Etravirine

Pronunciation: (E-tra-VIR-een)
Class: Antiretroviral agent, NNRTI

Trade Names

Intelence
- Tablets 100 mg

Pharmacology

Binds directly to reverse transcriptase and blocks RNA- and DNA-dependent DNA polymerase activities by disrupting the enzyme's catalytic site.

Pharmacokinetics

Absorption

T _max following oral administration is approximately 2.5 to 4 h. Bioavailability is unknown. Systemic exposure is decreased by approximately 50% when taken under fasting conditions.

Distribution

Protein binding is approximately 99.9%, primarily to albumin.

Metabolism

Etravirine is metabolized by CYP2C9, CYP2C19, and CYP3A4. The major metabolites are 90% less active than etravirine.

Elimination

Elimination is 93.7% in the feces and 1.2% in the urine. 81.2% to 86.4% of the dose recovered in the feces is unchanged etravirine. Mean terminal half-life is 41 h.

Special Populations

Renal Function Impairment

Pharmacokinetics have not been studied.

Hepatic Function Impairment

Etravirine is primarily metabolized by the liver; however, steady-state pharmacokinetics were similar in subjects with healthy, mildly impaired, and moderately impaired hepatic function. The effect of severe hepatic function impairment has not been studied.

Elderly

No difference in pharmacokinetics in patients 18 to 77 y of age.

Children

Pharmacokinetics have not been studied.

Gender

No pharmacokinetic difference has been noted between men and women.

Race

No pharmacokinetic difference has been demonstrated based on race.

Indications and Usage

Treatment of HIV-1 infection in combination with other antiretroviral agents.

Contraindications

None well documented.

Dosage and Administration

Adults

PO 200 mg twice daily following a meal.

General Advice

Tablets should be swallowed whole or may be dispersed in a glass of water. Once dispersed, stir well and drink immediately.
Tablets should be taken following a meal.

Storage/Stability

Store at 59° to 86°F. Protect from moisture.

Drug Interactions

Antiarrhythmic agents (eg, amiodarone, bepridil, disopyramide, flecainide lidocaine [systemic], mexiletine, propafenone, quinidine)

Concentrations of these antiarrhythmics may be decreased when coadministered with etravirine. Use with caution and monitor drug concentrations if available.

Atazanavir/Ritonavir

Atazanavir minimum plasma levels may be reduced while etravirine plasma levels may be increased. Avoid coadministration.

Carbamazepine, phenobarbital, phenytoin

May induce etravirine metabolism, decreasing plasma levels and resulting in loss of efficacy. Avoid coadministration.

Charcoal

Charcoal can decrease absorption of etravirine, reducing its effectiveness or toxicity.

Clarithromycin

Systemic exposure to clarithromycin may be decreased, while exposure to the active metabolite, 14-hydroxy-clarithromycin, may be increased. Consider azithromycin as alternative treatment against Mycobacterium avium complex.

Clopidogrel

Conversion of clopidogrel to its active metabolite may be decreased. Consider alternatives to clopidogrel treatment.

Darunavir/Ritonavir, saquinavir/ritonavir

Etravirine systemic exposure may be reduced. Dosage adjustments do not appear necessary. If etravirine is administered with darunavir/ritonavir or saquinavir/ritonavir, do not coadminister rifabutin because etravirine exposure will be reduced.

Delavirdine

Etravirine plasma levels may be increased. Do not coadminister.

Dexamethasone

Coadminister dexamethasone with caution or use an alternative agent.

Diazepam

Plasma levels may be increased by etravirine. A dosage decrease may be necessary.

Digoxin

When initiating treatment with etravirine and digoxin, start with the lowest dose of digoxin. When initiating etravirine treatment in a patient on a stable digoxin regimen, no dose adjustment in either etravirine or digoxin is needed. Monitor digoxin concentrations and adjust the dose as needed.

Efavirenz, nevirapine, St. John's wort, tipranavir/ritonavir

Etravirine plasma levels may be decreased, resulting in loss of efficacy. Do not coadminister.

Fluconazole, itraconazole, ketoconazole, posaconazole

May inhibit etravirine metabolism, resulting in elevated plasma levels. In addition, etravirine may increase itraconazole and ketoconazole metabolism, resulting in decreased plasma levels of these agents. Dose adjustments for itraconazole, ketoconazole, or posaconazole may be needed.

Food

Etravirine systemic exposure is reduced approximately 50% when administered under fasting conditions compared with after a meal. Always administer etravirine after a meal.

Fosamprenavir, nelfinavir

Plasma levels of amprenavir and nelfinavir may be elevated. Do not administer these protease inhibitors with etravirine without low-dose ritonavir.

Fosamprenavir/Ritonavir

Systemic exposure to amprenavir may be increased. Do not coadminister this combination with etravirine.

HMG-CoA reductase inhibitors (eg, atorvastatin, fluvastatin, lovastatin, simvastatin)

Coadministration may reduce lovastatin and simvastatin plasma levels and increase fluvastatin levels. Dose adjustments may be necessary. The combination of atorvastatin and etravirine may be given without dose adjustments; however, the dose of atorvastatin may need to be altered based on clinical response.

Immunosuppressants (eg, cyclosporine, sirolimus, tacrolimus)

Coadminister etravirine and systemic immunosuppressants with caution because plasma concentrations of cyclosporine, sirolimus, and tacrolimus may be affected.

Indinavir

Plasma levels may be decreased by etravirine. Do not administer without low-dose ritonavir.

Lopinavir/Ritonavir

Systemic exposure to etravirine may be increased. No dosage adjustment is needed.

Maraviroc

Maraviroc plasma concentrations may be reduced when etravirine is administered with maraviroc in the absence of a potent CYP3A inhibitor (eg, ritonavir-boosted protease inhibitor). In this instance, the recommended maraviroc dosage is 600 mg twice daily. Maraviroc plasma concentrations may be increased when etravirine is administered with maraviroc in the presence of a potent CYP3A inhibitor. In this instance, the recommended maraviroc dosage is 150 mg twice daily.

Methadone

Clinical monitoring for withdrawal symptoms is recommended because methadone maintenance therapy may need to be adjusted in some patients.

Phosphodiesterase type 5 inhibitors (eg, sildenafil, tadalafil, vardenafil)

Concomitant use of etravirine with protease inhibitors without coadministration of low-dose ritonavir may cause a significant alteration in the plasma concentrations of the protease inhibitor. Do not coadminister etravirine with protease inhibitors without low-dose ritonavir.

Rifabutin

If etravirine is not coadministered with a protease inhibitor plus ritonavir, rifabutin 300 mg daily is recommended. If etravirine is administered with darunavir/ritonavir or saquinavir/ritonavir, do not coadminister rifabutin because of the potential for reductions in etravirine exposure.

Rifampin, rifapentine

May induce etravirine metabolism, decreasing plasma levels and resulting in loss of efficacy. Avoid coadministration.

Ritonavir

Ritonavir 600 mg twice daily may decrease etravirine plasma levels, resulting in a loss of efficacy. Do not coadminister ritonavir 600 mg twice daily.

Voriconazole

Etravirine and voriconazole plasma levels may be increased. Use with caution.

Warfarin

Warfarin plasma levels may be increased. Monitor anticoagulant parameters.

Adverse Reactions

Cardiovascular

Angina pectoris, atrial fibrillation, MI (less than 2%).

CNS

Peripheral neuropathy (4%); abnormal dreams, anxiety, confusional state, disorientation, disturbance in attention, hypersomnia, hypoesthesia, insomnia, nervousness, nightmares, paresthesia, sleep disorder, sluggishness, somnolence, tremor (less than 2%).

Dermatologic

Rash (10%); dry skin, hyperhidrosis, lipohypertrophy, night sweats, prurigo, swelling face (less than 2%).

EENT

Blurred vision, vertigo (less than 2%).

GI

Abdominal distention, anorexia, constipation, dry mouth, flatulence, gastritis, gastroesophageal reflux disease, hematemesis, pancreatitis, retching, stomatitis (less than 2%).

Genitourinary

Acute renal failure, gynecomastia (less than 2%).

Hematologic-Lymphatic

Anemia, hemolytic anemia (less than 2%).

Hepatic

Cytolytic hepatitis, hepatic failure, hepatic stenosis, hepatitis, hepatomegaly (less than 2%).

Lab Tests

Elevated total cholesterol (20%); elevated glucose (15%); elevated LDL (13%); elevated triglycerides (9%); elevated ALT, AST, and creatinine (6%).

Metabolic-Nutritional

Diabetes mellitus, dyslipidemia (less than 2%).

Respiratory

Bronchospasm, external dyspnea (less than 2%).

Miscellaneous

Drug hypersensitivity, immune reconstitution syndrome (less than 2%).

Precautions

Pregnancy

Category B .

Lactation

Undetermined. HIV-infected mothers should not breast-feed to avoid potential transmission of HIV to infant.

Children

Safety and efficacy not established.

Fat redistribution

Redistribution/accumulation of body fat, including breast enlargement, central obesity, cushingoid appearance, dorsocervical fat enlargement (buffalo hump), and peripheral wasting, have been reported.

Immune reconstitution syndrome

Has been reported in patients treated with combination antiretroviral therapy.

Skin reactions

Severe, potentially life-threatening, and fatal skin reactions, including Stevens-Johnson syndrome, TEN, hypersensitivity reaction, and erythema multiforme, may occur.

Overdosage

Symptoms

Experience is limited.

Patient Information

Warn patient that this drug is not to be used by itself, but in combination with other antiretroviral agents, and not to change the dose or stop taking any other antiviral agents unless advised by health care provider.
Advise patient not to take etravirine on an empty stomach and that the type of food is not important.
Advise patients to take tablets whole with a liquid, such as water, and not to chew the tablets. If the tablets cannot be swallowed whole, they may be placed in a glass of water and stirred well until water looks milky; then drink immediately, rinsing the glass with water several times, swallowing the rinse each time to make sure the entire dose is taken.
Advise patient that etravirine may cause changes in body fat distribution and that the cause and long-term health effects of these changes are not known at this time. Advise patient to report changes in body fat distribution to heath care provider.
Advise patient that etravirine does not completely eliminate HIV virus and, therefore, does not reduce the risk of transmitting HIV to others. Appropriate precautions (eg, practicing safer sex using a latex or polyurethane condom) must be followed.
Advise patients that if a dose is missed within 6 h of the time they usually take the dose, to take the missed dose following a meal as soon as possible. Then, take the next dose at the regularly scheduled time. If a dose is missed by more than 6 h of the usual administration time, the patient should wait and take the next dose at the regularly scheduled time. The dose should not be doubled to make up for the missed dose.
Advise patients that severe and potentially life-threatening rash has been reported with etravirine. Advise patients to contact their health care provider immediately if they develop a rash. Instruct patients to immediately stop taking etravirine and seek medical attention if the rash is associated with any of the following symptoms: blisters, extreme tiredness, eye inflammation, facial swelling, fever, general ill feeling, muscle or joint aches, oral lesions, or signs of liver problems.