2.1 Recommended Dosage in Adult Patients

The recommended oral dosage of Etravirine for adult patients 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 [see Clinical Pharmacology (12.3)] .

2.2 Recommended Dosage During Pregnancy

The recommended oral dosage of Etravirine for pregnant individuals is 200 mg (one 200 mg tablet or two 100 mg tablets) taken twice daily following a meal [see Use in Specific Populations (8.1)] .

2.3 Recommended Dosage in Pediatric Patients (2 Years to Less Than 18 Years of Age)

The recommended dosage of Etravirine for pediatric patients 2 years to less than 18 years of age and weighing at least 10 kg is based on body weight (see Table 1) not exceeding the recommended adult dosage. Etravirine should be taken orally, following a meal. The type of food does not affect the exposure to Etravirine [see Clinical Pharmacology (12.3)] .

2.4 Method of Administration

Instruct patients to swallow the Etravirine tablet(s) whole with liquid such as water. Patients who are unable to swallow the Etravirine tablet(s) whole may disperse the tablet(s) in water. Instruct the patient to do the following:

• place the tablet(s) in 5 mL (1 teaspoon) of water, or at least enough liquid to cover the medication,
• stir well until the water looks milky,
• add approximately 15 mL (1 tablespoon) of liquid. Water may be used but other liquids, such as orange juice or milk, may improve taste. Patients should not place the tablets in orange juice or milk without first adding water. The use of warm (temperature greater than 104°F [greater than 40°C]) or carbonated beverages should be avoided.
• drink the mixture immediately,
• rinse the glass several times with orange juice, milk or water and completely swallow the rinse each time to make sure the patient takes the entire dose.

5.1 Severe Skin and Hypersensitivity Reactions

Severe, potentially life-threatening and fatal skin reactions have been reported. In clinical trials, 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 Etravirine compared to 0.2% of placebo subjects. A total of 2.2% of HIV-1-infected subjects receiving Etravirine discontinued from Phase 3 trials due to rash [see Adverse Reactions (6.1)] . Rash occurred most commonly during the first 6 weeks of therapy. The incidence of rash was higher in females [see Adverse Reactions (6.1)] . Stevens-Johnson syndrome was reported in 1.1% (2/177) of pediatric patients less than 18 years of age receiving Etravirine in combination with other HIV-1 antiretroviral agents in an observational study.

Discontinue Etravirine 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 Etravirine treatment after the onset of severe rash may result in a life-threatening reaction.

5.2 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions

The concomitant use of Etravirine and other drugs may result in potentially significant drug interactions, some of which may lead to [see Drug Interactions (7.3)] :

• Loss of therapeutic effect of concomitant drug or Etravirine and possible development of resistance.
• Possible clinically significant adverse reactions from greater exposures of Etravirine or other concomitant drugs.

See Table 4for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during Etravirine therapy and review concomitant medications during Etravirine therapy.

5.3 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Etravirine. 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 aviuminfection, cytomegalovirus, Pneumocystis jirovecipneumonia (PCP) or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves' disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) 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.

5.4 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.

6.1 Clinical Trials Experience

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.

6.2 Postmarketing Experience

The following events have been identified during postmarketing use of Etravirine. 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 [see Warnings and Precautions (5.1)] .

Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis

Skin and Subcutaneous Tissue Disorders: Fatal cases of toxic epidermal necrolysis and Stevens-Johnson syndrome have been reported [see Warnings and Precautions (5.1)] .

7.1 Potential for Other Drugs to Affect Etravirine

Etravirine is a substrate of CYP3A, CYP2C9, and CYP2C19. Therefore, co-administration of Etravirine with drugs that induce or inhibit CYP3A, CYP2C9, and CYP2C19 may alter the therapeutic effect or adverse reaction profile of Etravirine (see Table 4) [see Clinical Pharmacology (12.3)].

7.2 Potential for Etravirine to Affect Other Drugs

Etravirine is an inducer of CYP3A and inhibitor of CYP2C9, CYP2C19 and P-glycoprotein (P-gp). Therefore, co-administration of drugs that are substrates of CYP3A, CYP2C9 and CYP2C19 or are transported by P-gp with Etravirine may alter the therapeutic effect or adverse reaction profile of the co-administered drug(s) (see Table 4) [see Clinical Pharmacology (12.3)].

7.3 Significant Drug Interactions

Table 4 shows significant drug interactions based on which, alterations in dose or regimen of Etravirine and/or co-administered drug may be recommended. Drugs that are not recommended for co-administration with Etravirine are also included in Table 4 [see Clinical Pharmacology (12.3)] .

7.4 Drugs Without Clinically Significant Interactions with Etravirine

In addition to the drugs included in Table 4, the interaction between Etravirine and the following drugs were evaluated in clinical studies and no dose adjustment is needed for either drug [see Clinical Pharmacology (12.3)] : didanosine, enfuvirtide (ENF), ethinylestradiol/norethindrone, omeprazole, paroxetine, raltegravir, ranitidine, and tenofovir disoproxil fumarate.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of Etravirine have been established for the treatment of HIV-infected pediatric patients from 2 years of age to less than 18 years [see Indications and Usage (1)and Dosage and Administration (2.3)] . Use of Etravirine in pediatric patients 2 years to less than 18 years of age is supported by evidence from adequate and well-controlled studies of Etravirine in adults with additional data from two Phase 2 trials in treatment-experienced pediatric subjects, TMC125-C213, 6 years to less than 18 years of age (N=101) and TMC125-C234/IMPAACT P1090, 2 years to less than 6 years of age (N=20). Both studies were open-label, single arm trials of etravirine plus an optimized background regimen. In clinical trials, the safety, pharmacokinetics, and efficacy were comparable to that observed in adults except for rash (greater than or equal to Grade 2) which was observed more frequently in pediatric subjects [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)] . Postmarketing reports of Stevens-Johnson syndrome in pediatric patients receiving Etravirine have been reported [see Warnings and Precautions (5.1), and Adverse Reactions (6.2)] .

Treatment with Etravirine is not recommended in pediatric patients less than 2 years of age [see Clinical Pharmacology (12.3)] . Five HIV-infected subjects from 1 year to < 2 years of age were enrolled in TMC125-C234/IMPAACT P1090. Etravirine exposure was lower than reported in HIV-infected adults (AUC 12hgeometric mean ratio [90% CI] was 0.59 [0.34, 1.01] for pediatric subjects from 1 year to < 2 years of age compared to adults). Virologic failure at Week 24 (confirmed HIV-RNA greater than or equal to 400 copies/mL) occurred in 3 of 4 evaluable subjects who discontinued before or had reached Week 24. Genotypic and phenotypic resistance to etravirine developed in 1 of the 3 subjects who experienced virologic failure.

8.5 Geriatric Use

Clinical studies of Etravirine did not include sufficient numbers of subjects aged 65 years of age 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 [see Clinical Pharmacology (12.3)] .

8.6 Hepatic Impairment

No dose adjustment of Etravirine is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. The pharmacokinetics of Etravirine have not been evaluated in patients with severe hepatic impairment (Child-Pugh Class C) [see Clinical Pharmacology (12.3)] .

8.7 Renal Impairment

Since the renal clearance of etravirine is negligible (less than 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 [see Clinical Pharmacology (12.3)] .

12.1 Mechanism of Action

Etravirine is an antiretroviral drug [see Microbiology (12.4)] .

12.2 Pharmacodynamics

12.3 Pharmacokinetics

The pharmacokinetic properties of Etravirine were determined in healthy adult subjects and in treatment-experienced HIV-1-infected adult and pediatric subjects. The systemic exposures (AUC) to etravirine were lower in HIV-1-infected subjects (Table 5) than in healthy subjects.

Note: The median protein binding adjusted EC 50for MT4 cells infected with HIV-1/IIIB in vitroequals 4 ng/mL.

12.4 Microbiology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 Treatment-Experienced Adult Subjects

The clinical efficacy of Etravirine is derived from the analyses of 48-week data from 2 ongoing, randomized, double-blinded, placebo-controlled, Phase 3 trials, TMC125-C206 and TMC125-C216 (DUET-1 and DUET-2) in subjects with 1 or more NNRTI resistance-associated substitutions. These trials are identical in design and the results below are pooled data from the two trials.

TMC125-C206 and TMC125-C216 are Phase 3 studies designed to evaluate the safety and antiretroviral activity of Etravirine in combination with a background regimen (BR) as compared to placebo in combination with a BR. Eligible subjects were treatment-experienced HIV-1-infected subjects with plasma HIV-1 RNA greater than 5000 copies/mL while on an antiretroviral regimen for at least 8 weeks. In addition, subjects had 1 or more NNRTI resistance-associated substitutions at screening or from prior genotypic analysis, and 3 or more of the following primary PI substitutions at screening: D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50L/V, V82A/F/L/S/T, I84V, N88S, or L90M. Randomization was stratified by the intended use of ENF in the BR, previous use of darunavir/ritonavir, and screening viral load. Virologic response was defined as HIV-1 RNA less than 50 copies/mL at Week 48.

All study subjects received darunavir/ritonavir as part of their BR, and at least 2 other investigator-selected antiretroviral drugs (N[t]RTIs with or without ENF). Of Etravirine-treated subjects, 25.5% used ENF for the first time ( de novo) and 20.0% re-used ENF. Of placebo-treated subjects, 26.5% used de novoENF and 20.4% re-used ENF.

In the pooled analysis for TMC125-C206 and TMC125-C216, demographics and baseline characteristics were balanced between the Etravirine arm and the placebo arm (Table 13). Table 13 displays selected demographic and baseline disease characteristics of the subjects in the Etravirine and placebo arms.

Efficacy at Week 48 for subjects in the Etravirine and placebo arms for the pooled TMC125-C206 and TMC125-C216 study populations are shown in Table 14.

At Week 48, 70.8% of Etravirine-treated subjects achieved HIV-1 RNA less than 400 copies/mL as compared to 46.4% of placebo-treated subjects. The mean decrease in plasma HIV-1 RNA from baseline to Week 48 was -2.23 log 10copies/mL for Etravirine-treated subjects and -1.46 log 10copies/mL for placebo-treated subjects. The mean CD4+ cell count increase from baseline for Etravirine-treated subjects was 96 cells/mm 3and 68 cells/mm 3for placebo-treated subjects.

Of the study population who either re-used or did not use ENF, 57.4% of Etravirine-treated subjects and 31.7% of placebo-treated subjects achieved HIV-1 RNA less than 50 copies/mL. Of the study population using ENF de novo,67.3% of Etravirine-treated subjects and 57.2% of placebo-treated subjects achieved HIV-1 RNA less than 50 copies/mL.

Treatment-emergent CDC category C events occurred in 4% of Etravirine-treated subjects and 8.4% of placebo-treated subjects.

Study TMC125-C227 was a randomized, exploratory, active-controlled, open-label, Phase 2b trial. Eligible subjects were treatment-experienced, PI-naïve HIV-1-infected subjects with genotypic evidence of NNRTI resistance at screening or from prior genotypic analysis. The virologic response was evaluated in 116 subjects who were randomized to Etravirine (59 subjects) or an investigator-selected PI (57 subjects), each given with 2 investigator-selected N(t)RTIs. Etravirine-treated subjects had lower antiviral responses associated with reduced susceptibility to the N(t)RTIs and to Etravirine as compared to the control PI-treated subjects.

14.2 Treatment-Experienced Pediatric Subjects (2 Years to Less Than 18 Years of Age)

The efficacy of Etravirine for treatment-experienced pediatric subjects is based on two Phase 2 trials, TMC125-C213 and TMC125-C234/IMPAACT P1090.

Store Etravirine tablets at 25°C (77°F); with excursions permitted to 15° to 30°C (59° to 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.

Keep Etravirine and all medicines out of the reach of children.

Administration

Advise patients to take Etravirine following a meal twice a day on a regular dosing schedule, as missed doses can result in development of resistance. The type of food does not affect the exposure to etravirine. Inform patients not to take more or less than the prescribed dose of Etravirine or discontinue therapy with Etravirine without consulting their physician. Etravirine must always be used in combination with other antiretroviral drugs [see Dosage and Administration (2.4)].

Advise patients to swallow the Etravirine tablet(s) whole with a liquid such as water. Instruct patients not to chew the tablets. Patients who are unable to swallow the Etravirine tablet(s) whole may disperse the tablet(s) in water. The patient should be instructed to do the following:

• place the tablet(s) in 5 mL (1 teaspoon) of water, or at least enough liquid to cover the medication,
• stir well until the water looks milky,
• add approximately 15 mL (1 tablespoon) of liquid. Water may be used, but orange juice or milk may improve taste. Patients should not place the tablets in orange juice or milk without first adding water. The use of warm (temperature greater than 104°F [greater than 40°C]) or carbonated beverages should be avoided.
• drink the mixture immediately,
• rinse the glass several times with orange juice, milk or water and completely swallow the rinse each time to make sure the patient takes the entire dose.

Severe Skin Reactions

Inform patients that severe and potentially life-threatening rash has been reported with Etravirine. Rash has been reported most commonly in the first 6 weeks of therapy. Advise patients to immediately contact their healthcare provider if they develop rash. Instruct patients to immediately stop taking Etravirine and seek medical attention if they develop a rash associated with any of the following symptoms as it may be a sign of a more serious reaction such as Stevens-Johnson syndrome, toxic epidermal necrolysis or severe hypersensitivity: fever, generally ill feeling, extreme tiredness, muscle or joint aches, blisters, oral lesions, eye inflammation, facial swelling, swelling of the eyes, lips, mouth, breathing difficulty, and/or signs and symptoms of liver problems (e.g., yellowing of your skin or whites of your eyes, dark or tea colored urine, pale colored stools/bowel movements, nausea, vomiting, loss of appetite, or pain, aching or sensitivity on your right side below your ribs). Patients should understand that if severe rash occurs, they will be closely monitored, laboratory tests will be ordered and appropriate therapy will be initiated [see Warnings and Precautions (5.1)] .

Drug Interactions

Etravirine may interact with many drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John's wort [see Warnings and Precautions (5.2)] .

Immune Reconstitution Syndrome

Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started [see Warnings and Precautions (5.3)].

Fat Redistribution

Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy, including Etravirine, and that the cause and long-term health effects of these conditions are not known at this time [see Warnings and Precautions (5.4)] .

Pregnancy Registry

Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant individuals exposed to Etravirine [see Use in Specific Populations (8.1)] .

Lactation

Instruct mothers with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk [see Use in Specific Populations (8.2)] .