These Highlights Do Not Include All The Information Needed To Use Etravirine Safely And Effectively. See Full Prescribing Information For Etravirine.

Clinical Trials Experience in Adults

The safety assessment is based on all data from 1203 subjects in the Phase 3 placebo-controlled trials, TMC125-C206 and TMC125-C216, conducted in antiretroviral treatment-experienced HIV-1-infected adult subjects, 599 of whom received Etravirine (200 mg twice daily). In these pooled trials, the median exposure for subjects in the Etravirine arm and placebo arm was 52.3 and 51.0 weeks, respectively. Discontinuations due to adverse drug reactions (ADRs) were 5.2% in the Etravirine 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 less than 0.1% of subjects during clinical development with Etravirine [see Warnings and Precautions (5.1)] . A total of 2.2% of HIV-1-infected subjects in Phase 3 trials receiving Etravirine 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 to 2 weeks on continued therapy. The incidence of rash was higher in women compared to men in the Etravirine arm in the Phase 3 trials (rash ≥ Grade 2 was reported in 9/60 [15.0%] women versus 51/539 [9.5%] men; discontinuations due to rash were reported in 3/60 [5.0%] women versus 10/539 [1.9%] men) [see Warnings and Precautions (5.1)] . Patients with a history of NNRTI-related rash did not appear to be at increased risk for the development of Etravirine-related rash compared to patients without a history of NNRTI-related rash.

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.

There is no specific antidote for overdose with Etravirine. Human experience of overdose with Etravirine is limited. The highest dose studied in healthy volunteers was 400 mg once daily. Treatment of overdose with Etravirine consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Because etravirine is highly protein bound, dialysis is unlikely to result in significant removal of the active substance.

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 C ₂₀H ₁₅BrN ₆O and its molecular weight is 435.28. Etravirine has the following structural formula:

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).

Etravirine 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 colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate and microcrystalline cellulose.

Etravirine 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 colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose and silicified microcrystalline cellulose.

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.

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)] .

None.

The following adverse reactions are described in greater detail in other sections:

• Severe skin and hypersensitivity reactions [see Warnings and Precautions (5.1)] .
• Immune reconstitution syndrome [see Warnings and Precautions (5.3)] .

Co-administration of Etravirine with other drugs can alter the concentrations of other drugs and other drugs may alter the concentrations of etravirine. The potential drug-drug interactions must be considered prior to and during therapy. ( 7, 12.3)

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)] .

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.

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.

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)] .

Etravirine, 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 and pediatric patients 2 years of age and older [see Microbiology (12.4)and Clinical Studies (14)] .

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

• 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. ( 5.1)
• Monitor for immune reconstitution syndrome and fat redistribution. ( 5.3, 5.4)

• Adult patients: 200 mg (one 200 mg tablet or two 100 mg tablets) taken twice daily following a meal. ( 2.1, 2.2, 2.4)
• Pregnant patients: 200 mg (one 200 mg tablet or two 100 mg tablets) taken twice daily following a meal. ( 2.2)
• Pediatric patients (2 years to less than 18 years of age and weighing at least 10 kg): dosage of Etravirine is based on body weight and should not exceed the recommended adult dose. Etravirine tablets should be taken following a meal. ( 2.3)

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.

• 100 mg white to off-white oval tablets debossed with "TMC125" on one side and "100" on the other side.
• 200 mg white to off-white, biconvex, oblong tablets debossed with "T200" on one side.

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)] .

• Lactation: Breastfeeding is not recommended due to the potential for HIV-1 transmission. ( 8.2)

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.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

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)] .

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.

Etravirine 100 mg tablets are supplied as white to off-white, oval tablets containing 100 mg of etravirine. Each tablet is debossed with "TMC125" on one side and "100" on the other side.

Etravirine 200 mg tablets are supplied as white to off-white, biconvex, oblong tablets containing 200 mg of etravirine. Each tablet is debossed with "T200" on one side.

Etravirine tablets are packaged in bottles in the following configuration:

• 100 mg tablets—bottles of 120 (NDC 10147-0570-1). Each bottle contains 3 desiccant pouches.
• 200 mg tablets—bottles of 60 (NDC 10147-0571-1). Each bottle contains 3 desiccant pouches.

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)] .

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)] .

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.

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.

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)].

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)].

120 Tablets

NDC 10147-0570-1

Etravirine

tablets

100 mg

Each tablet contains

100 mg of etravirine.

Rx only

PATRIOT

PHARMACEUTICALS LLC

ALERT: Find out about medicines that

should NOT be taken with Etravirine tablets

from your healthcare provider.

60 Tablets

NDC 10147-0571-1

Etravirine

tablets

200 mg

Each tablet contains

200 mg of etravirine.

Rx only

PATRIOT

PHARMACEUTICALS LLC

ALERT: Find out about medicines that

should NOT be taken with Etravirine tablets

from your healthcare provider.

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.

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)] .

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

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.

Clinical Trials Experience in Adults

The safety assessment is based on all data from 1203 subjects in the Phase 3 placebo-controlled trials, TMC125-C206 and TMC125-C216, conducted in antiretroviral treatment-experienced HIV-1-infected adult subjects, 599 of whom received Etravirine (200 mg twice daily). In these pooled trials, the median exposure for subjects in the Etravirine arm and placebo arm was 52.3 and 51.0 weeks, respectively. Discontinuations due to adverse drug reactions (ADRs) were 5.2% in the Etravirine 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 less than 0.1% of subjects during clinical development with Etravirine [see Warnings and Precautions (5.1)] . A total of 2.2% of HIV-1-infected subjects in Phase 3 trials receiving Etravirine 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 to 2 weeks on continued therapy. The incidence of rash was higher in women compared to men in the Etravirine arm in the Phase 3 trials (rash ≥ Grade 2 was reported in 9/60 [15.0%] women versus 51/539 [9.5%] men; discontinuations due to rash were reported in 3/60 [5.0%] women versus 10/539 [1.9%] men) [see Warnings and Precautions (5.1)] . Patients with a history of NNRTI-related rash did not appear to be at increased risk for the development of Etravirine-related rash compared to patients without a history of NNRTI-related rash.

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.

There is no specific antidote for overdose with Etravirine. Human experience of overdose with Etravirine is limited. The highest dose studied in healthy volunteers was 400 mg once daily. Treatment of overdose with Etravirine consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Because etravirine is highly protein bound, dialysis is unlikely to result in significant removal of the active substance.

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 C ₂₀H ₁₅BrN ₆O and its molecular weight is 435.28. Etravirine has the following structural formula:

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).

Etravirine 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 colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate and microcrystalline cellulose.

Etravirine 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 colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose and silicified microcrystalline cellulose.

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.

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)] .

None.

The following adverse reactions are described in greater detail in other sections:

• Severe skin and hypersensitivity reactions [see Warnings and Precautions (5.1)] .
• Immune reconstitution syndrome [see Warnings and Precautions (5.3)] .

Co-administration of Etravirine with other drugs can alter the concentrations of other drugs and other drugs may alter the concentrations of etravirine. The potential drug-drug interactions must be considered prior to and during therapy. ( 7, 12.3)

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)] .

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.

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.

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)] .

Etravirine, 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 and pediatric patients 2 years of age and older [see Microbiology (12.4)and Clinical Studies (14)] .

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

• 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. ( 5.1)
• Monitor for immune reconstitution syndrome and fat redistribution. ( 5.3, 5.4)

• Adult patients: 200 mg (one 200 mg tablet or two 100 mg tablets) taken twice daily following a meal. ( 2.1, 2.2, 2.4)
• Pregnant patients: 200 mg (one 200 mg tablet or two 100 mg tablets) taken twice daily following a meal. ( 2.2)
• Pediatric patients (2 years to less than 18 years of age and weighing at least 10 kg): dosage of Etravirine is based on body weight and should not exceed the recommended adult dose. Etravirine tablets should be taken following a meal. ( 2.3)

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.

• 100 mg white to off-white oval tablets debossed with "TMC125" on one side and "100" on the other side.
• 200 mg white to off-white, biconvex, oblong tablets debossed with "T200" on one side.

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)] .

• Lactation: Breastfeeding is not recommended due to the potential for HIV-1 transmission. ( 8.2)

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.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

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)] .

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.

Etravirine 100 mg tablets are supplied as white to off-white, oval tablets containing 100 mg of etravirine. Each tablet is debossed with "TMC125" on one side and "100" on the other side.

Etravirine 200 mg tablets are supplied as white to off-white, biconvex, oblong tablets containing 200 mg of etravirine. Each tablet is debossed with "T200" on one side.

Etravirine tablets are packaged in bottles in the following configuration:

• 100 mg tablets—bottles of 120 (NDC 10147-0570-1). Each bottle contains 3 desiccant pouches.
• 200 mg tablets—bottles of 60 (NDC 10147-0571-1). Each bottle contains 3 desiccant pouches.

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)] .

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)] .

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.

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.

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)].

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)].

120 Tablets

NDC 10147-0570-1

Etravirine

tablets

100 mg

Each tablet contains

100 mg of etravirine.

Rx only

PATRIOT

PHARMACEUTICALS LLC

ALERT: Find out about medicines that

should NOT be taken with Etravirine tablets

from your healthcare provider.

60 Tablets

NDC 10147-0571-1

Etravirine

tablets

200 mg

Each tablet contains

200 mg of etravirine.

Rx only

PATRIOT

PHARMACEUTICALS LLC

ALERT: Find out about medicines that

should NOT be taken with Etravirine tablets

from your healthcare provider.

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.

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)] .

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

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.