients 6 years to less than 18 years of age and weighing at least 16 kg is based on body weight (see TABLE BELOW) not exceeding the recommended adult dose. INTELENCE® tablet(s) should be taken orally, following a meal. The type of food does not affect the exposure to etravirine.
This image is provided by the National Library of Medicine.
The safety and efficacy of INTELENCE® have not been established in children less than 6 years of age
DOSAGE FORMS AND STRENGTHS
INTELENCE® 25 mg Tablets
INTELENCE® 25 mg tablets are supplied as white to off-white, oval, scored tablets debossed with "TMC" on one side.
INTELENCE® 100 mg Tablets
INTELENCE® 100 mg tablets are supplied as white to off-white oval tablets debossed with "TMC125" on one side and "100" on the other side.
INTELENCE® 200 mg Tablets
INTELENCE® 200 mg tablets are supplied as white to off-white, biconvex, oblong tablets debossed with "T200" on one side.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Etravirine in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Etravirine in pediatric patients.
Contraindications
None
Warnings
Severe Skin and Hypersensitivity Reactions
Severe, potentially life-threatening, and fatal skin reactions have been reported. These include cases of Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme. Hypersensitivity reactions including drug rash with eosinophilia and Systemic Symptoms (DRESS) have also been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure. In Phase 3 clinical trials, Grade 3 and 4 rashes were reported in 1.3% of subjects receiving INTELENCE® compared to 0.2% of placebo subjects. A total of 2.2% of HIV-1-infected subjects receiving INTELENCE® discontinued from Phase 3 trials due to rash. Rash occurred most commonly during the first 6 weeks of therapy. The incidence of rash was higher in females.
Discontinue INTELENCE® immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema). Clinical status including liver transaminases should be monitored and appropriate therapy initiated. Delay in stopping INTELENCE® treatment after the onset of severe rash may result in a life-threatening reaction.
Fat Redistribution
Redistribution/accumulation of body fat, including central obesity, dorso cervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including INTELENCE®. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia (PCP) or tuberculosis), which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.
Adverse Reactions
Clinical Trials Experience
The following adverse reactions are described in greater detail in other sections:
Severe skin and hypersensitivity reactions
Clinical Trials Experience: Adults
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 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). 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 1. Laboratory abnormalities considered ADRs are included in Table 2.
This image is provided by the National Library of Medicine.
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:
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.
This image is provided by the National Library of Medicine.
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: Pediatric Subjects (6 years to less than 18 years of age)
The safety assessment in children and adolescents is based on the Week 24 analysis of the single-arm, Phase 2 trial TMC125-C213 in which 101 antiretroviral treatment-experienced HIV-1 infected subjects 6 years to less than 18 years of age and weighing at least 16 kg received INTELENCE® in combination with other antiretroviral agents. The frequency, type and severity of adverse drug reactions in pediatric subjects 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. 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.
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 DRESS and cases of hepatic failure have been reported.
Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis
Skin and Subcutaneous Tissue Disorders: Fatal cases of toxic epidermal necrolysis have been reported.
Drug Interactions
Etravirine is a substrate of CYP3A, CYP2C9, and CYP2C19. Therefore, co-administration of INTELENCE® with drugs that induce or inhibit CYP3A, CYP2C9, and CYP2C19 may alter the therapeutic effect or adverse reaction profile of INTELENCE® (see TABLE 3).
Etravirine is an inducer of CYP3A and inhibitor of CYP2C9, CYP2C19 and P-glycoprotein. Therefore, co-administration of drugs that are substrates of CYP3A, CYP2C9 and CYP2C19 or are transported by P-glycoprotein with INTELENCE® may alter the therapeutic effect or adverse reaction profile of the co-administered drug(s) (see TABLE 3).
Table 3 shows the established and other potentially significant drug interactions based on which, alterations in dose or regimen of INTELENCE® and/or co-administered drug may be recommended. Drugs that are not recommended for co-administration with INTELENCE® are also included in Table 3.
This image is provided by the National Library of Medicine.
In addition to the drugs included in Table 3, the interaction between INTELENCE® and the following drugs were evaluated in clinical studies and no dose adjustment is needed for either drug: didanosine, enfuvirtide (ENF),ethinylestradiol/norethindrone, omeprazole, paroxetine, raltegravir, ranitidine, and tenofovir disoproxil fumarate.
No adequate and well-controlled studies of INTELENCE® use in pregnant women have been conducted. In addition, no pharmacokinetic studies have been conducted in pregnant patients. INTELENCE® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Antiretroviral Pregnancy Registry
To monitor maternal-fetal outcomes of pregnant women exposed to INTELENCE®, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
Animal Data
Reproductive and developmental toxicity studies were performed in rabbits (at oral doses up to 375 mg per kg per day) and rats (at oral doses up to 1000 mg per kg per day). In both species, no treatment-related embryo-fetal effects including malformations were observed. In addition, no treatment-related effects were observed in a separate pre- and postnatal study performed in rats at oral doses up to 500 mg per kg per day. The systemic drug exposures achieved in these animal studies were equivalent to those at the recommended human dose (400 mg per day).
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Etravirine in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Etravirine during labor and delivery.
Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. It is not known whether etravirine is secreted in human milk. Because of both the potential for HIV transmission and the potential for adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving INTELENCE®.
Pediatric Use
Treatment with INTELENCE® is not recommended in children less than 6 years of age. The pharmacokinetics, safety, tolerability and efficacy of INTELENCE® in children less than 6 years of age have not been established.
The safety, pharmacokinetic profile, and virologic and immunologic responses of INTELENCE® were evaluated in treatment-experienced HIV-1-infected pediatric subjects 6 years to less than 18 years of age and weighing at least 16 kg. Frequency, type, and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adults, except for rash. Please see DOSAGE AND ADMINISTRATION (2.2) for dosing recommendations for pediatric subjects 6 years to less than 18 years of age and weighing at least 16 kg.
Geriatic Use
There is no FDA guidance on the use of Etravirine with respect to geriatric patients.
Gender
There is no FDA guidance on the use of Etravirine with respect to specific gender populations.
Race
There is no FDA guidance on the use of Etravirine with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Etravirine in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Etravirine in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Etravirine in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Etravirine in patients who are immunocompromised.
Administration and Monitoring
Administration
Oral
Intravenous
Monitoring
There is limited information regarding Monitoring of Etravirine in the drug label.
Description
IV Compatibility
There is limited information regarding IV Compatibility of Etravirine in the drug label.
Overdosage
Acute Overdose
Signs and Symptoms
Description
Management
Description
Chronic Overdose
There is limited information regarding Chronic Overdose of Etravirine in the drug label.
Pharmacology
There is limited information regarding Etravirine Pharmacology in the drug label.
