Drug Description

INTELENCE (etravirine) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1).

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.

HIV/AIDS-Related Uses

INTELENCE, in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-experienced adult patients, who have evidence of viral replication and HIV-1 strains resistant to a non-nucleoside reverse transcriptase inhibitor (NNRTI) and other antiretroviral agents.

This indication 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 following points should be considered when initiating therapy with INTELENCE:

• Treatment history and, when available, resistance testing, should guide the use of INTELENCE.

• The use of other active antiretroviral agents with INTELENCE is associated with an increased likelihood of treatment response.

• In patients who have experienced virologic failure on an NNRTI-containing regimen, do not use INTELENCE in combination with only N[t]RTIs.

• The risks and benefits of INTELENCE have not been established in pediatric patients or in treatment-naïve adult patients.

Dosing Information

Mode of Delivery

Oral.

Dosage Form

Tablets containing etravirine 100 mg or 200 mg.


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.

Storage

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.

Pharmacology

Mechanism of Action
Etravirine is an antiviral drug.

Pharmacodynamics
Effects on Electrocardiogram
In a randomized, double-blind, active, and placebo-controlled crossover study, 41 healthy subjects were administered INTELENCE 200 mg b.i.d., INTELENCE 400 mg q.d., placebo, and moxifloxacin 400 mg. After 8 days of dosing, etravirine did not prolong the QT interval. The maximum mean (upper 1-sided 95% CI) baseline and placebo-adjusted QTcF were 0.6 ms (3.3 ms) for 200 mg b.i.d. and -1.0 ms (2.5 ms) for 400 mg q.d. dosing regimens.

Pharmacokinetics
Pharmacokinetics in Adults
The pharmacokinetic properties of INTELENCE were determined in healthy adult subjects and in treatment-experienced HIV-1-infected adult subjects. The systemic exposures (AUC) to etravirine were lower in HIV-1infected subjects than in healthy subjects.

Population Pharmacokinetic Estimates of Etravirine 200 mg b.i.d. in HIV-1-Infected Subjects (Integrated Data from Phase 3 Trials at Week 48)*

Parameter: Etravirine 200 mg b.i.d. (N = 575)

• AUC12h (ng•h/mL)
     Geometric Mean ± Standard Deviation: 4522 ± 4710
     Median (Range): 4380 (458 - 59084)
• C_0h (ng/mL)
     Geometric Mean ± Standard Deviation: 297 ± 391
     Median (Range): 298 (2 - 4852)

* All HIV-1-infected subjects enrolled in Phase 3 clinical trials received darunavir/ritonavir 600/100 mg b.i.d. as part of their background regimen. Therefore, the pharmacokinetic parameter estimates shown above account for reductions in the pharmacokinetic parameters of etravirine due to co-administration of INTELENCE with darunavir/ritonavir.

Note: The median protein binding adjusted EC₅₀ for MT4 cells infected with HIV-1/IIIB in vitro = 4 ng/mL.

Absorption and Bioavailability
Following oral administration, etravirine was absorbed with a T_max of about 2.5 to 4 hours. The absolute oral bioavailability of INTELENCE is unknown.

In healthy subjects, the absorption of etravirine is not affected by co-administration of oral ranitidine or omeprazole, drugs that increase gastric pH.

Effects of Food on Oral Absorption
The systemic exposure (AUC) to etravirine was decreased by about 50% when INTELENCE was administered under fasting conditions, as compared to when INTELENCE was administered following a meal. Therefore, INTELENCE should always be taken following a meal. Within the range of meals studied, the systemic exposures to etravirine were similar. The total caloric content of the various meals evaluated ranged from 345 kilocalories (17 grams fat) to 1160 kilocalories (70 grams fat).

Distribution
Etravirine is about 99.9% bound to plasma proteins, primarily to albumin (99.6%) and alpha 1-acid glycoprotein (97.66%-99.02%) in vitro. The distribution of etravirine into compartments other than plasma (e.g., cerebrospinal fluid, genital tract secretions) has not been evaluated in humans.

Metabolism
In vitro experiments with human liver microsomes (HLMs) indicate that etravirine primarily undergoes metabolism by CYP3A, CYP2C9, and CYP2C19 enzymes. The major metabolites, formed by methyl hydroxylation of the dimethylbenzonitrile moiety, were at least 90% less active than etravirine against wild-type HIV in cell culture.

Elimination
After single dose oral administration of 800 mg ¹⁴C-etravirine, 93.7% and 1.2% of the administered dose of ¹⁴Cetravirine was recovered in the feces and urine, respectively. Unchanged etravirine accounted for 81.2% to 86.4% of the administered dose in feces. Unchanged etravirine was not detected in urine. The mean (± standard deviation) terminal elimination half-life of etravirine was about 41 (± 20) hours.

Special Populations
Hepatic Impairment
Etravirine is primarily metabolized by the liver. The steady state pharmacokinetic parameters of etravirine were similar after multiple dose administration of INTELENCE to subjects with normal hepatic function (n = 16), mild hepatic impairment (Child-Pugh Class A, n = 8), and moderate hepatic impairment (Child-Pugh Class B, n = 8). The effect of severe hepatic impairment on the pharmacokinetics of etravirine has not been evaluated.

Hepatitis B and/or Hepatitis C Virus Co-infection
Population pharmacokinetic analysis of the TMC125-C206 and TMC125-C216 trials showed reduced clearance for etravirine in HIV-1-infected subjects with hepatitis B and/or C virus co-infection. Based upon the safety profile of INTELENCE [see Adverse Reactions], no dose adjustment is necessary in patients co-infected with hepatitis B and/or C virus.

Renal Impairment
The pharmacokinetics of etravirine have not been studied in patients with renal impairment. The results from a mass balance study with ¹⁴C-etravirine showed that <1.2% of the administered dose of etravirine is excreted in the urine as metabolites. No unchanged drug was detected in the urine. As etravirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.

Gender
No significant pharmacokinetic differences have been observed between men and women. A limited number of women were included in clinical studies.

Race
Population pharmacokinetic analysis of etravirine in HIV-infected subjects did not show an effect of race on exposure to etravirine.

Geriatric Patients
Population pharmacokinetic analysis in HIV-infected subjects showed that etravirine pharmacokinetics are not considerably different within the age range (18 to 77 years) evaluated.

Pediatric Patients
The pharmacokinetics of etravirine in pediatric patients have not been evaluated. Dosing recommendations for pediatric patients cannot be made due to insufficient data.

Drug Interactions
[See also 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.

Etravirine is an inducer of CYP3A and inhibitor of CYP2C9, CYP2C19 and P-glycoprotein. Therefore, coadministration 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).

Drug interaction studies were performed with INTELENCE and other drugs likely to be co-administered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of other drugs on the AUC, C_max, and C_min values of etravirine are summarized in Table 5 (effect of other drugs on INTELENCE). The effect of co-administration of INTELENCE on the AUC, C_max, and C_min values of other drugs are summarized in Table 6 (effect of INTELENCE on other drugs). [Consult the INTELENCE full prescribing information to view Tables 5 and 6]. For information regarding clinical recommendations, see Drug Interactions.

Microbiology

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 α, β, and γ.

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.

Resistance
In Cell Culture
Etravirine-resistant strains were selected in cell culture originating from wild-type HIV-1 of different origins and subtypes, as well as NNRTI resistant HIV-1. Development of reduced susceptibility to etravirine typically required more than one substitution in reverse transcriptase of which the following were observed most frequently: L100I, E138K, E138G, V179I, Y181C, and M230I.

In Treatment-Experienced Subjects
In the Phase 3 trials TMC125-C206 and TMC125-C216, substitutions that developed most commonly in subjects with virologic failure at Week 48 to the INTELENCE-containing regimen were V179F, V179I, and Y181C which usually emerged in a background of multiple other NNRTI resistance-associated substitutions. In all the trials conducted with INTELENCE in HIV-1 infected subjects, the following substitutions emerged most commonly: L100I, E138G, V179F, V179I, Y181C and H221Y. Other NNRTI-resistance associated substitutions which emerged on etravirine treatment in < 10% of the virologic failure isolates included K101E/H/P, K103N/R, V106I/M, V108I, Y181I, Y188L, V189I, G190S/C, N348I and R356K. The emergence of NNRTI substitutions on etravirine treatment contributed to decreased susceptibility to etravirine with a median fold-change in etravirine susceptibility of 40-fold from reference and a median fold-change of 6-fold from baseline.

Cross-Resistance
Site-Directed NNRTI Mutant Virus
Etravirine showed antiviral activity against 55 of 65 HIV-1 strains (85%) with single amino acid substitutions at RT positions associated with NNRTI resistance, including the most commonly found K103N. The single amino acid substitutions associated with an etravirine reduction in susceptibility > 3-fold were K101A, K101P, K101Q, E138G, E138Q, Y181C, Y181I, Y181T, Y181V, and M230L, and of these, the greatest reductions were Y181I (13-fold change in EC₅₀ value) and Y181V (17-fold change in EC₅₀ value). Mutant strains containing a single NNRTI resistance associated substitution (K101P, K101Q, E138Q, or M230L) had cross-resistance between etravirine and efavirenz. The majority (39 of 61; 64%) of the NNRTI mutant viruses with 2 or 3 amino acid substitutions associated with NNRTI resistance had decreased susceptibility to etravirine (fold-change > 3). The highest levels of resistance to etravirine were observed for HIV-1 harboring a combination of substitutions V179F + Y181C (187 fold-change), V179F + Y181I (123 fold-change), or V179F + Y181C + F227C (888 fold-change).

Clinical Isolates
Etravirine retained a fold-change ≤ 3 against 60% of 6171 NNRTI-resistant clinical isolates. In the same panel, the proportion of clinical isolates resistant to delavirdine, efavirenz and/or nevirapine (defined as a fold-change above their respective biological cutoff values in the assay) was 79%, 87%, and 95%, respectively. In TMC125C206 and TMC125-C216, 34% of the baseline isolates had decreased susceptibility to etravirine (fold-change > 3) and 60%, 69%, and 78% of all baseline isolates were resistant to delavirdine, efavirenz, and nevirapine, respectively. Of subjects who received etravirine and were virologic failures in TMC125-C206 and TMC125-C216, 90%, 84%, and 96% of viral isolates obtained at the time of treatment failure were resistant to delavirdine, efavirenz, and nevirapine, respectively. Therefore, cross-resistance to delavirdine, efavirenz, and/or nevirapine is expected after virologic failure with an etravirine-containing regimen for the virologic failure isolates.

Baseline Genotype/Phenotype and Virologic Outcome Analyses
In TMC125-C206 and TMC125-C216, the presence at baseline of the substitutions L100I, E138A, I167V, V179D, V179F, Y181I, Y181V, or G190S was associated with a decreased virologic response to etravirine. Additional substitutions associated with a decreased virologic response to etravirine when in the presence of 3 or more additional 2008 IAS-USA defined NNRTI substitutions include A98G, K101H, K103R, V106I, V179T, and Y181C. The presence of K103N, which was the most prevalent NNRTI substitution in TMC125-C206 and TMC125-C216 at baseline, did not affect the response in the INTELENCE arm. Overall, response rates to etravirine decreased as the number of baseline NNRTI substitutions increased (shown as the proportion of subjects achieving viral load < 50 plasma HIV RNA copies/mL at Week 48) [Consult the INTELENCE full prescribing information, Clinical Pharmacology, Table 7].

Response rates assessed by baseline etravirine phenotype are shown in Table 8. [Consult INTELENCE full prescribing information to view Table 8]. These baseline phenotype groups are based on the select subject populations in TMC125-C206 and TMC125-C216 and are not meant to represent definitive clinical susceptibility breakpoints for INTELENCE. The data are provided to give clinicians information on the likelihood of virologic success based on pre-treatment susceptibility to etravirine in treatment-experienced patients. The proportion of virologic responders (viral load < 50 HIV-1 RNA copies/mL) by the phenotypic susceptibility score (PSS) of the background therapy, including enfuvirtide, is shown in Table 9. [Consult the INTELENCE full prescribing information to view Table 9].

USE IN SPECIFIC POPULATIONS

Pregnancy
Pregnancy Category B
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. Animal reproduction studies in rats and rabbits at systemic exposures equivalent to those at the recommended human dose of 400 mg/day revealed no evidence of fetal harm. 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.

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
Safety and effectiveness in pediatric patients have not been established.
 
Geriatric use
Clinical studies of INTELENCE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Hepatic Impairment
No dose adjustment of INTELENCE is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. The pharmacokinetics of INTELENCE have not been evaluated in patients with severe hepatic impairment (Child-Pugh Class C).

Renal Impairment
Since the renal clearance of etravirine is negligible (< 1.2%), a decrease in total body clearance is not expected in patients with renal impairment. No dose adjustments are required in patients with renal impairment. As etravirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.

Adverse Events/Toxicity

WARNINGS AND PRECAUTIONS

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 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.

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, dorsocervical 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 complex, cytomegalovirus, Pneumocystis jiroveci pneumonia, and tuberculosis), which may necessitate further evaluation and treatment.

Clinical Trials Experience
The safety assessment is based on all data from 1203 subjects in the Phase 3 placebo-controlled trials, TMC125C206 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]. 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.

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.

Drug and Food 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 below).

Etravirine is an inducer of CYP3A and inhibitor of CYP2C9, CYP2C19 and P-glycoprotein. Therefore, coadministration 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 below).

Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction

HIV-Antiviral Agents
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
• Efavirenz, nevirapine: Combining two NNRTIs has not been shown to be beneficial. Concomitant use of INTELENCE with efavirenz or nevirapine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE. INTELENCE and other NNRTIs should not be co-administered.

• Delavirdine: Combining two NNRTIs has not been shown to be beneficial. INTELENCE and delavirdine should not be co-administered.

Protease Inhibitors (PIs)
• Atazanavir (without ritonavir): Concomitant use of INTELENCE with atazanavir without low dose ritonavir may cause a significant alteration in the plasma concentration of atazanavir. INTELENCE should not be coadministered with atazanavir without low-dose ritonavir.

• Atazanavir/ritonavir: Concomitant use of INTELENCE with atazanavir/ritonavir may cause a significant decrease in atazanavir Cmin and loss of therapeutic effect of atazanavir. In addition, the mean systemic exposure (AUC) of etravirine after co-administration of INTELENCE with atazanavir/ritonavir is anticipated to be higher than the mean systemic exposure of etravirine observed in the Phase 3 trials after co-administration of INTELENCE and darunavir/ritonavir (as part of the background regimen). INTELENCE and atazanavir/ritonavir should not be coadministered.

• Darunavir/ritonavir: The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE was co-administered with darunavir/ritonavir. Because all subjects in the Phase 3 trials received darunavir/ritonavir as part of the background regimen and etravirine exposures from these trials were determined to be safe and effective, INTELENCE and darunavir/ritonavir can be coadministered without dose adjustments.

• Fosamprenavir: Concomitant use of INTELENCE with fosamprenavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of amprenavir. INTELENCE should not be coadministered with fosamprenavir without low-dose ritonavir.

• Fosamprenavir/ritonavir: Due to a significant increase in the systemic exposure of amprenavir, the appropriate doses of the combination of INTELENCE and fosamprenavir/ritonavir have not been established. INTELENCE and fosamprenavir/ritonavir should not be co-administered.

• Indinavir (without ritonavir): Concomitant use of INTELENCE with indinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of indinavir. INTELENCE should not be coadministered with indinavir without low-dose ritonavir.

• Lopinavir/ritonavir: The mean systemic exposure (AUC) of etravirine was reduced after co-administration of INTELENCE with lopinavir/ritonavir (tablet). Because the reduction in the mean systemic exposures of etravirine in the presence of lopinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE and lopinavir/ritonavir can be co-administered without dose adjustments.

• Nelfinavir (without ritonavir): Concomitant use of INTELENCE with nelfinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of nelfinavir. INTELENCE should not be coadministered with nelfinavir without low-dose ritonavir.

• Ritonavir: Concomitant use of INTELENCE with ritonavir 600 mg b.i.d. may cause a significant decrease in the plasma concentration of etravirine and loss of therapeutic effect of INTELENCE. INTELENCE and ritonavir 600 mg b.i.d. should not be coadministered.

• Saquinavir/ritonavir: The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE was co-administered with saquinavir/ritonavir. Because the reduction in the mean systemic exposures of etravirine in the presence of saquinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE and saquinavir/ritonavir can be co-administered without dose adjustments.

• Tipranavir/ritonavir: Concomitant use of INTELENCE with tipranavir/ritonavir may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE. INTELENCE and tipranavir/ritonavir should not be coadministered.

CCR5 Antagonists
• Maraviroc: When INTELENCE is co-administered with maraviroc in the absence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 600 mg b.i.d. No dose adjustment of INTELENCE is needed.

• Maraviroc/darunavir/ ritonavir: When INTELENCE is co-administered with maraviroc in the presence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 150 mg b.i.d. No dose adjustment of INTELENCE is needed.

Other Agents
Antiarrhythmics
• Digoxin: For patients who are initiating a combination of INTELENCE and digoxin, the lowest dose of digoxin should initially be prescribed. For patients on a stable digoxin regimen and initiating INTELENCE, no dose adjustment of either INTELENCE or digoxin is needed. The serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.

• Amiodarone, bepridil, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine: Concentrations of these antiarrhythmics may be decreased when coadministered with INTELENCE. INTELENCE and antiarrhythmics should be co-administered with caution. Drug concentration monitoring is recommended, if available.

Anticoagulants
• Warfarin: Warfarin concentrations may be increased when co-administered with INTELENCE. The international normalized ratio (INR) should be monitored when warfarin is combined with INTELENCE.

Anticonvulsants
• Carbamazepine, phenobarbital, phenytoin: Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. INTELENCE should not be used in combination with carbamazepine, phenobarbital, or phenytoin as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE.

Antifungals
• Fluconazole: Co-administration of etravirine and fluconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and fluconazole should be co-administered with caution. No dose adjustment of INTELENCE or fluconazole is needed.

• Voriconazole: Co-administration of etravirine and voriconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and voriconazole should be co-administered with caution. No dose adjustment of INTELENCE or voriconazole is needed.

• Itraconazole, ketoconazole, posaconazole: Posaconazole, a potent inhibitor of CYP3A4, may increase plasma concentrations of etravirine. Itraconazole and ketoconazole are potent inhibitors as well as substrates of CYP3A4. Concomitant systemic use of itraconazole or ketoconazole and INTELENCE may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of itraconazole or ketoconazole may be decreased by INTELENCE. Dose adjustments for itraconazole, ketoconazole or posaconazole may be necessary depending on the other co-administered drugs.

Antiinfectives
• Clarithromycin: Clarithromycin exposure was decreased by INTELENCE; however, concentrations of the active metabolite, 14-hydroxyclarithromycin, were increased. Because 14-hydroxy-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered for the treatment of MAC.

Antimycobacterials
• Rifampin, rifapentine: Rifampin and rifapentine are potent inducers of CYP450 enzymes. INTELENCE should not be used with rifampin or rifapentine as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE.

• Rifabutin: If INTELENCE is NOT co-administered with a protease inhibitor/ritonavir, then rifabutin at a dose of 300 mg q.d. is recommended. If INTELENCE is co-administered with darunavir/ritonavir, lopinavir/ritonavir or saquinavir/ritonavir, then rifabutin should not be co-administered due to the potential for significant reductions in etravirine exposure.

Benzodiazepines
• Diazepam: Concomitant use of INTELENCE with diazepam may increase plasma concentrations of diazepam. A decrease in diazepam dose may be needed.

Corticosteroids
• Dexamethasone (systemic): Systemic dexamethasone induces CYP3A and can decrease etravirine plasma concentrations. This may result in loss of therapeutic effect of INTELENCE. Systemic dexamethasone should be used with caution or alternatives should be considered, particularly for long-term use.

Herbal Products
• St. John's wort (Hypericum perforatum): Concomitant use of INTELENCE with products containing St. John’s wort may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE. INTELENCE and products containing St. John’s wort should not be co-administered.

HMG-CoA Reductase Inhibitors
• Atorvastatin: The combination of INTELENCE and atorvastatin can be given without dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response.

• Fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin: No interaction between pravastatin, rosuvastatin and INTELENCE is expected.
Lovastatin and simvastatin are CYP3A substrates and coadministration with INTELENCE may result in lower plasma concentrations of the HMG-CoA reductase inhibitor. Fluvastatin is metabolized by CYP2C9 and co-administration with INTELENCE may result in higher plasma concentrations of the HMG-CoA reductase inhibitor. Dose adjustments for these HMG-CoA reductase inhibitors may be necessary.

Immunosuppressants
• Cyclosporine, sirolimus, tacrolimus: INTELENCE and systemic immunosuppressants should be co-administered with caution because plasma concentrations of cyclosporine, sirolimus, or tacrolimus may be affected.

Narcotic Analgesics/Treatment of Opioid Dependence
• Buprenorphine, buprenorphine/naloxone: INTELENCE and buprenorphine (or buprenorphine/naloxone) can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as buprenorphine (or buprenorphine/naloxone) maintenance therapy may need to be adjusted in some patients.

• Methadone: INTELENCE and methadone can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as methadone maintenance therapy may need to be adjusted in some patients.

Phosphodiesterase Type 5 (PDE-5) Inhibitors
• Sildenafil, tadalafil, vardenafil: INTELENCE and sildenafil can be co-administered without dose adjustments, however, the dose of sildenafil may need to be altered based on clinical effect.

Platelet Aggregation Inhibitors
• Clopidogrel: Activation of clopidogrel to its active metabolite may be decreased when clopidogrel is co-administered with INTELENCE. Alternatives to clopidogrel should be considered.

In addition to the drugs included above, 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.

Contraindications

None [1]

References

[1] FDA Intelence Prescribing Information, October 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022187s008lbl.pdf. Accessed 10/17/2011.

Clinical Trials

Click here to search ClinicalTrials.gov for trials that use Etravirina.

Chemistry

CAS Name

Benzonitrile, 4-((6-amino-5-bromo-2- ((4-cyanophenyl)amino)-4-pyrimidinyl)oxy) -3,5-dimethyl- [1]

CAS Number

269055-15-4 [2]

Molecular Formula

C20-H15-Br-N6-O [3]

Molecular Weight

435.28 [4]

Physical Description

White to slightly yellowish brown powder. [5]

Solubility

Practically insoluble in water over a wide pH range; very slightly soluble in propylene glycol; 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). [6]

References

[1] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 10/17/2011.

[2] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 10/17/2011.

[3] FDA Intelence Prescribing Information, October 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022187s008lbl.pdf. Accessed 10/17/2011.

[4] FDA Intelence Prescribing Information, October 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022187s008lbl.pdf. Accessed 10/17/2011.

[5] FDA Intelence Prescribing Information, October 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022187s008lbl.pdf. Accessed 10/17/2011.

[6] FDA Intelence Prescribing Information, October 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022187s008lbl.pdf. Accessed 10/17/2011.

Further Reading

Intelence Prescribing Information from the FDA Web site: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022187s008lbl.pdf. A more current version may be available on the manufacturer's Web site.
Lazzarin A, Campbell T, Clotet B, Johnson M, Katlama C, Moll A, Towner W, Trottier B, Peeters M, Vingerhoets J, de Smedt G, Baeten B, Beets G, Sinha R, Woodfall B; DUET-2 study group. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet. 2007 Jul 7;370(9581):39-48.
Madruga JV, Cahn P, Grinsztejn B, Haubrich R, Lalezari J, Mills A, Pialoux G, Wilkin T, Peeters M, Vingerhoets J, de Smedt G, Leopold L, Trefiglio R, Woodfall B; DUET-1 study group. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised,double-blind, placebo-controlled trial.Lancet. 2007 Jul 7;370(9581):29-38.
Nadler JP. Efficacy and Safety of Etravirine (TMC125) in Patients With Highly Resistant HIV-1: Primary 24-Week Analysis. AIDS. 2007;21(6):F1-F10.
Scholler-Gyure M, Kakuda TN, Sekar V, Woodfall B, De Smedt G, Lefebvre E, Peeters M, Hoetelmans RM. Pharmacokinetics of darunavir/ritonavir and TMC125 alone and coadministered in HIV-negative volunteers. Antivir Ther. 2007;12(5):789-96.

Manufacturer Information

Etravirine

Tibotec
1029 Stony Hill Road
Suite 300
Yardley, PA 19067
Phone: 877-732-2488

Intelence

Tibotec
1029 Stony Hill Road
Suite 300
Yardley, PA 19067
Phone: 877-732-2488