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Initial U.S. Approval - 2008
INTELENCE® (etravirine) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1).
The chemical name for etravirine is 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile. Its molecular formula is C20H15BrN6O and its molecular weight is 435.28.
Etravirine is a white to slightly yellowish brown powder. Etravirine is practically insoluble in water over a wide pH range. It is very slightly soluble in propylene glycol and slightly soluble in ethanol. Etravirine is soluble in polyethylene glycol (PEG)400 and freely soluble in some organic solvents (e.g., N,N-dimethylformamide and tetrahydrofuran).
INTELENCE® 100 mg tablets are available as white to off-white, oval tablets for oral administration. Each 100 mg tablet contains 100 mg of etravirine and the inactive ingredients hypromellose, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate and lactose monohydrate.
INTELENCE® 200 mg tablets are available as white to off-white, biconvex, oblong tablets for oral administration. Each 200 mg tablet contains 200 mg of etravirine and the inactive ingredients hypromellose, silicified microcrystalline cellulose, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium and magnesium stearate.
Mechanism of Action
Etravirine is an NNRTI of human immunodeficiency virus type 1 (HIV-1). Etravirine binds directly to reverse transcriptase (RT) and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme's catalytic site. Etravirine does not inhibit the human DNA polymerases , and .
Antiviral Activity in Cell Culture
Etravirine exhibited activity against laboratory strains and clinical isolates of wild-type HIV-1 in acutely infected T-cell lines, human peripheral blood mononuclear cells, and human monocytes/macrophages with median EC50 values ranging from 0.9 to 5.5 nM (i.e., 0.4 to 2.4 ng/mL). Etravirine demonstrated antiviral activity in cell culture against a broad panel of HIV-1 group M isolates (subtype A, B, C, D, E, F, G) with EC50 values ranging from 0.29 to 1.65 nM and EC50 values ranging from 11.5 to 21.7 nM against group O primary isolates. Etravirine did not show antagonism when studied in combination with the following antiretroviral drugs—the NNRTIs delavirdine, efavirenz, and nevirapine; the N(t)RTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine; the PIs amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir; the fusion inhibitor enfuvirtide; the integrase strand transfer inhibitor raltegravir and the CCR5 co-receptor antagonist maraviroc
INDICATIONS AND USAGE
INTELENCE® is a human immunodeficiency virus type 1 (HIV-1) specific, non-nucleoside reverse transcriptase inhibitor (NNRTI) indicated:
In combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adult patients, who have evidence of viral replication and HIV-1 strains resistant to an NNRTI and other antiretroviral agents.
In patients who have experienced virologic failure on an NNRTI-containing regimen, do not use INTELENCE® in combination with onlyN[t]RTIs.
The safety and efficacy of INTELENCE® have not been established in pediatric patients or treatment-naïve adult patients.
USE IN SPECIFIC POPULATIONS
Pregnancy: Pregnancy Category B- Use during pregnancy only if the potential benefit justifies the potential risk. Antiviral Pregnancy Registry available. Register patients by calling 1-800-258-4263.
Nursing Mothers: Mothers should not breastfeed due to the potential for HIV transmission.
WARNINGS AND PRECAUTIONS
Severe, potentially life threatening and fatal skin reactions have been reported. This includes cases of Stevens-Johnson syndrome, hypersensitivity reaction, toxic epidermal necrolysis and erythema multiforme. Immediately discontinue treatment if severe hypersensitivity, severe rash or rash with systemic symptoms or liver transaminase elevations develops and monitor clinical status, including liver transaminases closely.
INTELENCE® should not be co-administered with the following antiretrovirals:
-Tipranavir/ritonavir, fosamprenavir/ritonavir, atazanavir/ritonavir
-Protease inhibitors administered without ritonavir
Co-administration of INTELENCE® with drugs that inhibit or induce CYP3A, CYP2C9, and/or CYP2C19 may alter the therapeutic effect or adverse reaction profile of etravirine.
Co-administration of INTELENCE® with drugs that are substrates of CYP3A, CYP2C9, and/or CYP2C19 or are transported by P-glycoprotein may alter the therapeutic effect or adverse reaction profile of the co-administered drug(s).
Refer to the Full Prescribing Information for other drugs that should not be co-administered with INTELENCE® and for other drugs that may require a change in dose or regimen.
The most common adverse drug reactions of moderate to severe intensity (>/= 2%) which occurred at a higher rate than placebo are rash and peripheral neuropathy.
To report SUSPECTED ADVERSE REACTIONS, contact Tibotec Therapeutics at 1-877-REACH-TT or 1-877-732-2488 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DOSAGE AND ADMINISTRATION
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. Patients who are unable to swallow INTELENCE® tablet(s) whole may disperse the tablet(s) in a glass of water. Once dispersed, patients should stir the dispersion well and drink it immediately. The glass should be rinsed with water several times and each rinse completely swallowed to ensure the entire dose is consumed.
DOSAGE FORMS AND STRENGTHS
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
Store INTELENCE® tablets at 25°C (77°F); with excursions permitted to 15°–30°C (59°–86°F) [see USP controlled room temperature]. Store in the original bottle. Keep the bottle tightly closed in order to protect from moisture. Do not remove the desiccant pouches
Package Insert data:
Manufactured for Tibotec, Inc. by:
Janssen Cilag S.p.A., Latina, Italy
Tibotec Therapeutics, Division of Centocor Ortho Biotech Products, L.P., Raritan NJ 08869
© Tibotec, Inc. 2008