ETRAVIRINE by Leading Pharma, LLC / Carnegie Pharmaceuticals LLC ETRAVIRINE tablet

ETRAVIRINE by

Drug Labeling and Warnings

ETRAVIRINE by is a Prescription medication manufactured, distributed, or labeled by Leading Pharma, LLC, Carnegie Pharmaceuticals LLC. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • 1 INDICATIONS AND USAGE

    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)]

  • 2 DOSAGE AND ADMINISTRATION

    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)].

    Table 1: Recommended Dosage of Etravirine Tablets for Pediatric Patients 2 Years to Less Than 18 Years of Age

    Body Weight

    kilograms (kg)

    Dose

    greater than or equal to 10 kg to less than 20 kg

    100 mg twice daily

    greater than or equal to 20 kg to less than 25 kg

    125 mg twice daily

    greater than or equal to 25 kg to less than 30 kg

    150 mg twice daily

    greater than or equal to 30 kg

    200 mg twice daily

    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.
  • 3 DOSAGE FORMS AND STRENGTHS

    • 100 mg white to off-white, uncoated, oval shaped tablet, debossed “CP112” on one side and plain on other side.
    • 200 mg white to off-white, uncoated, oval shaped tablet, debossed “CP113” on one side and plain on other side.
  • 4 CONTRAINDICATIONS

    None.

  • 5 WARNINGS AND PRECAUTIONS

    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 4 for 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 avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia (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 ADVERSE REACTIONS

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

    6.1 Clinical Trial 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.

    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 tablets (200 mg twice daily). In these pooled trials, the median exposure for subjects in the etravirine tablets 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 tablets 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 tablets [see Warnings and Precautions (5.1)]. A total of 2.2% of HIV-1-infected subjects in Phase 3 trials receiving etravirine tablets 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 tablets 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 tablets-related rash compared to patients without a history of NNRTI- related rash.

    Common Adverse Reactions

    Clinical ADRs of moderate intensity or greater (greater than or equal to Grade 2) and reported in at least 2% of subjects treated with etravirine tablets and occurring at a higher rate compared to placebo (excess

    of 1%) are presented in Table 2. Laboratory abnormalities considered ADRs are included in Table 3.

    Table 2: Adverse Drug Reactions (Grades 2 to 4) in at Least 2% of Adult Subjects (Pooled TMC125-C206 and TMC125-C216 Trials)

    Preferred Term

    Etravirine tablets + BR
    N=599
    %

    Placebo + BR
    N=604
    %

    Rash

    10%

    3%

    Peripheral neuropathy

    4%

    2%

    N=total number of subjects per treatment group; BR=background regimen

    Less Common Adverse Reactions

    Treatment-emergent ADRs occurring in less than 2% of subjects (599 subjects) receiving etravirine tablets and of at least moderate intensity (greater than or equal to Grade 2) are listed below by body system:

    Cardiac Disorders: myocardial infarction, angina pectoris, atrial fibrillation

    Ear and Labyrinth Disorders: vertigo Eye Disorders: blurred vision

    Gastrointestinal Disorders: gastroesophageal reflux disease, flatulence, gastritis, abdominal distension, pancreatitis, constipation, dry mouth, hematemesis, retching, stomatitis

    General Disorders and Administration Site Conditions: sluggishness Hematologic Disorders: hemolytic anemia

    Hepatobiliary Disorders: hepatic failure, hepatomegaly, cytolytic hepatitis, hepatic steatosis, hepatitis

    Immune System Disorders: drug hypersensitivity, immune reconstitution syndrome

    Metabolism and Nutrition Disorders: diabetes mellitus, anorexia, dyslipidemia

    Nervous System Disorders: paresthesia, somnolence, convulsion, hypoesthesia, amnesia, syncope, disturbance in attention, hypersomnia, tremor

    Psychiatric Disorders: anxiety, sleep disorders, abnormal dreams, confusional state, disorientation, nervousness,, nightmares

    Renal and Urinary Disorders: acute renal failure

    Reproductive System and Breast Disorders: gynecomastia

    Respiratory, Thoracic and Mediastinal Disorders: exertional dyspnea, bronchospasm

    Skin and Subcutaneous Tissue Disorders: night sweats, lipohypertrophy, prurigo, hyperhidrosis, dry skin, swelling face

    Additional ADRs of at least moderate intensity observed in other trials were acquired lipodystrophy, angioneurotic edema, erythema multiforme and hemorrhagic stroke, each reported in no more than 0.5% of subjects.

    Laboratory Abnormalities in Treatment-Experienced Patients

    Selected Grade 2 to Grade 4 laboratory abnormalities that represent a worsening from baseline observed in adult subjects treated with etravirine tablets are presented in Table 3.

    Table 3: Selected Grade 2 to 4 Laboratory Abnormalities Observed in Treatment-Experienced Subjects (Pooled TMC125-C206 and TMC125- C216 Trials)

    Laboratory Parameter


    DAIDS Toxicity Range

    Etravirine tablets + BR

    N=599

    %

    Placebo + BR N=604

    %

    GENERAL BIOCHEMISTRY

    Pancreatic amylase

    Grade 2

    > 1.5–2 × ULN

    7%

    8%

    Grade 3

    > 2–5 × ULN

    7%

    8%

    Grade 4

    5 × ULN

    2%

    1%

    Lipase

    Grade 2

    > 1.5–3 × ULN

    4%

    6%

    Grade 3

    > 3–5 × ULN

    2%

    2%

    Grade 4

    5 × ULN

    1%

    < 1%

    Creatinine

    Grade 2

    > 1.4–1.8 × ULN

    6%

    5%

    Grade 3

    > 1.9–3.4 × ULN

    2%

    1%

    Grade 4

    > 3.4 × ULN

    0%

    < 1%

    HEMATOLOGY

    Decreased

    hemoglobin

    Grade 2

    90–99 g/L

    2%

    4%

    Grade 3

    70–89 g/L

    < 1%

    < 1%

    Grade 4

    < 70 g/L

    < 1%

    < 1%

    White blood cell count

    Grade 2

    1,500–1,999/mm3

    2%

    3%

    Grade 3

    1,000–1,499/mm3

    1%

    4%

    Grade 4

    < 1,000/mm3

    1%

    < 1%

    Neutrophils

    Grade 2

    750–999/mm3

    5%

    6%

    Grade 3

    500–749/mm3

    4%

    4%

    Grade 4

    < 500/mm3

    2%

    3%

    Platelet count

    Grade 2

    50,000–

    99,999/mm3

    3%

    5%

    Grade 3

    25,000–

    49,999/mm3

    1%

    1%

    Grade 4

    < 25,000/mm3

    < 1%

    < 1%

    LIPIDS AND GLUCOSE

    Total cholesterol


    Grade 2

    > 6.20–7.77

    mmol/L 240–300 mg/dL

    20%

    17%

    Grade 3

    > 7.77 mmol/L

    300 mg/dL

    8%

    5%

    Low density

    lipoprotein

    Grade 2

    4.13–4.9 mmol/L

    160–190 mg/dL

    13%

    12%

    Grade 3

    > 4.9 mmol/L

    > 190 mg/dL

    7%

    7%

    Triglycerides

    Grade 2

    5.65–8.48 mmol/L

    500–750 mg/dL

    9%

    7%

    Grade 3

    8.49–13.56

    mmol/L 751–1200 mg/dL

    6%

    4%

    Grade 4

    > 13.56 mmol/L

    > 1200 mg/dL

    4%

    2%

    Elevated glucose levels


    Grade 2

    6.95–13.88

    mmol/L 161–250 mg/dL

    15%

    13%

    Grade 3

    13.89–27.75

    mmol/L 251–500 mg/dL

    4%

    2%

    Grade 4

    > 27.75 mmol/L

    > 500 mg/dL

    0%

    < 1%

    HEPATIC PARAMETERS

    Alanine amino transferase

    Grade 2

    2.6–5 × ULN

    6%

    5%

    Grade 3

    5.1–10 × ULN

    3%

    2%

    Grade 4

    > 10 × ULN

    1%

    < 1%

    Aspartate amino transferase

    Grade 2

    2.6–5 × ULN

    6%

    8%

    Grade 3

    5.1–10 × ULN

    3%

    2%

    Grade 4

    > 10 × ULN

    < 1%

    < 1%

    ULN=Upper Limit of Normal; BR=background regimen

    Patients Co-Infected With Hepatitis B and/or Hepatitis C Virus

    In Phase 3 trials TMC125-C206 and TMC125-C216, 139 subjects (12.3%) with chronic hepatitis B and/or hepatitis C virus co-infection out of 1129 subjects were permitted to enroll. AST and ALT abnormalities occurred more frequently in hepatitis B and/or hepatitis C virus co-infected subjects for both treatment groups. Grade 2 or higher laboratory abnormalities that represent a worsening from baseline of AST, ALT or total bilirubin occurred in 27.8%, 25.0% and 7.1% respectively, of etravirine tablets-treated co-infected subjects as compared to 6.7%, 7.5% and 1.8% of non-co-infected etravirine tablets-treated subjects. In general, adverse events reported by etravirine tablets-treated subjects with hepatitis B and/or hepatitis C virus co-infection were similar to etravirine tablets-treated subjects without hepatitis B and/or hepatitis C virus co-infection.

    Clinical Trials Experience inPediatric Subjects (2 Years to Less Than18 years of age)

    The safety assessment in pediatric subjects is based on two single-arm trials. TMC125-C213 is a Phase 2 trial in which 101 antiretroviral treatment-experienced HIV-1 infected pediatric subjects 6 years to less than 18 years of age received etravirine tablets in combination with other antiretroviral agents (Week 24 analysis). TMC125-C234/IMPAACT P1090 is a Phase 1/2 trial in which 20 antiretroviral treatment- experienced HIV-1 infected pediatric subjects 2 years to less than 6 years of age received etravirine tablets in combination with other antiretroviral agents (Week 24 analysis) [see Clinical Studies (14.2)].

    In TMC125-C213, the frequency, type and severity of adverse drug reactions in pediatric subjects 6 years to less than 18 years of age were comparable to those observed in adult subjects, except for rash which was observed more frequently in pediatric subjects. The most common adverse drug reactions in at least 2% of pediatric subjects were rash and diarrhea. Rash was reported more frequently in female subjects than in male subjects (rash ≥ Grade 2 was reported in 13/64 [20.3%] females versus 2/37 [5.4%] males; discontinuations due to rash were reported in 4/64 [6.3%] females versus 0/37 [0%] males). Rash (greater than or equal to Grade 2) occurred in 15% of pediatric subjects from 6 years to less than 18 years of age. In the majority of cases, rash was mild to moderate, of macular/papular type, and occurred in the second week of therapy. Rash was self-limiting and generally resolved within 1 week on continued therapy. The safety profile for subjects who completed 48 weeks of treatment was similar to the safety profile for subjects who completed 24 weeks of treatment.

    In TMC125-C234/IMPAACT P1090, the frequency, type and severity of adverse drug reactions in pediatric subjects 2 years to less than 6 years of age through Week 24 were comparable to those observed in adults. The most common adverse drug reactions (any grade) of pediatric subjects were rash (50% [10/20]) and diarrhea (25% [5/20]). In this age group, no subjects had Grade 3 or Grade 4 rash and no subjects discontinued prematurely due to rash. One subject discontinued etravirine due to asymptomatic lipase elevation.

    6.2 Postmarketing Experience

    The following events have been identified during postmarketing use of etravirine tablets. 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 DRUG INTERACTIONS


    7.1 Potential for Other Drugs to Affect Etravirine Tablets

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

    7.2 Potential for Etravirine Tablets 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 tablets 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 tablets and/or co-administered drug may be recommended. Drugs that are not recommended for co-administration with etravirine tablets are also included in Table 4 [see Clinical Pharmacology (12.3) ].

    Table 4: Significant Drug Interactions
    Concomitant Drug Class:
    Drug Name    		Effect on Concentration of Etravirine or Concomitant DrugClinical Comment
  • * The interaction between INTELENCE and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.
  • † The reference for etravirine exposure is the pharmacokinetic parameters of etravirine in the presence of darunavir/ritonavir.
    		•
    ↑ = increase; ↓ = decrease; ↔ = no change

    HIV-antiviral agents: integrase strand inhibitors

    dolutegravir*

    ↓ dolutegravir

    ↔ etravirine

    Etravirine significantly reduced plasma concentrations of dolutegravir. Using cross-study comparisons to historical pharmacokinetic data for etravirine, dolutegravir did not appear to affect the pharmacokinetics of etravirine.

    dolutegravir/darunavir/ritonavir*

    ↓ dolutegravir

    ↔ etravirine

    The effect of etravirine on dolutegravir plasma concentrations was mitigated by co- administration of darunavir/ritonavir or lopinavir/ritonavir, and is expected to be mitigated by atazanavir/ritonavir.

    dolutegravir/lopinavir/ritonavir*

    ↔ dolutegravir

    ↔ etravirine

    Dolutegravir should only be used with etravirine tablets when co- administered with atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir.

    HIV-antiviral agents: non-nucleoside reverse transcriptase inhibitors (NNRTIs)

    efavirenz*
    nevirapine*

    ↓ etravirine

    Combining two NNRTIs has not been shown to be beneficial. Concomitant use of etravirine tablets with efavirenz or nevirapine may cause a significant decrease in the   plasma concentrations of Etravirine and loss of therapeutic effect of etravirine tablets. Co-administration of etravirine tablets and other NNRTIs is not recommended.

    delavirdine



    rilpivirine

    ↓ etravirine



    ↓ rilpivirine

    ↔ etravirine

    Combining two NNRTIs has not been shown to be beneficial. Etravirine tablets and delavirdine should not be co-administered. Combining two NNRTIs has not been shown to be beneficial. Co- administration of etravirine tablets and

    rilpivirine is not recommended.

    HIV-antiviral agents: protease inhibitors (PIs)

    atazanavir*

    (without ritonavir)






    atazanavir/ritonavir*









    atazanavir/cobicistat








    darunavir/ritonavir*





    darunavir/cobicistat




    fosamprenavir

    (without ritonavir)





    fosamprenavir/ritonavir*







    indinavir*

    (without ritonavir)








    lopinavir/ritonavir*


    ↓ atazanavir






    ↓ atazanavir

    ↔ etravirine








    ↓ atazanavir

    ↓ cobicistat







    ↓ etravirine





    ↓ cobicistat darunavir: effect unknown



    ↑ amprenavir





    ↑ amprenavir








    ↓ indinavir








    ↓ etravirine

    Co-administration of etravirine tablets and atazanavir without low- dose ritonavir is not recommended.

    Concomitant use of etravirine tablets with atazanavir/ritonavir decreased atazanavir Cmin but it is not considered clinically relevant. The mean systemic exposure (AUC) of etravirine after co-administration of etravirine tablets with atazanavir/ritonavir in HIV-infected subjects was similar to the mean systemic exposure of etravirine observed in the Phase 3 trials after co-administration of etravirine tablets and darunavir/ritonavir (as part of the background regimen). Etravirine tablets and atazanavir/ritonavir can be co-administered without dose adjustments.

    Co-administration of etravirine tablets with atazanavir/cobicistat is not recommended because it may result in loss of therapeutic effect and development of resistance to atazanavir.

    The mean systemic exposure (AUC) of etravirine was reduced when etravirine tablets 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, etravirine tablets and darunavir/ritonavir can be co-administered without dose adjustments.

    Co-administration of etravirine tablets with darunavir/cobicistat is not recommended because it may result in loss of therapeutic effect and development of resistance to darunavir.

    Concomitant use of etravirine tablets with fosamprenavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of amprenavir. Co-administration of etravirine tablets and fosamprenavir without low-dose ritonavir is not recommended.

    Due to a significant increase in the systemic exposure of amprenavir, the appropriate doses of the combination of etravirine tablets and fosamprenavir /ritonavir have not been established. Co- administration of etravirine tablets and fosamprenavir/ritonavir is not recommended.

    Concomitant use of etravirine tablets with indinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of indinavir. Co-administration of etravirine tablets and indinavir without low- dose ritonavir is not recommended.

    The mean systemic exposure (AUC) of Etravirine was reduced after co-administration of etravirine tablets 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, etravirine tablets and

    lopinavir/ritonavir can be co-administered without dose adjustments.

    nelfinavir

    (without ritonavir)








    ritonavir*






    saquinavir/ritonavir*









    tipranavir/ritonavir*

    ↑ nelfinavir








    ↓ etravirine







    ↓ etravirine









    ↓ etravirine

    Concomitant use of etravirine tablets with nelfinavir without low- dose ritonavir may cause a significant alteration in the plasma concentration of nelfinavir. Co- administration of etravirine tablets and nelfinavir without low- dose ritonavir is not recommended.

    Concomitant use of etravirine tablets with ritonavir 600 mg twice daily may cause a significant decrease in the plasma concentration of Etravirine and loss of therapeutic effect of etravirine tablets. Co-administration of etravirine tablets and ritonavir 600 mg twice daily is not recommended.

    The mean systemic exposure (AUC) of etravirine was reduced when etravirine tablets were 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, etravirine tablets and saquinavir/ritonavir can be co-administered without dose adjustments.

    Concomitant use of etravirine tablets with tipranavir/ritonavir may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of etravirine tablets. Co-administration of etravirine tablets and tipranavir/ritonavir is not recommended.

    CCR5 antagonists

    maraviroc*






    maraviroc/darunavir/ritonavir*†

    ↔ etravirine

    ↓ maraviroc





    ↑ maraviroc

    When etravirine tablets are 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 twice daily. No dose adjustment of etravirine tablets is needed.

    When etravirine tablets are co-administered with maraviroc in the presence of a potent CYP3A inhibitor (e.g., protease inhibitor), the recommended dose of maraviroc is 150 mg twice daily. No dose adjustment of etravirine tablets is needed.

    Other agents


    Antiarrhythmics

    : digoxin*





    amiodarone

    bepridil

    disopyramide

    flecainide

    lidocaine

    (systemic)

    mexiletine

    propafenone

    quinidine

    ↔ etravirine

    ↑ digoxin








    ↓ antiarrhythmics

    For patients who are initiating a combination of etravirine tablets and digoxin, the lowest dose of digoxin should initially be prescribed. For patients on a stable digoxin regimen and initiating etravirine tablets, no dose adjustment of either etravirine tablets 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.


    Concentrations of these antiarrhythmics may be decreased when co- administered with etravirine tablets. Etravirine tablets and antiarrhythmics   should be co-administered with caution. Drug concentration monitoring is recommended, if available.



    Anticoagulant:

    warfarin


    ↑ anticoagulants

    Warfarin concentrations   may be increased when co-administered with etravirine tablets. The international normalized ratio (INR) should be monitored when warfarin is combined with etravirine tablets.

    Anticonvulsants:

    carbamazepine

    phenobarbital

    phenytoin

    ↓ etravirine

    Carbamazepine, phenobarbital and phenytoin are   inducers of CYP450 enzymes. Etravirine tablets should not with carbamazepine, phenobarbital, or phenytoin as co- administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of etravirine tablets.



    Antifungals :

    fluconazole*






    voriconazole*




    ↑ etravirine

    ↔ fluconazole






    voriconazole

    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 etravirine tablets or

    fluconazole is needed.

    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 etravirine tablets or

    voriconazole is needed.



    Antifungals:

    itraconazole

    ketoconazole

    posaconazole


    ↑ etravirine

    ↓ 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 etravirine tablets may increase plasma concentrations of etravirine.

    Simultaneously, plasma concentrations of itraconazole or ketoconazole may be decreased by etravirine tablets. Dose

    Adjustments for itraconazole, ketoconazole or posaconazole may be necessary depending on the other co- administered drugs.


    Antiinfective:

    clarithromycin*



    ↑ etravirine

    ↓ clarithromycin

    ↑ 14-OH-

    clarithromycin

    Clarithromycin exposure was decreased by etravirine tablets; however, concentrations of the active metabolite, 14- hydroxy-clarithromycin, 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.


    Antimalarial:

    artemether/lumefantrine*



    ↔ etravirine

    ↓ artemether

    ↓ dihydroartemisinin

    ↓ lumefantrine

    Caution is warranted when co-administering etravirine tablets and artemether/lumefantrine as it is unknown whether the decrease in exposure of artemether or its active metabolite, dihydroartemisinin, could   result   in decreased antimalarial efficacy. No dose adjustment is needed for etravirine tablets.


    Antimycobacterials:

    rifampin

    rifapentine


    ↓ etravirine

    Rifampin and rifapentine are potent inducers of CYP450 enzymes. Etravirine tablets 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 etravirine tablets.



    Antimycobacterial:

    rifabutin*



    ↓ etravirine

    ↓ rifabutin

    ↓ 25-O-

    desacetylrifabutin

    If etravirine tablets are NOT co-administered with a protease inhibitor/ritonavir, then rifabutin at a dose of 300 mg once daily is recommended.

    If etravirine tablets are 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.

    Benzodiazepine:

    diazepam

    ↑ diazepam

    Concomitant use of etravirine tablets with diazepam may increase plasma concentrations of diazepam. A decrease in diazepam dose may be needed.


    Corticosteroid:

    dexamethasone (systemic)


    ↓ etravirine

    Systemic dexamethasone induces CYP3A and can decrease etravirine plasma concentrations.

    This may result in loss of therapeutic effect of etravirine tablets. 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)


    ↓ etravirine

    Concomitant use of etravirine tablets with products containing St. John's wort may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of etravirine tablets. Etravirine tablets and products containing St. John's wort should not be co-administered.

    Hepatitis C virus (HCV) direct-acting antivirals :


    daclatasvir

    ↓ daclatasvir

    Co-administration of etravirine tablets with daclatasvir may decrease daclatasvir concentrations. Increase the daclatasvir dose to 90 mg once daily.

    elbasvir/grazoprevir

    ↓ elbasvir

    ↓ grazoprevir

    Co-administration of etravirine tablets with elbasvir/grazoprevir may decrease elbasvir and grazoprevir concentrations, leading to reduced therapeutic effect of elbasvir/grazoprevir. Co-administration is not recommended.

    simeprevir

    ↓ simeprevir

    Co-administration of etravirine tablets with simeprevir may decrease simeprevir concentrations. Co- administration is not recommended.

    HMG-CoA reductase inhibitors:

    atorvastatin*


    ↔ etravirine

    ↓ atorvastatin

    ↑ 2-OH-atorvastatin

    The combination of etravirine tablets and atorvastatin can be given without dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response.

    pravastatin rosuvastatin

    ↔ etravirine

    ↔ pravastatin

    ↔ rosuvastatin

    No interaction between pravastatin, rosuvastatin and etravirine tablets are expected.

    Lovastatin

    simvastatin




    fluvastatin

    pitavastatin

    ↓ lovastatin

    ↓ simvastatin




    ↑ fluvastatin

    ↑ pitavastatin

    Lovastatin and simvastatin are CYP3A substrates and co-administration with etravirine tablets may result in lower plasma concentrations of the HMG-CoA reductase inhibitor.

    Fluvastatin and pitavastatin are metabolized by CYP2C9 and co-administration with etravirine tablets 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

    ↓ immunosuppressant

    Etravirine tablets 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*

    methadone*



    ↔ etravirine

    ↓ buprenorphine

    ↔

    Norbuprenorphine

    ↔ methadone

    Etravirine tablets 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. Etravirine tablets 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

    ↓ sildenafil

    ↓ N-desmethyl- sildenafil

    Etravirine tablets 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

    ↓ clopidogrel

    (active) metabolite

    Activation of clopidogrel to its active metabolite may be decreased when clopidogrel is co- administered with etravirine tablets. Alternatives to clopidogrel should be considered.

    7.4 Drugs Without Clinically Significant Interactions with Etravirine Tablets

    In addition to the drugs included in Table 4, the interaction between etravirine tablets 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.

  • 10 OVERDOSAGE

    There is no specific antidote for overdose with etravirine tablets. Human experience of overdose with etravirine tablets is limited. The highest dose studied in healthy volunteers was 400 mg once daily.

    Treatment of overdose with etravirine tablets 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.

  • 11 DESCRIPTION

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

    The chemical name for etravirine is 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4- pyrimidinyl]oxy]-3,5-dimethylbenzonitrile. Its molecular formula is C20H15BrN6O and its molecular weight is 435.28. Etravirine has the following structural formula:

    chemicalstructure

    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 povidone, microcrystalline cellulose, sodium lauryl sulfate, crospovidone, sodium starch glycolate, silicon dioxide and magnesium stearate.

    Etravirine 200 mg tablets are available as white to off-white, oval tables for oral administration. Each 200 mg tablet contains 200 mg of etravirine and the inactive ingredients povidone, microcrystalline cellulose, sodium lauryl sulfate, crospovidone, sodium starch glycolate, silicon dioxide and magnesium stearate.

  • 12 CLINICAL PHARMACOLOGY


    12.1 Mechanism of Action

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

    12.2 Pharmacodynamics

    Cardiac Electrophysiology

    In a thorough QT/QTc study in 41 healthy subjects, etravirine tablets 200 mg twice daily or 400 mg once daily did not affect the QT/QTc interval.

    12.3 Pharmacokinetics

    The pharmacokinetic properties of etravirine tablets 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.

    Table 5: Population Pharmacokinetic Estimates of Etravirine 200 mg Twice Daily in HIV-1-Infected Adult Subjects (Integrated Data from Phase 3 Trials at Week 48)*
  • * All HIV- 1- infected subjects enrolled in Phase 3 clinical trials received darunavir/ritonavir 600/100 mg twice daily as part of their background regimen. Therefore, the pharmacokinetic parameter estimates shown in Table 5 account for reductions in the pharmacokinetic parameters of etravirine due to co-administration of etravirine tablets with darunavir/ritonavir.
    		•

    Parameter

    Etravirine

    N=575

    AUC12h (ng·h/mL)

      Geometric mean ± standard deviation

    4522 ± 4710

      Median (range)

    4380 (458-59084)

    C0h (ng/mL)

      Geometric mean ± standard deviation

    297 ± 391

      Median (range)

    298 (2-4852)

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

    Absorption and Bioavailability

    Following oral administration, Etravirine was absorbed with a Tmax of about 2.5 to 4 hours. The absolute oral bioavailability of etravirine tablets are 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 etravirine tablets were administered under fasting conditions, as compared to when etravirine tablets were administered 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% to 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 14C-etravirine 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.

    Specific Populations

    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 [see Use in Specific Populations (8.5)].

    Pediatric Patients

    The pharmacokinetics of etravirine in 115 treatment-experienced HIV-1-infected pediatric subjects, 2 years to less than 18 years of age showed that the administered weight-based dosages resulted in etravirine exposure comparable to that in adults receiving etravirine tablets 200 mg twice daily [see Dosage and Administration (2.3)]. The pharmacokinetic parameters for etravirine (AUC12h and C0h) are summarized in Table 6.

    Table 6: Pharmacokinetic Parameters for Etravirine in Treatment- Experienced HIV-1-Infected Pediatric Subjects 2 Years to Less Than 18 Years of Age (TMC125-C213 [Population PK] and TMC125- C234/P1090)

    Study

    TMC125-C213

    TMC125- C234/IMPAACT

    P1090

    Age Range (years)

    (6 years to less than 18 years)

    (2 years to less than 6 years)

    Parameter

    N=101

    N=14

    AUC12h (ng·h/mL)

    Geometric mean ± standard deviation

    3742 ± 4314

    3504 ± 2923

    Median (range)

    4499 (62-28865)

    3579 (1221-11815)

    C0h (ng/mL)

    Geometric mean ± standard deviation

    205 ± 342

    183 ± 240

    Median (range)

    287 (2-2276)

    162 (54-908)

    The pharmacokinetics and dose of etravirine in pediatric subjects less than 2 years of age have not been established [see Use in Specific Populations (8.4)].

    Male and Female Patients

    No significant pharmacokinetic differences have been observed between males and females.

    Racial or Ethnic Groups

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

    Patients with 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 less than 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 [see Use in Specific Populations (8.7)].

    Patients with Hepatic Impairment

    Etravirine is primarily metabolized by the liver. The steady state pharmacokinetic parameters of etravirine were similar after multiple dose administration of etravirine tablets to subjects with normal hepatic function (16 subjects), mild hepatic impairment (Child-Pugh Class A, 8 subjects), and moderate hepatic impairment (Child-Pugh Class B, 8 subjects). The effect of severe hepatic impairment on the pharmacokinetics of etravirine has not been evaluated [see Use in Specific Populations (8.6)].

    Pregnancy and Postpartum

    After intake of etravirine tablets 200 mg twice daily in combination with other antiretroviral agents (13 subjects with 2 NRTIs, 1 subject with 2 NRTIs + lopinavir + ritonavir, 1 subject with 2 NRTIs + raltegravir), based on intra-individual comparison, the Cmax and AUC12h of total etravirine were 23 to 42% higher during pregnancy compared with postpartum (612 weeks). The Cmin of total etravirine was 78 to 125% higher during pregnancy compared with postpartum (612 weeks), while two subjects had Cmin <10 ng/mL in the postpartum period (612 weeks) [Cmin of total etravirine was 11 to 16% higher when these 2 subjects are excluded] (see Table 7) [see Use in Specific Populations (8.1)]. Increased etravirine exposures during pregnancy are not considered clinically significant. The protein binding of etravirine was similar (>99%) during the second trimester, third trimester, and postpartum period.

    Table 7: Pharmacokinetic Results of Total Etravirine After Administration of Etravirine 200 mg Twice Daily as Part of an Antiretroviral Regimen, During the 2nd Trimester of Pregnancy, the 3rd Trimester of Pregnancy, and Postpartum.
  • * n=9 for AUC12h
  • † Two subjects had Cmin <10 ng/mL, Cmin was 334 ± 135 (315) in the postpartum period when these subjects were excluded from the descriptive analysis (N=8).
    		•

    Parameter Mean ± SD (median)

    Postpartum N=10

    2nd Trimester N=13

    3rd Trimester N=10*

    Cmin, ng/mL

    269 ± 182 (284)†

    383 ± 210 (346)

    349 ± 103 (371)

    Cmax, ng/mL

    569 ± 261 (528)

    774 ± 300 (828)

    785 ± 238 (694)

    AUC12h, ng·h/mL

    5004 ± 2521

    6617 ± 2766

    6846 ± 1482

    (5246)

    (6836)

    (6028)

    Patients with 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 etravirine tablets [see Adverse Reactions (6)], no dose adjustment is necessary in patients co-infected with hepatitis B and/or C virus.

    Drug Interactions

    Etravirine is a substrate of CYP3A, CYP2C9, and CYP2C19. Therefore, co-administration of etravirine tablets with drugs that induce or inhibit CYP3A, CYP2C9, and CYP2C19 may alter the therapeutic effect or adverse reaction profile of etravirine tablets.

    Etravirine is an inducer of CYP3A and inhibitor of CYP2C9, CYP2C19 and P-gp. Therefore, co-administration of drugs that are substrates of CYP3A, CYP2C9 and CYP2C19 or are transported by P-gp with etravirine tablets may alter the therapeutic effect or adverse reaction profile of the co-administered drug(s).

    Drug interaction studies were performed with etravirine tablets 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, Cmax, and Cmin values of etravirine are summarized in Table 8 (effect of other drugs on etravirine tablets). The effect of co-administration of etravirine tablets on the AUC, Cmax, and Cmin values of other drugs are summarized in Table 9 (effect of etravirine tablets on other drugs). For information regarding clinical recommendations, [see Drug Interactions (7)].

    Table 8: Drug Interactions: Pharmacokinetic Parameters for Etravirine in the Presence of Co-administered Drugs
    Co-administered DrugDose/Schedule of Co-administered DrugNExposureMean Ratio of Etravirine
    Pharmacokinetic Parameters
    90% CI; No Effect = 1.00
    CmaxAUCCmin
  • * The systemic exposure of etravirine when co-administered with atazanavir/ritonavir in HIV infected subjects is similar to exposures of etravirine observed in the Phase 3 trials after co-administration of etravirine tablets and darunavir/ritonavir (as part of the background regimen).
  • † The reference for etravirine exposure is the pharmacokinetic parameters of etravirine in the presence of darunavir/ritonavir.
    		•
    CI = Confidence Interval; N = number of subjects with data; N.A. = not available; ↑ = increase; ↓ = decrease; ↔ = no change

    Co-administration with HIV protease inhibitors (PIs)

    Atazanavir

    400 mg once

    daily

    14

    		↑

    1.47

    (1.36

    1.59)

    1.50

    (1.41

    1.59)

    1.58

    (1.46

    1.70)

    Atazanavir/ritonavir*

    300/100 mg once daily

    14

    		↑

    1.30

    (1.17

    1.44)

    1.30

    (1.18

    1.44)

    1.26

    (1.12

    1.42)

    Darunavir/ritonavir

    600/100 mg twice daily

    14

    		↓

    0.68

    (0.57

    0.82)

    0.63

    (0.54

    0.73)

    0.51

    (0.44

    0.61)

    Lopinavir/ritonavir (tablet)

    400/100 mg twice daily

    16

    		↓

    0.70

    (0.64

    0.78)

    0.65

    (0.59

    0.71)

    0.55

    (0.49

    0.62)

    Ritonavir

    600 mg twice daily

    11

    		↓

    0.68

    (0.55

    0.85)

    0.54

    (0.41

    0.73)

    N.A.

    Saquinavir/ritonavir

    1000/100 mg twice daily

    14

    		↓

    0.63

    (0.53

    0.75)

    0.67

    (0.56

    0.80)

    0.71

    (0.58

    0.87)

    Tipranavir/ritonavir

    500/200 mg twice daily

    19

    		↓

    0.29

    (0.22

    0.40)

    0.24

    (0.18

    0.33)

    0.18

    (0.13

    0.25)

    Co-administration with nucleoside reverse transcriptase inhibitors (NRTIs)

    Didanosine

    400 mg once daily

    15

    		↔

    1.16

    (1.02

    1.32)

    1.11

    (0.99

    1.25)

    1.05

    (0.93

    1.18)

    Tenofovir disoproxil fumarate

    300 mg once daily

    23

    		↓

    0.81

    (0.75

    0.88)

    0.81

    (0.75

    0.88)

    0.82

    (0.73

    0.91)

    Co-administration with CCR5 antagonists

    Maraviroc

    300 mg twice  daily

    14

    		↔

    1.05

    (0.95

    1.17)

    1.06

    (0.99

    1.14)

    1.08

    (0.98

    1.19)

    Maraviroc (when co- administered with darunavir/ritonavir)†

    150/600/100

    mg twice daily

    10

    		↔

    1.08

    (0.98

    1.20)

    1.00

    (0.86

    1.15)

    0.81

    (0.65

    1.01)

    Co-administration with integrase strand transfer inhibitors

    Raltegravir

    400 mg twice daily

    19

    		↔

    1.04
    (0.971.12)

    1.10
    (1.031.16)

    1.17
    (1.101.26)

    Co-administration with other drugs

    Artemether/lumefantrine

    80/480 mg, 6

    doses at 0, 8,

    24, 36, 48, and

    60 hours

    14

    		↔

    1.11

    (1.06

    1.17)

    1.10

    (1.06

    1.15)

    1.08

    (1.04

    1.14)

    Atorvastatin

    40 mg once daily

    16

    		↔

    0.97

    (0.93

    1.02)

    1.02

    (0.97

    1.07)

    1.10

    (1.02

    1.19)

    Clarithromycin

    500 mg twice daily

    15

    		↑

    1.46

    (1.38

    1.56)

    1.42

    (1.34

    1.50)

    1.46

    (1.36

    1.58)

    Fluconazole

    200 mg once daily in the morning

    16

    		↑

    1.75

    (1.60

    1.91)

    1.86

    (1.73

    2.00)

    2.09

    (1.90

    2.31)

    Omeprazole

    40 mg once daily

    18

    		↑

    1.17

    (0.96

    1.43)

    1.41

    (1.22

    1.62)

    N.A.

    Paroxetine

    20 mg once daily

    16

    		↔

    1.05

    (0.96

    1.15)

    1.01

    (0.93

    1.10)

    1.07

    (0.98

    1.17)

    Ranitidine

    150 mg twice daily

    18

    		↓

    0.94

    (0.75

    1.17)

    0.86

    (0.76

    0.97)

    N.A.

    Rifabutin

    300 mg once daily

    12

    		↓

    0.63

    (0.53

    0.74)

    0.63

    (0.54

    0.74)

    0.65

    (0.56

    0.74)

    Voriconazole

    200 mg twice daily

    16

    		↑

    1.26

    (1.16

    1.38)

    1.36

    (1.25

    1.47)

    1.52

    (1.41

    1.64)
    Table 9: Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Etravirine Tablets
    Co-administered DrugDose/Schedule of Co-administered DrugNExposureMean Ratio of Co-administered Drug
    Pharmacokinetic Parameters
    90% CI; No effect = 1.00
    CmaxAUCCmin
  • * HIV-infected subjectsHIV-infected subjects
  • † compared to maraviroc 150 mg twice dailycompared to maraviroc 150 mg twice daily
    		•
    CI = Confidence Interval; N = number of subjects with data; N.A. = not available; ↑ = increase; ↓ = decrease; ↔ = no change

    Co-administration with HIV protease inhibitors (PIs)


    Atazanavir

    400 mg once daily

    14

    		↓

    0.97

    (0.73

    1.29)

    0.83

    (0.63

    1.09)

    0.53

    (0.38

    0.73)

    Atazanavir/ritonavir

    300/100 mg once daily

    13

    		↓

    0.97

    (0.89

    1.05)

    0.86

    (0.79

    0.93)

    0.62

    (0.55

    0.71)

    Atazanavir/ritonavir*

    300/100 mg once daily

    20

    		↓

    0.96

    (0.80

    1.16)

    0.96

    (0.76

    1.22)

    0.82

    (0.55

    1.22)

    Darunavir/ritonavir

    600/100 mg twice daily

    15

    		↔

    1.11

    (1.01

    1.22)

    1.15

    (1.05

    1.26)

    1.02

    (0.90

    1.17)

    Fosamprenavir/ritonavir

    700/100 mg twice daily

    8

    		↑

    1.62

    (1.47

    1.79)

    1.69

    (1.53

    1.86)

    1.77

    (1.39

    2.25)

    Lopinavir/ritonavir (tablet)

    400/100 mg twice daily

    16

    		↔

    0.89

    (0.82

    0.96)

    0.87

    (0.83

    0.92)

    0.80

    (0.73

    0.88)

    Saquinavir/ritonavir

    1000/100 mg twice daily

    15

    		↔

    1.00

    (0.70

    1.42)

    0.95

    (0.64

    1.42)

    0.80

    (0.46

    1.38)

    Tipranavir/ritonavir

    500/200 mg twice daily

    19

    		↑

    1.14

    (1.02

    1.27)

    1.18

    (1.03

    1.36)

    1.24

    (0.96

    1.59)

    Co-administration with nucleoside reverse transcriptase inhibitors (NRTIs)


    Didanosine

    400 mg once daily

    14

    		↔

    0.91

    (0.58

    1.42)

    0.99

    (0.79

    1.25)

    N.A.

    Tenofovir disoproxil fumarate

    300 mg once daily

    19

    		↔

    1.15

    (1.04

    1.27)

    1.15

    (1.09

    1.21)

    1.19

    (1.13

    1.26)

    Co-administration with CCR5 antagonists


    Maraviroc

    300 mg twice daily

    14

    		↓

    0.40

    (0.28

    0.57)

    0.47

    (0.38

    0.58)

    0.61

    (0.53

    0.71)

    Maraviroc (when co- administered with darunavir/ritonavir)†

    150/600/100

    mg twice daily

    10

    		↑

    1.77

    (1.20

    2.60)

    3.10

    (2.57

    3.74)

    5.27

    (4.51

    6.15)

    Co-administration with integrase strand transfer inhibitors


    Dolutegravir

    50 mg once daily

    16

    		↓

    0.48

    (0.43

    to 0.54)

    0.29

    (0.26

    to 0.34)

    0.12

    (0.09

    to 0.16)

    Dolutegravir (when co- administered with darunavir/ritonavir)

    50 mg once daily + 600/100 mg twice daily

    9

    		↓

    0.88

    (0.78

    to 1.00)

    0.75

    (0.69

    to 0.81)

    0.63

    (0.52

    to 0.76)

    Dolutegravir (when co- administered with lopinavir/ritonavir

    50 mg once daily + 400/100 mg twice daily

    8

    		↔

    1.07

    (1.02

    to 1.13)

    1.11

    (1.02

    to 1.20)

    1.28

    (1.13 to

    1.45)

    Raltegravir

    400 mg twice

    0.89

    0.90

    0.66

    daily

    19

    		↓

    (0.68

    1.15)

    (0.68

    1.18)

    (0.34

    1.26)

    Co-administration with other drugs


    Artemether



    Dihydroartemisinin




      Lumefantrine

    80/480 mg, 6

    doses at 0, 8,

    24, 36, 48, and

    60 hours

    15




    15




    15

    ↓




    ↓




    ↓

    0.72

    (0.55

    0.94)


    0.84

    (0.71

    0.99)


    1.07

    (0.94

    1.23)

    0.62

    (0.48

    0.80)


    0.85

    (0.75

    0.97)


    0.87

    (0.77

    0.98)

    0.82

    (0.67

    1.01)


    0.83

    (0.71

    0.97)


    0.97

    (0.83

    1.15)

    Atorvastatin



    2-hydroxy-atorvastatin

    40 mg once daily

    16



    16

    ↓



    ↑

    1.04

    (0.84

    1.30)

    1.76

    (1.60

    1.94)

    0.63

    (0.58

    0.68)

    1.27

    (1.19

    1.36)

    N.A.



    N.A.


    Buprenorphine




    Norbuprenorphine

    Individual dose regimen ranging from 4/1 mg to 16/4 mg once daily

    16




    16

    ↓




    ↔

    0.89

    (0.76

    1.05)


    1.08

    (0.95

    1.23)

    0.75

    (0.66

    0.84)


    0.88

    (0.81

    0.96)

    0.60

    (0.52

    0.68)


    0.76

    (0.67

    0.87)

    Clarithromycin


    14-hydroxy- clarithromycin

    500 mg twice daily

    15



    15

    ↓



    ↑

    0.66

    (0.57

    0.77)

    1.33

    (1.13

    1.56)

    0.61

    (0.53

    0.69)

    1.21

    (1.05

    1.39)

    0.47

    (0.38

    0.57)

    1.05

    (0.90

    1.22)

    Digoxin

    0.5 mg single dose

    16

    		↑

    1.19

    (0.96

    1.49)

    1.18

    (0.90

    1.56)

    N.A.

    Ethinylestradiol



    Norethindrone

    0.035 mg once daily


    1 mg once daily

    16



    16

    ↑



    ↔

    1.33

    (1.21

    1.46)

    1.05

    (0.98

    1.12)

    1.22

    (1.13

    1.31)

    0.95

    (0.90

    0.99)

    1.09

    (1.01

    1.18)

    0.78

    (0.68

    0.90)

    Fluconazole

    200 mg once daily in the morning

    15

    ↔

    0.92

    (0.85

    1.00)

    0.94

    (0.88

    1.01)

    0.91

    (0.84

    0.98)


    R(-) Methadone

    Individual dose regimen ranging from 60 to 130

    mg/day

    16

    ↔

    1.02

    (0.96

    1.09)

    1.06

    (0.99

    1.13)

    1.10

    (1.02

    1.19)

    S(+) Methadone

    16

    ↔

    0.89

    (0.83

    0.97)

    0.89

    (0.82

    0.96)

    0.89

    (0.81

    0.98)

    Paroxetine

    20 mg once daily

    16

    ↔

    1.06

    (0.95

    1.20)

    1.03

    (0.90

    1.18)

    0.87

    (0.75

    1.02)

    Rifabutin



    25-O-desacetylrifabutin

    300 mg once daily


    300 mg once daily

    12



    12

    ↓



    ↓

    0.90

    (0.78

    1.03)

    0.85

    (0.72

    1.00)

    0.83

    (0.75

    0.94)

    0.83

    (0.74

    0.92)

    0.76

    (0.66

    0.87)

    0.78

    (0.70

    0.87)

    Sildenafil



    N-desmethyl-sildenafil

    50 mg single dose

    15



    15

    ↓



    ↓

    0.55

    (0.40

    0.75)

    0.75

    (0.59

    0.96)

    0.43

    (0.36

    0.51)

    0.59

    (0.52

    0.68)

    N.A.



    N.A.

    Voriconazole

    200 mg twice daily

    14

    ↑

    0.95

    (0.75

    1.21)

    1.14

    (0.88

    1.47)

    1.23

    (0.87

    1.75)

    12.4 Microbiology

    Mechanism of Action

    Etravirine is an NNRTI of 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 inCell 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 drugsthe NNRTIs delavirdine, efavirenz, and nevirapine; the N(t)RTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zidovudine; the PIs amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir; the gp41 fusion inhibitor ENF; 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 etravirine tablets-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 etravirine tablets 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 less than 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

    Cross-resistance among NNRTIs has been observed. Cross-resistance to delavirdine, efavirenz, and/or nevirapine is expected after virologic failure with an etravirine-containing regimen. Virologic failure on a rilpivirine-containing regimen with development of rilpivirine resistance is likely to result in cross-resistance to etravirine (see Treatment-Naïve HIV-1-Infected Subjects in the Phase 3 Trials for EDURANT (rilpivirine) below). Cross-resistance to etravirine has been observed after virologic failure on a doravirine-containing regimen with development of doravirine resistance. Some NNRTI-resistant viruses are susceptible to etravirine, but genotypic and phenotypic testing should guide the use of etravirine (see Baseline Genotype/Phenotype and Virologic Outcome Analyses below).

    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 greater than 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 greater than 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 less than or equal to 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 TMC125-C206 and TMC125-C216, 34% of the baseline isolates had decreased susceptibility to etravirine (fold-change greater than 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.

    Treatment-Naïve HIV-1-Infected Subjects in the Phase 3 Trials for EDURANT (Rilpivirine)

    There are currently no clinical data available on the use of etravirine in subjects who experienced virologic failure on a rilpivirine-containing regimen. However, in the rilpivirine adult clinical development program, there was evidence of phenotypic cross-resistance between rilpivirine and etravirine. In the pooled analyses of the Phase 3 clinical trials for rilpivirine, 38 rilpivirine virologic failure subjects had evidence of HIV-1 strains with genotypic and phenotypic resistance to rilpivirine. Of these subjects, 89% (34 subjects) of virologic failure isolates were cross-resistant to etravirine based on phenotype data. Consequently, it can be inferred that cross-resistance to etravirine is likely after virologic failure and development of rilpivirine resistance. Refer to the prescribing information for EDURANT (rilpivirine) for further information.

    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 etravirine tablets arm. Overall, response rates to etravirine decreased as the number of baseline NNRTI substitutions increased (shown as the proportion of subjects achieving viral load less than 50 plasma HIV RNA copies/mL at Week 48) (Table 10).

    Table 10: Proportion of Subjects With Less Than 50 HIV-1 RNA Copies/mL at Week 48 by Baseline Number of IAS-USA-Defined NNRTI Substitutions* in the Non-VF Excluded Population of the Pooled TMC125-C206 and TMC125-C216
  • * 2008 IAS- USA defined substitutions = V90I, A98G, L100I, K101E/H/P, K103N, V106A/I/M, V108I, E138A, V179D/F/T, Y181C/I/V, Y188C/H/L, G190A/S, P225H, M230L2008 IAS- USA defined substitutions = V90I, A98G, L100I, K101E/H/P, K103N, V106A/I/M, V108I, E138A, V179D/F/T, Y181C/I/V, Y188C/H/L, G190A/S, P225H, M230L2008 IAS- USA defined substitutions = V90I, A98G, L100I, K101E/H/P, K103N, V106A/I/M, V108I, E138A, V179D/F/T, Y181C/I/V, Y188C/H/L, G190A/S, P225H, M230L2008 IAS- USA defined substitutions = V90I, A98G, L100I, K101E/H/P, K103N, V106A/I/M, V108I, E138A, V179D/F/T, Y181C/I/V, Y188C/H/L, G190A/S, P225H, M230L2008 IAS- USA defined substitutions = V90I, A98G, L100I, K101E/H/P, K103N, V106A/I/M, V108I, E138A, V179D/F/T, Y181C/I/V, Y188C/H/L, G190A/S, P225H, M230L2008 IAS- USA defined substitutions = V90I, A98G, L100I, K101E/H/P, K103N, V106A/I/M, V108I, E138A, V179D/F/T, Y181C/I/V, Y188C/H/L, G190A/S, P225H, M230L2008 IAS- USA defined substitutions = V90I, A98G, L100I, K101E/H/P, K103N, V106A/I/M, V108I, E138A, V179D/F/T, Y181C/I/V, Y188C/H/L, G190A/S, P225H, M230L2008 IAS- USA defined substitutions = V90I, A98G, L100I, K101E/H/P, K103N, V106A/I/M, V108I, E138A, V179D/F/T, Y181C/I/V, Y188C/H/L, G190A/S, P225H, M230L
    		•
    ENF: enfuvirtide

    # IAS-USA-Defined NNRTI

    substitutions*

    Etravirine

    N=561

    Re-used/not used

     ENF

    de novo ENF

    All ranges

    61% (254/418)

    76% (109/143)

    0

    68% (52/76)

    95% (20/21)

    1

    67% (72/107)

    77% (24/31)

    2

    64% (75/118)

    86% (38/44)

    3

    55% (36/65)

    62% (16/26)

    ≥ 4

    37% (19/52)

    52% (11/21)

    Placebo

    N=592

    All ranges

    34% (147/435)

    59% (93/157)

    Response rates assessed by baseline etravirine phenotype are shown in Table 11. 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 etravirine tablets. 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.

    Table 11: Proportion of Subjects With Less Than 50 HIV-1 RNA Copies/mL at Week 48 by Baseline Phenotype and ENF Use in the Pooled TMC125-C206 and TMC125-C216*

    Table 11: Proportion of Subjects With Less Than 50 HIV-1 RNA Copies/mL at Week 48 by Baseline Phenotype and ENF Use in the Pooled TMC125-C206 and TMC125-C216*
  • * Non- VF excluded analysisNon- VF excluded analysis
    		•
    ENF: enfuvirtide

    Fold Change

    Etravirine

    N=559

    Re-used/not used

    ENF

    de novo ENF

    Clinical response range

    All ranges

    61% (253/416)

    76% (109/143)

    Overall Response

    03

    69% (188/274)

    83% (75/90)

    Higher than Overall Response

    >3-13

    50% (39/78)

    66% (25/38)

    Lower than Overall Response

    >13

    41% (26/64)

    60% (9/15)

    Lower than Overall Response

    Placebo

     N=583

    All ranges

    34% (145/429)

    60% (92/154)

    The proportion of virologic responders (viral load less than 50 HIV-1 RNA copies/mL) by the phenotypic susceptibility score (PSS) of the background therapy, including ENF, is shown in Table 12.

    Table 12: Virologic Response (Viral Load Less Than 50 HIV-1 RNA Copies/mL) at Week 48 by Phenotypic Susceptibility Score (PSS) in the Non-VF Excluded Population of TMC125-C206 and TMC125-C216
    PSS*Etravirine tablets + BR
    N=559    		Placebo + BR
    N=586
  • * The phenotypic susceptibility score (PSS) was defined as the total number of active antiretroviral drugs in the background therapy to which a subject's baseline viral isolate showed sensitivity in phenotypic resistance tests. Each drug in the background therapy was scored as a '1' or '0' based on whether the viral isolate was considered susceptible or resistant to that drug, respectively. In the calculation of the PSS, darunavir was counted as a sensitive antiretroviral if the FC was less than or equal to 10; ENF was counted as a sensitive antiretroviral if it had not been used previously. INTELENCE was not included in this calculation.
    		•

    0

    43% (40/93)

    5% (5/95)

    1

    61% (125/206)

    28% (64/226)

    2

    77% (114/149)

    59% (97/165)

    ≥ 3

    75% (83/111)

    72% (72/100)

  • 13 NONCLINICAL TOXICOLOGY


    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    Carcinogenesis

    Etravirine was evaluated for carcinogenic potential by oral gavage administration to mice and rats for up to approximately 104 weeks. Daily doses of 50, 200 and 400 mg/kg were administered to mice and doses of 70, 200 and 600 mg/kg were administered to rats in the initial period of approximately 41 to 52 weeks. The high and middle doses were subsequently adjusted due to tolerability and reduced by 50% in mice and by 50 to 66% in rats to allow for completion of the studies. In the mouse study, statistically significant increases in the incidences of hepatocellular carcinoma and incidences of hepatocellular adenomas or carcinomas combined were observed in treated females. In the rat study, no statistically significant increases in tumor findings were observed in either sex. The relevance of these liver tumor findings in mice to humans is not known. Because of tolerability of the formulation in these rodent studies, maximum systemic drug exposures achieved at the doses tested were lower than those in humans at the clinical dose (400 mg/day), with animal vs. human AUC ratios being 0.6-fold (mice) and 0.2-to-0.7-fold (rats).

    Mutagenesis

    Etravirine tested negative in the in vitro Ames reverse mutation assay, in vitro chromosomal aberration assay in human lymphocyte, and in vitro clastogenicity mouse lymphoma assay, tested in the absence and presence of a metabolic activation system. Etravirine did not induce chromosomal damage in the in vivo micronucleus test in mice.

    Impairment of Fertility

    No effects on fertility and early embryonic development were observed when etravirine was tested in rats at maternal doses up to 500 mg/day, resulting in systemic drug exposure up to the recommended human dose (400 mg/day).

  • 14 CLINICAL STUDIES


    14.1 Treatment-Experienced Adult Subjects

    The clinical efficacy of etravirine tablets are 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 tablets-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 novo ENF 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 tablets arm and the placebo arm (Table 13). Table 13 displays selected demographic and baseline disease characteristics of the subjects in the etravirine tablets and placebo arms.

    Table 13: Demographic and Baseline Disease Characteristics of Subjects (Pooled Analysis TMC125-C206 and TMC125-C216)--
    Etravirine + BR
    N=599    		Placebo + BR
    N=604
    RASs = Resistance-Associated Substitutions, BR=background regimen, FC = fold change in EC50
  • * IAS- USA primary PI substitutions [August/September 2007]: D30N, V32I, L33F, M4 6I/L, I4 7A/V, G4 8V, I50L/V, I54 L/M, L76V, V82A/F/L/S/T, I84 V, N88S, L90MIAS- USA primary PI substitutions [August/September 2007]: D30N, V32I, L33F, M4 6I/L, I4 7A/V, G4 8V, I50L/V, I54 L/M, L76V, V82A/F/L/S/T, I84 V, N88S, L90M
  • † Tibotec NNRTI RASs [June 2008]: A98G, V90I, L100I, K101E/H/P/Q, K103H/N/S/T, V106A/M/I, V108I, E138A/G/K/Q, V179D/E/F/G/I/T, Y181C/I/V, Y188C/H/L, V189I, G190A/C/E/Q/S, H221Y, P255H, F227C/L, M230I/L, P236L, K238N/T, Y318FTibotec NNRTI RASs [June 2008]: A98G, V90I, L100I, K101E/H/P/Q, K103H/N/S/T, V106A/M/I, V108I, E138A/G/K/Q, V179D/E/F/G/I/T, Y181C/I/V, Y188C/H/L, V189I, G190A/C/E/Q/S, H221Y, P255H, F227C/L, M230I/L, P236L, K238N/T, Y318F
  • ‡ The PSS was calculated for the background therapy (as determined on Day 7). Percentages are based on the number of subjects with available phenotype data. For fusion inhibitors (enfuvirtide), subjects were considered resistant if the drug was used in previous therapy up to baseline. Etravirine tablets are not included in this calculation.The PSS was calculated for the background therapy (as determined on Day 7). Percentages are based on the number of subjects with available phenotype data. For fusion inhibitors (enfuvirtide), subjects were considered resistant if the drug was used in previous therapy up to baseline. Etravirine tablets are not included in this calculation.
    		•

    Demographic characteristics

    Median age, years (range)

    46

    (18-77)

    45

    (18-72)

    Sex

    Male

    90.0%

    88.6%

    Female

    10.0%

    11.4%

    Race

    White

    70.1%

    69.8%

    Black

    13.2%

    13.0%

    Hispanic

    11.3%

    12.2%

    Asian

    1.3%

    0.6%

    Other

    4.1%

    4.5%

    Baseline disease characteristics

    Median baseline plasma HIV-1 RNA (range), log10 copies/mL

    4.8

    (2.76.8)

    4.8

    (2.26.5)

    Percentage of subjects with baseline viral load:

      < 30,000 copies/mL

      ≥ 30,000 copies/mL and < 100,000 copies/mL

      ≥ 100,000 copies/mL

    27.5%

    34.4%

    38.1%

    28.8%

    35.3%

    35.9%

    Median baseline CD4+ cell count (range), cells/mm3

    99

    (1-789)

    109

    (0-912)

    Percentage of subjects with baseline CD4+ cell count:

    < 50 cells/mm3

    ≥ 50 cells/mm3 and < 200 cells/mm3

    ≥ 200 cells/mm3



    35.6%

    34.8%

    29.6%

    34.7%

    34.5%

    30.8%

    Median (range) number of primary PI substitutions*

    4

    (0-7)

    4

    (0-8)

    Percentage of subjects with previous use of NNRTIs:

    0

    1

     >1

    8.2%

    46.9%

    44.9%

    7.9%

    46.7%

    45.4%

    Percentage of subjects with previous use of the following NNRTIs:

    Efavirenz

    Nevirapine

    Delavirdine

    70.3%

    57.1%

    13.7%

    72.5%

    58.6%

    12.6%

    Median (range) number of NNRTI RASs†

    2

    (0-8)

    2

    (0-7)

    Median fold change of the virus for the following NNRTIs:

    Delavirdine

    Efavirenz

    Etravirine 

    Nevirapine

    27.3

    63.9

    1.6

    74.3

    26.1

    45.4

    1.5

    74.0

    Percentage of subjects with previous use of a fusion inhibitor

    39.6%

    42.2%

    Percentage of subjects with a Phenotypic Sensitivity Score (PSS) for the background therapy‡ of:

    0

    17.0%

    16.2%

    1

    36.5%

    38.7%

    2

    26.9%

    27.8%

    ≥ 3

    19.7%

    17.3%

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

    Table 14: Treatment Outcomes at Week 48 (Pooled Analysis TMC125- C206 and TMC125-C216)
    Etravirine Tablets + BR
    N=599    		Placebo + BR
    N=604
    BR=background regimen

    Virologic responders at Week 48

    Viral Load < 50 HIV-1 RNA

    copies/mL

    359 (60%)

    232 (38%)

    Virologic failures at Week 48

    Viral Load ≥ 50 HIV-1 RNA

    copies/mL

    123 (21%)

    201 (33%)

    Death

    11 (2%)

    19 (3%)

    Discontinuations before Week 48:

      due to virologic failures

    58 (10%)

    110 (18%)

      due to adverse events

    31 (5%)

    14 (2%)

      due to other reasons

    17 (3%)

    28 (5%)

    At Week 48, 70.8% of etravirine tablets-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 log10 copies/mL for etravirine tablets-treated subjects and -1.46 log10 copies/mL for placebo-treated subjects. The mean CD4+ cell count increase from baseline for etravirine tablets-treated subjects was 96 cells/mm3 and 68 cells/mm3 for placebo-treated subjects.

    Of the study population who either re-used or did not use ENF, 57.4% of etravirine tablets-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 tablets-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 tablets-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 tablets (59 subjects) or an investigator- selected PI (57 subjects), each given with 2 investigator-selected N(t)RTIs. Etravirine tablets-treated subjects had lower antiviral responses associated with reduced susceptibility to the N(t)RTIs and to etravirine tablets 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 tablets for treatment-experienced pediatric subjects is based on two Phase 2 trials, TMC125-C213 and TMC125-C234/IMPAACT P1090.

    Pediatric Subjects (6 Years to Less Than18 Years of Age [TMC125-C213])

    TMC125-C213, a single-arm, Phase 2 trial evaluating the pharmacokinetics, safety, tolerability, and efficacy of etravirine tablets enrolled 101 antiretroviral treatment-experienced HIV-1 infected pediatric subjects 6 years to less than 18 years of age and weighing at least 16 kg. Subjects eligible for this trial were on an antiretroviral regimen with confirmed plasma HIV-1 RNA of at least 500 copies/mL and viral susceptibility to etravirine tablets at screening.

    The median baseline plasma HIV-1 RNA was 3.9 log10 copies/mL, and the median baseline CD4+ cell count was 385 × 106 cells/mm3.

    At Week 24, 52% of subjects had HIV-1 RNA less than 50 copies per mL. The proportion of subjects with HIV-1 RNA less than 400 copies/mL was 67%. The mean CD4+ cell count increase from baseline was 112 × 106 cells/mm3.

    Pediatric Subjects (2 Years to Less Than6 Years of Age [TMC125-C234/IMPAACT P1090])

    TMC125-C234/IMPAACT P1090 is a Phase 1/2 trial evaluating the pharmacokinetics, safety, tolerability, and efficacy of etravirine tablets in 20 antiretroviral treatment-experienced HIV-1 infected pediatric subjects 2 years to less than 6 years of age. The study enrolled subjects who had virologic failure on an antiretroviral treatment regimen after at least 8 weeks of treatment, or who had interrupted treatment for at least 4 weeks. Enrolled subjects had a history of virologic failure while on an antiretroviral regimen, with a confirmed HIV-1 RNA plasma viral load greater than 1,000 copies/mL and with no evidence of phenotypic resistance to etravirine at screening.

    The median baseline plasma HIV-1 RNA was 4.4 log10 copies/mL, the median baseline CD4+ cell count was 817.5 × 106 cells/mm3, and the median baseline CD4+ percentage was 28%.

    Virologic response, defined as achieving plasma viral load less than 400 HIV-1 RNA copies/mL, was evaluated.

    Study treatment included etravirine plus an optimized background regimen of antiretroviral drugs. In addition to etravirine, all 20 subjects received a ritonavir-boosted protease inhibitor in combination with 1 or 2 NRTIs (n=14) and/or in combination with an integrase inhibitor (n=7).

    At the time of the Week 24 analysis, seventeen subjects had completed at least 24 weeks of treatment or discontinued earlier. At Week 24, the proportion of subjects with less than 400 HIV-1 RNA copies/mL was 88% (15/17), and the proportion of subjects with less than 50 HIV-1 RNA copies/mL was 50% (7/14), for those with available data. The median change in plasma HIV-1 RNA from baseline to Week 24 was -2.14 log10 copies/mL. The median CD4+ cell count increase and the median CD4+ percentage increase from baseline was 298 × 106 cells/mm3 and 5%, respectively.

  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    Etravirine 100 mg tablets are supplied as white to off-white, uncoated, oval shaped tablet, debossed "CP112" on one side and plain on other side.

    Etravirine 200 mg tablets are supplied as white to off-white, uncoated, oval shaped tablet, debossed "CP113" on one side and plain on other side.

    Etravirine tablets are packaged in bottles in the following configuration:

    • 100 mg tablets—bottles of 120 (NDC: 69315-285-20). Each bottle contains 3 desiccant pouches.
    • 200 mg tablets—bottles of 60 (NDC: 69315-286-06). Each bottle contains 3 desiccant pouches. 

    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.

  • 17 PATIENT COUNSELING INFORMATION

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

    Administration

    Advise patients to take etravirine tablets 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 tablets or discontinue therapy with etravirine tablets without consulting their physician. Etravirine tablets 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 SkinReactions

    Inform patients that severe and potentially life-threatening rash has been reported with etravirine tablets. 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 tablets 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 tablets 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 ReconstitutionSyndrome

    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 tablets, 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 tablets [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)].

    Product of USA

    Finished Product manufactured by:
    Carnegie Pharmaceuticals LLC
    Delran, NJ 08075

    Distributed by:
    Leading Pharma, LLC
    Fairfield, NJ 07004, USA

    Rev. 01 04/22

  • PATIENT PACKAGE INSERT

    PATIENT INFORMATION

    Etravirine (et-ra-vi-rine)

    Important: Ask your healthcare provider or pharmacist about medicines that should not be taken with Etravirine Tablets. For more information, see the section "What should I tell my healthcare provider before taking etravirine tablets?"

    What is Etravirine Tablets?

    Etravirine tablet is a prescription medicine that is used to treat human immunodeficiency virus-1 (HIV-1) infection in combination with other HIV-1 medicines, in adults and children 2 years of age and older who have taken HIV-1 medicines in the past.

    HIV-1 is the virus that causes AIDS (Acquired Immune Deficiency Syndrome). Etravirine tablet is not recommended for use in children less than 2 years of age.

    What should I tell my healthcare provider before taking Etravirine Tablets?

    Before taking etravirine tablets tell your healthcare provider about all of your medical conditions, including if you:

    • have liver problems, including hepatitis B or C.
    • are pregnant or plan to become pregnant. Tell your healthcare provider if you become pregnant during treatment with etravirine tablets.

    Pregnancy Registry: There is a pregnancy registry for people who take etravirine tablets during pregnancy. The purpose of this registry is to collect information about the health of you and your

    baby. Talk to your healthcare provider about how you can take part in this registry.

    • are breastfeeding or plan to breastfeed. Do not breastfeed if you take etravirine tablets.

    You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.

    Etravirine tablets can pass to your baby in your breast milk.

    Talk with your healthcare provider about the best way to feed your baby.


    Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

    Some medicines may interact with etravirine tablets. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.

    • You can ask your healthcare provider or pharmacist for a list of medicines that interact with etravirine tablets.
    • Do not start a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take etravirine tablets with other medicines.

    How should I take Etravirine Tablets?

    • Stay under the care of your healthcare provider during treatment with etravirine tablets.
    • Take etravirine tablets every day exactly as prescribed by your healthcare provider.
    • Your healthcare provider will tell you how many etravirine tablets to take and when to take them. Talk to your healthcare provider if you have questions about when to take etravirine tablets.
    • Take etravirine tablets 2 times each day.
    • If your child takes etravirine tablets, your healthcare provider will prescribe the right dose based on your child's weight.
    • Always take etravirine tablets following a meal. Do not take etravirine tablets on an empty stomach. Etravirine tablets may not work as well if you take it on an empty stomach.
    • Do not change your dose or stop taking etravirine tablets without first talking with your healthcare provider.
    • Swallow etravirine tablets whole, with liquid, such as water. Do not chew the tablet(s).
    • If you are unable to swallow etravirine tablets whole, you may take your dose of etravirine tablets as follows:

    Step 1: Measure approximately 5 mL (1 teaspoon) of water and pour into a cup.

    Step 2: Place the tablets in the cup containing 5 mL of water. If needed, add more water to cover the tablets. Do not put the tablets in other liquids.

    Step 3: Stir well until the water looks milky.

    Step 4: Add a small amount (approximately 15 mL or 1 tablespoon) of liquid. Water may be used but adding orange juice or milk rather than water may make it easier to take. Do not use warm (temperature more than 104°F or 40°C) or carbonated beverages.

    Step 5: Drink the mixture right away.

    Step 6: Add more orange juice, milk, or water to the cup to rinse the cup several times and completely swallow each time to make sure you take your entire dose of etravirine tablets.

    • It is important that you do not miss or skip doses of etravirine tablets during treatment.
    • When your supply of etravirine tablets starts to run low, get more from your healthcare provider or pharmacy. It is important not to run out of etravirine tablets. The amount of HIV in your blood may increase if the medicine is stopped even for a short time.
    • If you take too much etravirine tablets, call your healthcare provider or go to the nearest emergency room right away.

    What are the possible side effects of Etravirine Tablets?

    Etravirine tablets can cause serious side effects including:

    • Severe skin rash and allergic reactions. Skin rash is a common side effect of etravirine tablets. The risk of getting a skin rash is higher in females. Rarely, rash can be severe and may lead to death. Severe skin rash with blisters or peeling skin, including the area around the mouth or eyes, may happen more frequently in children less than 18 years of age who take etravirine tablets in combination with other HIV-1 medicines than in adults. Call your healthcare provider right away if a rash develops; severe cases may need to be treated in a hospital.

    If you get a rash with any of the following symptoms, stop taking Etravirine Tablets and call your healthcare provider or get medical help right away:

    • fever
    • muscle or joint aches
    • redness or swelling of the eyes
      • generally ill feeling
      • blisters or sores in mouth
      • swelling of the mouth, lips, or face
        • extreme tiredness
        • blisters or peeling of the skin
        • problems breathing

    Sometimes allergic reactions can affect body organs, such as your liver. Call your healthcare provider right away if you have any of the following signs or symptoms of liver problems:


    • yellowing of your skin or whites of your eyes
      • nausea or vomiting
      • dark or tea colored urine
        • loss of appetite
        • pale colored stools (bowel movements
          • pain, aching, or tenderness on the right side of your stomach area
            • Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Call your healthcare provider right away if you start having any new symptoms after starting your HIV-1 medicines.
            • Changes in body fat can happen in people taking HIV-1 medicines. These changes may include an increased amount of fat in the upper back and neck ("buffalo hump"), breast, and around the middle of your body (trunk). Loss of fat from the legs, arms, and face may also happen. The exact cause and long-term health effects of these problems are not known.

    The most common side effects of etravirine tablets in adults include rash as well as numbness, tingling or pain in the hands or feet.

    The most common side effects of etravirine tablets in children include rash and diarrhea. These are not all the possible side effects of etravirine tablets.

    • Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800- FDA-1088.

    How should I store Etravirine Tablets?

    • Store etravirine tablets at room temperature between 68°F to 77°F (20°C to 25°C).     
    • Keep etravirine tablets in the original bottle.
    • Keep the bottle tightly closed to protect etravirine tablets from moisture.
    • The etravirine tablets bottle contains a desiccant packet to help keep your medicine dry (protect it from moisture). The bottles of 100 mg and 200 mg tablets contain 3 desiccant packets. Keep the desiccant packets in the bottle. Do not eat the desiccant packets.

    Keep etravirine tablets and all medicines out of the reach of children.

    General information about the safe and effective use of Etravirine Tablets

    Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use etravirine tablets for a condition for which it was not prescribed. Do not give etravirine tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about etravirine tablets that is written for health professionals.

    What are the ingredients in Etravirine Tablets?

    Active ingredient: etravirine.

    100 mg and 200 mg etravirine tablets contain the following inactive ingredients: povidone, microcrystalline cellulose, sodium lauryl sulfate, crospovidone, sodium starch glycolate, silicon dioxide and magnesium stearate.


    Product of USA

    Finished Product Manufactured by:                                                                                                                       Distributed by:

    Carnegie Pharmaceuticals LLC                                                                                                                            Leading Pharma, LLC

    Delran, NJ 08075                                                                                                                                                Fairfield, NJ 07004, USA

    This Patient Information has been approved by the U.S. Food and Drug Administration.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 Rev. 01 04/22

  • PRINCIPAL DISPLAY PANEL - 100 mg Tablet Bottle Label

    120 Tablets
    NDC 69315-285-20
    Etravirine tablets
    100 mg

    Each tablet contains
    100 mg of etravirine.

    Rx only

    Leading Pharma, LLC

    ALERT: Find out about medicines that
    should NOT be taken with etravirine tablets
    from your healthcare provider.

    containerlabel100mg

  • PRINCIPAL DISPLAY PANEL - 200 mg Tablet Bottle Label

    60 Tablets
    NDC 69315-286-06
    Etravirine tablets
    200 mg

    Each tablet contains
    200 mg of etravirine.

    Rx only

    Leading Pharma, LLC

    ALERT: Find out about medicines that
    should NOT be taken with etravirine tablets
    from your healthcare provider.

    containerlabel200mg

  • INGREDIENTS AND APPEARANCE
    ETRAVIRINE 
    etravirine tablet
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 69315-285
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    ETRAVIRINE (UNII: 0C50HW4FO1) (ETRAVIRINE - UNII:0C50HW4FO1) ETRAVIRINE100 mg
    Inactive Ingredients
    Ingredient NameStrength
    Povidone (UNII: FZ989GH94E)  
    MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)  
    SODIUM LAURYL SULFATE (UNII: 368GB5141J)  
    CROSPOVIDONE (UNII: 2S7830E561)  
    SODIUM STARCH GLYCOLATE TYPE A (UNII: H8AV0SQX4D)  
    SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    Product Characteristics
    ColorWHITE (White to off-white) Scoreno score
    ShapeOVALSize19mm
    FlavorImprint Code CP;112
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 69315-285-20120 in 1 BOTTLE; Type 0: Not a Combination Product06/05/2022
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA21540206/05/2022
    ETRAVIRINE 
    etravirine tablet
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 69315-286
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    ETRAVIRINE (UNII: 0C50HW4FO1) (ETRAVIRINE - UNII:0C50HW4FO1) ETRAVIRINE200 mg
    Inactive Ingredients
    Ingredient NameStrength
    Povidone (UNII: FZ989GH94E)  
    MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)  
    SODIUM LAURYL SULFATE (UNII: 368GB5141J)  
    CROSPOVIDONE (UNII: 2S7830E561)  
    SODIUM STARCH GLYCOLATE TYPE A (UNII: H8AV0SQX4D)  
    SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    Product Characteristics
    ColorWHITE (White to off-white) Scoreno score
    ShapeOVALSize22mm
    FlavorImprint Code CP;113
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 69315-286-0660 in 1 BOTTLE; Type 0: Not a Combination Product06/05/2022
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA21540206/05/2022
    Labeler - Leading Pharma, LLC (079575060)
    Registrant - Carnegie Pharmaceuticals LLC (079839141)
    Establishment
    NameAddressID/FEIBusiness Operations
    Carnegie Pharmaceuticals LLC079839141manufacture(69315-285, 69315-286) , analysis(69315-285, 69315-286) , pack(69315-285, 69315-286)
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