Etravirine

Pregnancy Category: B

Lactation: It is not known whether etravirine is excreted in milk. It should not be administered to nursing mothers. The CDC advises HIV-infected women not to breast-feed to avoid postnatal transmission of HIV.

Pregnancy Registry: Physicians are encouraged to enroll pregnant women exposed to etravirine by calling 1-800-258-4263.

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Before taking etravirine,

• tell your doctor and pharmacist if you are allergic to etravirine, or any other medications.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, and nutritional supplements you are taking or plan to take. Be sure to mention the following: anticoagulants ('blood thinners') such as warfarin (Coumadin); antiarrhythmics (medications to treat abnormal heart beats) including amiodarone (Cordarone), bepridil (Vascor), disopyramide (Norpace), flecainide (Tambocor), lidocaine (Xylocaine), mexiletine (Mexitil), propafenone (Rythmol), and quinidine (Quinidex); certain medications to treat seizures such as carbamazepine (Tegretol, Carbatrol), phenobarbital (Luminal), and phenytoin (Dilantin, Phenytek); clarithromycin (Biaxin, in Prevpac); cholesterol-lowering medications (statins) including atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Advicor, Altoprev, Mevacor), rosuvastatin (Crestor), and simvastatin (Vytorin, Zocor); clopidogrel (Plavix); diazepam (Valium); dexamethasone (Decadron, Dexone, others); certain medications that suppress the immune system such as cyclosporine (Sandimmune, Neoral), sirolimus (Rapamune), and tacrolimus (Prograf); medications to treat erectile dysfunction including sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra); medications to treat fungal infections including fluconazole (Diflucan), itraconazole (Sporanox), ketoconazole (Nizoral), posaconazole (Noxafil), and voriconazole (Vfend); methadone (Dolophine); other medications to treat HIV including amprenavir (Agenerase) atazanavir (Reyataz), delavirdine (Rescriptor), efavirenz (Sustiva, in Atripla), fosamprenavir (Lexiva), indinavir (Crixivan), lopinavir (in Kaletra), nelfinavir (Viracept), and nevirapine (Viramune) ritonavir (Norvir, in Kaletra), and tipranavir (Aptivus); rifabutin (Mycobutin); rifampin (Rifadin, Rifater, Rifamate); rifapentine (Priftin). Many other medications may also interact with etravirine, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list. Do not start taking any new medications while you are taking etravirine without first talking with your doctor or pharmacist.
• tell your doctor what herbal products you are taking, especially St. John's wort.
• tell your doctor if you have or have ever had liver disease, including hepatitis.
• tell your doctor if you are pregnant or plan to become pregnant. If you become pregnant while taking etravirine, call your doctor.
• you should not breast-feed if you are infected with HIV or are taking etravirine.
• you should know that your body fat may increase or move to different areas of your body such as your breasts, neck, chest, stomach, and upper back. Loss of fat from your legs, arms, and face may also happen.

Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended. Etravirine must be taken in combination with other HIV medications. Follow your doctor's dosing instructions very carefully.

If a child is taking this medication, tell your doctor if the child has any changes in weight. Etravirine doses are based on weight in children.

Etravirine works best if you take it after a meal. Do not take it on an empty stomach.

Do not crush, chew, or break an etravirine tablet. Swallow it whole with liquid such as water.

If you cannot swallow an etravirine tablet whole, place it into a glass of water and allow the tablet to disperse in the liquid. The tablet will not dissolve completely. Drink this mixture right away. To make sure you get the entire dose, add a little more liquid to the same glass, swirl gently and drink right away.

While using etravirine, you may need frequent blood tests at your doctor's office.

Use all medications as directed by your doctor. Read the medication guide or patient instructions provided with each medication. Do not change your doses or medication schedule without your doctor's advice. Every person with HIV or AIDS should remain under the care of a doctor.

Store at room temperature away from moisture and heat. Keep the tablets in their original container.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

If you are less than 6 hours late in taking your medicine, take the missed dose after your next meal. Then return to your regular dosing schedule. Do not take extra medicine to make up the missed dose.

Etravirine is a prescription medication used in combination with other medications to treat human immunodeficiency virus (HIV) in people who are at least 6 years of age. Etravirine is given when other medications have not been successful.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Etravirine can cause serious side effects including:

• Severe skin rash and allergic reactions. Skin rash is a common side effect of etravirine. Rash can be serious. Call your doctor right away if you get a rash. In some cases, severe rash and allergic reaction may need to be treated in a hospital and may potentially lead to death.
  If you get a rash with any of the following symptoms, stop taking etravirine and call your doctor or get medical help right away:
  • hives or sores in your mouth, or your skin blisters and peels
  • trouble swallowing or breathing
  • swelling of your face, eyes, lips, tongue, or throat
  • fever, yellowing of the skin or whites of the eyes, dark urine, or pain on the right side of the stomach-area (abdominal pain).
• Changes in body fat can happen in people taking HIV medicines. These changes may include an increased amount of fat in the upper back and neck ("buffalo hump"), breast, and around the middle of your body (trunk). Loss of fat from the legs, arms, and face may also happen. The exact cause and long-term health effects of these problems are not known.
• Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Call your doctor right away if you start having any new symptoms after starting your HIV medicine.

Avoid doing things that can spread HIV-1 infection to others:

• Do not share or re-use needles or other injection equipment.
• Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
• Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.

Ask your doctor if you have any questions on how to prevent passing HIV to other people.

Avoid using grapefruit juice or warm (more than 104°F or 40°C) or carbonated beverages when taking this medication.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Antiretroviral; HIV nonnucleoside reverse transcriptase inhibitor (NNRTI).1 2 3 200

Treatment of HIV Infection

Treatment of HIV-1 infection in adults, adolescents, and pediatric patients ≥6 years of age who are antiretroviral-experienced (previously treated) and have evidence of ongoing HIV-1 replication and HIV-1 resistant to an HIV NNRTI and other antiretrovirals;1 2 3 used in conjunction with other antiretrovirals.1

Because of concerns regarding cross-resistance, use individual’s prior antiretroviral treatment and viral resistance testing to guide therapy;1 use in conjunction with other active antiretrovirals is associated with greater likelihood of treatment response.1 A regimen that includes only etravirine and HIV nucleoside reverse transcriptase inhibitors (NRTIs) not recommended in those who experienced virologic failure while receiving a previous NNRTI-containing regimen.1

Concomitant use of etravirine and another NNRTI (e.g., delavirdine, efavirenz, nevirapine, rilpivirine) not recommended.1 200 226

Safety and efficacy not established in antiretroviral-naive (have not previously received antiretroviral therapy) adults or pediatric patients;1 do not use in initial treatment regimens in such patients.200 201

Postexposure Prophylaxis following Occupational Exposure to HIV

Postexposure prophylaxis of HIV infection following occupational exposure† (PEP) in health-care personnel and others exposed via percutaneous injury (e.g., needlestick, cut with sharp object) or mucous membrane or nonintact skin (e.g., chapped, abraded, dermatitis) contact with blood, tissue, or other body fluids that might contain HIV.199

USPHS recommends 3-drug regimen of raltegravir in conjunction with emtricitabine and tenofovir disoproxil fumarate (tenofovir DF) as the preferred regimen for PEP following occupational exposures to HIV.199 Etravirine and 2 NRTIs is one of several alternative regimens.199 Preferred dual NRTI option for use in PEP regimens is emtricitabine and tenofovir DF (may be given as emtricitabine/tenofovir DF; Truvada); alternatives are tenofovir DF and lamivudine, lamivudine and zidovudine (may be given as lamivudine/zidovudine; Combivir), or zidovudine and emtricitabine.199

Management of occupational exposures to HIV is complex and evolving; consult infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or National Clinicians’ Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) whenever possible.199 Do not delay initiation of PEP while waiting for expert consultation.199

Administration

Oral Administration

Administer orally twice daily after a meal.1 Food enhances bioavailability.1 11 (See Food under Pharmacokinetics.)

Swallow tablets whole with a liquid (e.g., water);1 do not chew.1

For patients unable to swallow tablets whole, administer as a dispersion.1 Place dose of tablets in 5 mL of water (enough water to cover the tablets) and stir until a uniform, milky dispersion occurs.1 If desired, add more water or, alternatively, orange juice or milk;1 do not use grapefruit juice or carbonated or warm (>40°C) beverage.1 Consume dispersion promptly; to ensure consumption of entire dose, rinse the glass several times with water, orange juice, or milk and swallow each rinse.1

Dosage

Must be used in conjunction with other antiretrovirals.1

Pediatric Patients

To avoid medication errors, use extra care in calculating dose, transcribing medication order, dispensing prescription, and providing dosing instructions.1

Children 6 years to <18 years of age weighing ≥16 kg: Dosage is based on weight and should not exceed recommended adult dosage.1 (See Table 1.)

Adults

200 mg twice daily.1 Give dose as a single 200-mg tablet or two 100-mg tablets.1

200 mg twice daily.199 Use in conjunction with 2 NRTIs (see Postexposure Prophylaxis following Occupational Exposure to HIV under Uses).199

Initiate PEP as soon as possible following occupational exposure to HIV (preferably within hours); continue for 4 weeks, if tolerated.199

Special Populations

Hepatic Impairment

Dosage adjustments not necessary in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).1 12 200 Pharmacokinetics not studied in patients with severe hepatic impairment (Child-Pugh class C);1 dosage recommendations not available for such patients.200 (See Special Populations under Pharmacokinetics.)

Dosage adjustments not necessary in HIV-infected adults coinfected with HBV and/or HCV.1 (See Special Populations under Pharmacokinetics.)

Renal Impairment

Dosage adjustments not necessary.1 200 (See Special Populations under Pharmacokinetics.)

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1

• Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.1 200 Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.1

• Importance of using in conjunction with other antiretroviralsnot for monotherapy.1 200

• Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.1

• Advise patients that sustained decreases in plasma HIV RNA have been associated with reduced risk of progression to AIDS and death.1

• Advise patients that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others.200 Importance of continuing to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids), never sharing personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reusing or sharing needles.1 200

• Importance of reading patient information provided by the manufacturer.1

• Importance of taking etravirine twice daily after a meal.1 Food enhances absorption of the drug;1 11 magnitude of the food effect is similar with all meal types (standard, light, enhanced-fiber, high-fat).1 11

• Advise patients to swallow the tablets whole with liquid (e.g., water) without chewing.1 Patients unable to swallow tablets whole may disperse the tablets in 5 mL of water (enough to cover the tablets); after dispersion in water, orange juice or milk may be added to the mixture.1 Ingest the liquid containing the dispersed etravirine tablets immediately, then rinse the glass several times with water, orange juice, or milk and drink the rinse each time to ensure entire dose is ingested.1

• If a missed dose is remembered within 6 hours of the usually scheduled time, it should be taken after a meal as soon as possible and the next dose taken at the regularly scheduled time.1 If missed dose is remembered >6 hours after the scheduled time, the dose should be omitted and the next dose taken at the regularly scheduled time.1

• Advise patients that severe and potentially life-threatening rash has occurred (usually within the first few weeks of etravirine therapy).1 Importance of immediately contacting clinician if rash occurs.1 Importance of immediately discontinuing etravirine and seeking medical care if rash associated with systemic symptoms (e.g., fever, generally ill feeling, extreme tiredness, muscle or joint aches, blisters, oral lesions, eye inflammation, swelling of the face, eyes, lips, or mouth, breathing difficulties, yellowing of the eyes or skin, dark or tea colored urine, pale colored stools, nausea, vomiting, loss of appetite, or right upper quadrant tenderness/pain) occurs.1

• Advise patients that redistribution/accumulation of body fat may occur with antiretroviral therapy, with as yet unknown long-term health effects.1

• Advise patients to contact their clinician if signs or symptoms of an infection occur.1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements (e.g., St. John’s wort), and any concomitant illnesses.1

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Advise HIV-infected women not to breast-feed.1

• Importance of advising patients of other important precautionary information.1 (See Cautions.)

Etravirine is used together with other medicines to treat an infection caused by human immunodeficiency virus (HIV). HIV is the virus that causes acquired immune deficiency syndrome (AIDS). etravirine is usually given to patients who have received HIV treatment in the past.

Etravirine will not cure or prevent HIV infection or AIDS; however, it helps keep the HIV virus from reproducing and appears to slow the destruction of the immune system. This may help delay some of the problems related to AIDS or HIV disease. Etravirine will not keep you from spreading HIV to other people. People who take etravirine may continue to have other problems related to AIDS or HIV disease.

etravirine is available only with your doctor's prescription.

It is very important that your doctor check the progress of you or your child at regular visits to make sure etravirine is working properly and to check for unwanted effects.

When you start taking HIV medicines, your immune system may get stronger. If you have certain infections, such as pneumonia or tuberculosis, you or your child may notice new symptoms when your body tries to fight them. If this occurs, be sure to tell your doctor.

Serious skin reactions can occur with etravirine. Stop using etravirine and check with your doctor right away if you or your child have more than one of the following symptoms: blistering, peeling, or loosening of the skin, itching, joint or muscle pain, rash, red skin lesions, sore throat, or sores, ulcers, or white spots in the mouth or on the lips.

etravirine may cause you to have excess body fat. Tell your doctor if you or your child notice changes in your body shape, such as an increased amount of fat in the upper back and neck, or around the chest and stomach area; or a loss of fat from the legs, arms, and face.

etravirine will not keep you from giving HIV to your partner during sex. Make sure you understand and practice safe sex, even if your partner also has HIV. Do not share needles with anyone.

Do not take any other medicines without checking first with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal (e.g., St. John's wort) or vitamin supplements. To do so may increase the chance of side effects from etravirine.

Mild-to-moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary.

Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Take after meals.

Applies to etravirine: oral tablet

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. Discontinuation due to side effects occurred in 5.2% of patients using etravirine. 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.[Ref]

Dermatologic

Very common (10% or more): Rash (all intensities: 16.9%; at least moderate intensity: 10%)
Common (1% to 10%): Less than 2% (at least moderate intensity): Dry skin, face swelling, hyperhidrosis, lipohypertrophy, night sweats, prurigo
Uncommon (0.1% to 1%): Erythema multiforme (at least moderate intensity: up to 0.5%)
Rare (less than 0.1%): Stevens-Johnson syndrome, erythema multiforme
Frequency not reported: Contact dermatitis, erythema, pruritus
Postmarketing reports: Toxic epidermal necrolysis (fatal cases)[Ref]

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 (at least moderate severity: 15%) compared to men (at least moderate severity: 9.5%). Discontinuation due to rash occurred in 5% of women compared to 1.9% of men. Patients with a history of nonnucleoside reverse transcriptase inhibitor-related rash did not appear to be at increased risk.

Erythema multiforme has been reported in no more than 0.5% of patients in other trials.[Ref]

Gastrointestinal

Common (1% to 10%): Elevated pancreatic amylase (Grade 2: 7%; Grade 3: 7%; Grade 4: 2%), elevated lipase (Grade 2: 4%; Grade 3: 2%; Grade 4: 1%); Less than 2% (at least moderate intensity): Abdominal distension, constipation, dry mouth, flatulence, gastritis, gastroesophageal reflux disease, hematemesis, pancreatitis, retching, stomatitis
Frequency not reported: Nausea, diarrhea, abdominal pain, vomiting[Ref]

Nervous system

Common (1% to 10%): Peripheral neuropathy (at least moderate intensity: 4%); Less than 2% (at least moderate intensity): Amnesia, convulsion, disturbance in attention, hypersomnia, hypoesthesia, paresthesia, somnolence, syncope, tremor, vertigo
Frequency not reported: Headache[Ref]

Hypersensitivity

Common (1% to 10%): Drug hypersensitivity (at least moderate intensity: less than 2%)
Postmarketing reports: Severe hypersensitivity reactions (including drug rash with eosinophilia and systemic symptoms [DRESS] and cases of hepatic failure)[Ref]

Cardiovascular

Common (1% to 10%): Less than 2% (at least moderate intensity): Angina pectoris, atrial fibrillation, myocardial infarction
Uncommon (0.1% to 1%): Angioneurotic edema (at least moderate intensity: up to 0.5%), hemorrhagic stroke (at least moderate intensity: up to 0.5%)
Frequency not reported: Hypertension, mild atrioventricular block[Ref]

Angioneurotic edema and hemorrhagic stroke have been reported in no more than 0.5% of patients in other trials.[Ref]

Metabolic

Very common (10% or more): Elevated total cholesterol (Grade 2: 20%), elevated glucose levels (Grade 2: 15%), elevated low density lipoprotein (Grade 2: 13%)
Common (1% to 10%): Elevated triglycerides (Grade 2: 9%; Grade 3: 6%; Grade 4: 4%), elevated total cholesterol (Grade 3: 8%), elevated low density lipoprotein (Grade 3: 7%), elevated glucose levels (Grade 3: 4%); Less than 2% (at least moderate intensity): Anorexia, diabetes mellitus, dyslipidemia
Uncommon (0.1% to 1%): Acquired lipodystrophy (at least moderate intensity: up to 0.5%)[Ref]

Acquired lipodystrophy has been reported in no more than 0.5% of patients in other trials.[Ref]

Hepatic

Very common (10% or more): Worsening from baseline of AST (at least moderate intensity: 27.8% coinfected patients), worsening from baseline of ALT (at least moderate intensity: 25% coinfected patients)
Common (1% to 10%): Worsening from baseline of ALT (at least moderate intensity: 7.5% non-coinfected patients), worsening from baseline of total bilirubin (at least moderate intensity: 7.1% coinfected patients), worsening from baseline of AST (at least moderate intensity: 6.7% non-coinfected patients), elevated ALT (Grade 2: 6%; Grade 3: 3%; Grade 4: 1%), elevated AST (Grade 2: 6%; Grade 3: 3%), worsening from baseline of total bilirubin (at least moderate intensity: 1.8% non-coinfected patients); Less than 2% (at least moderate intensity): Cytolytic hepatitis, hepatic steatosis, hepatitis, hepatic failure, hepatomegaly
Uncommon (0.1% to 1%): Elevated AST (Grade 4: less than 1%)[Ref]

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.[Ref]

Hematologic

Common (1% to 10%): Decreased neutrophils (Grade 2: 5%; Grade 3: 4%; Grade 4: 2%), decreased platelet count (Grade 2: 3%; Grade 3: 1%), decreased hemoglobin (Grade 2: 2%), decreased white blood cell count (Grade 2: 2%; Grade 3: 1%; Grade 4: 1%), hemolytic anemia (at least moderate intensity: less than 2%)
Uncommon (0.1% to 1%): Decreased hemoglobin (Grade 3: less than 1%; Grade 4: less than 1%), decreased platelet count (Grade 4: less than 1%)
Frequency not reported: Anemia[Ref]

Renal

Common (1% to 10%): Elevated creatinine (Grade 2: 6%; Grade 3: 2%), acute renal failure (at least moderate intensity: less than 2%)[Ref]

Other

Common (1% to 10%): Sluggishness (at least moderate intensity: less than 2%)
Frequency not reported: Fatigue, pyrexia[Ref]

Immunologic

Common (1% to 10%): Immune reconstitution syndrome (at least moderate intensity: less than 2%)
Frequency not reported: Autoimmune disorders in the setting of immune reconstitution (e.g., Graves' disease, polymyositis, Guillain-Barre syndrome)[Ref]

Respiratory

Common (1% to 10%): Bronchospasm (at least moderate intensity: less than 2%), exertional dyspnea (at least moderate intensity: less than 2%)[Ref]

Psychiatric

Common (1% to 10%): Less than 2% (at least moderate intensity): Abnormal dreams, anxiety, confusional state, disorientation, nervousness, nightmares, sleep disorders
Frequency not reported: Insomnia[Ref]

Endocrine

Common (1% to 10%): Gynecomastia (at least moderate intensity: less than 2%)[Ref]

Ocular

Common (1% to 10%): Blurred vision (at least moderate intensity: less than 2%)[Ref]

Musculoskeletal

Rare (less than 0.1%): Severe myopathy (including articular pain, muscular pain, weakness, stiffness, increased creatine kinase; at least 1 case)
Postmarketing reports: Rhabdomyolysis[Ref]

Some side effects of etravirine may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.