STORAGE AND HANDLING SECTION.

Store INTELENCE tablets at 25C (77F); with excursions permitted to 15 to 30C (59 to 86F) [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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Breastfeeding is not recommended due to the potential for HIV-1 transmission. (8.2). Lactation: Breastfeeding is not recommended due to the potential for HIV-1 transmission. (8.2). 8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to INTELENCE during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.. Risk SummaryProspective pregnancy data from clinical trials and the APR are not sufficient to adequately assess the risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Etravirine use during pregnancy has been evaluated in limited number of individuals as reported by the APR, and available data show birth defect in 66 first trimester exposures to etravirine-containing regimens (see Data).The estimated background rate for major birth defects is 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15-20%. The background risk of major birth defects and miscarriage for the indicated population is unknown.In animal reproduction studies, no adverse developmental effects were observed with orally administered etravirine at exposures equivalent to those at the maximum recommended human dose (MRHD) of 400 mg daily (see Data).. Data. Human DataBased on prospective reports to the APR of 116 live births following exposure to etravirine-containing regimens during pregnancy (including 66 exposed in the first trimester and 38 exposed in the second/third trimester), the number of birth defects in live births for etravirine was out of 66 with first trimester exposure and out of 38 with second/third trimester exposure. Prospective reports from the APR of overall major birth defects in pregnancies exposed to INTELENCE is compared with U.S. background major birth defect rate. Methodological limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease; these limitations preclude an accurate comparison of outcomes.INTELENCE (200 mg twice daily) in combination with other antiretroviral agents was evaluated in clinical trial enrolling 15 pregnant subjects during the second and third trimesters of pregnancy and postpartum. Thirteen subjects completed the trial through postpartum period (6-12 weeks after delivery). The pharmacokinetic data demonstrated that exposure to total etravirine was generally higher during pregnancy compared with postpartum [see Clinical Pharmacology (12.3)].Among subjects who were virologically suppressed (HIV-1 RNA less than 50 copies/mL) at baseline (9/13), virologic suppression was maintained through the third trimester and postpartum period. Among subjects with HIV-1 RNA greater than 50 copies/mL and less than 400 copies/mL at baseline (3/13), viral loads remained less than 400 copies/mL. In one subject with HIV-1 RNA greater than 1,000 copies/mL at baseline (1/13), HIV-1 RNA remained greater than 1,000 copies/mL during the study period. Thirteen infants were born to 13 HIV-infected pregnant individuals in this study. HIV-1 test results were not available for infants. Among the eleven infants with HIV-1 test results available, who were born to 11 HIV-infected pregnant individuals who completed the study, all had test results that were negative for HIV-1 at the time of delivery. No unexpected safety findings were observed compared with the known safety profile of INTELENCE in non-pregnant adults.. Animal DataReproductive and developmental toxicity studies were performed in rats (at 250, 500 and 1,000 mg/kg/day) and rabbits (at 125, 250 and 375 mg/kg/day) administered etravirine on gestation days through 16, and through 19, respectively. In both species, no treatment-related embryo-fetal effects were observed. In addition, no treatment-related effects were observed in pre- and postnatal development study performed in rats administered oral doses up to 500 mg/kg/day on gestation days through lactation day 7. The systemic drug exposures achieved at the high dose in these animal studies were equivalent to those at the MRHD.. 8.2 Lactation. Risk SummaryThe Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV.Based on limited data, etravirine has been shown to be present in human breast milk. There are no data on the effects of etravirine on the breastfed infant, or the effects of etravirine on milk production.Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants) and (3) adverse reactions in breastfed infants similar to those seen in adults, instruct mothers not to breastfeed if they are receiving INTELENCE.. 8.4 Pediatric Use. The safety and effectiveness of INTELENCE have been established for the treatment of HIV-infected pediatric patients from years of age to less than 18 years [see Indications and Usage (1) and Dosage and Administration (2.3)]. Use of INTELENCE in pediatric patients years to less than 18 years of age is supported by evidence from adequate and well-controlled studies of INTELENCE in adults with additional data from two Phase trials in treatment-experienced pediatric subjects, TMC125-C213, years to less than 18 years of age (N=101) and TMC125-C234/IMPAACT P1090, years to less than years of age (N=20). Both studies were open-label, single arm trials of etravirine plus an optimized background regimen. In clinical trials, the safety, pharmacokinetics, and efficacy were comparable to that observed in adults except for rash (greater than or equal to Grade 2) which was observed more frequently in pediatric subjects [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)]. Postmarketing reports of Stevens-Johnson syndrome in pediatric patients receiving INTELENCE have been reported [see Warnings and Precautions (5.1), and Adverse Reactions (6.2)]. Treatment with INTELENCE is not recommended in pediatric patients less than years of age [see Clinical Pharmacology (12.3)]. Five HIV-infected subjects from year to 2 years of age were enrolled in TMC125-C234/IMPAACT P1090. Etravirine exposure was lower than reported in HIV-infected adults (AUC12h geometric mean ratio [90% CI] was 0.59 [0.34, 1.01] for pediatric subjects from year to 2 years of age compared to adults). Virologic failure at Week 24 (confirmed HIV-RNA greater than or equal to 400 copies/mL) occurred in of evaluable subjects who discontinued before or had reached Week 24. Genotypic and phenotypic resistance to etravirine developed in of the subjects who experienced virologic failure.. 8.5 Geriatric Use. Clinical studies of INTELENCE did not include sufficient numbers of subjects aged 65 years of age and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].. 8.6Hepatic Impairment. No dose adjustment of INTELENCE is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. The pharmacokinetics of INTELENCE have not been evaluated in patients with severe hepatic impairment (Child-Pugh Class C) [see Clinical Pharmacology (12.3)].. 8.7Renal Impairment. Since the renal clearance of etravirine is negligible (less than 1.2%), decrease in total body clearance is not expected in patients with renal impairment. No dose adjustments are required in patients with renal impairment. As etravirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Severe, potentially life threatening and fatal skin reactions have been reported. This includes cases of Stevens-Johnson syndrome, hypersensitivity reaction, toxic epidermal necrolysis and erythema multiforme. Immediately discontinue treatment if severe hypersensitivity, severe rash or rash with systemic symptoms or liver transaminase elevations develops and monitor clinical status, including liver transaminases closely. (5.1)Monitor for immune reconstitution syndrome and fat redistribution. (5.3, 5.4). Severe, potentially life threatening and fatal skin reactions have been reported. This includes cases of Stevens-Johnson syndrome, hypersensitivity reaction, toxic epidermal necrolysis and erythema multiforme. Immediately discontinue treatment if severe hypersensitivity, severe rash or rash with systemic symptoms or liver transaminase elevations develops and monitor clinical status, including liver transaminases closely. (5.1). Monitor for immune reconstitution syndrome and fat redistribution. (5.3, 5.4). 5.1Severe 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 clinical trials, Grade and rashes were reported in 1.3% of subjects receiving INTELENCE compared to 0.2% of placebo subjects. total of 2.2% of HIV-1-infected subjects receiving INTELENCE discontinued from Phase trials due to rash [see Adverse Reactions (6.1)]. Rash occurred most commonly during the first 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 INTELENCE in combination with other HIV-1 antiretroviral agents in an observational study.Discontinue INTELENCE immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema). Clinical status including liver transaminases should be monitored and appropriate therapy initiated. Delay in stopping INTELENCE treatment after the onset of severe rash may result in life-threatening reaction.. 5.2Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions. The concomitant use of INTELENCE 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 INTELENCE and possible development of resistance.Possible clinically significant adverse reactions from greater exposures of INTELENCE or other concomitant drugs.See Table 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 INTELENCE therapy and review concomitant medications during INTELENCE therapy.. Loss of therapeutic effect of concomitant drug or INTELENCE and possible development of resistance.. Possible clinically significant adverse reactions from greater exposures of INTELENCE or other concomitant drugs.. 5.3Immune Reconstitution Syndrome. Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including INTELENCE. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia (PCP) or tuberculosis), which may necessitate further evaluation and treatment.Autoimmune disorders (such as Graves disease, polymyositis, Guillain-Barre 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.. 5.4Fat 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. causal relationship has not been established.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are described in greater detail in other sections:Severe skin and hypersensitivity reactions [see Warnings and Precautions (5.1)].Immune reconstitution syndrome [see Warnings and Precautions (5.3)].. Severe skin and hypersensitivity reactions [see Warnings and Precautions (5.1)].. Immune reconstitution syndrome [see Warnings and Precautions (5.3)].. The most common adverse drug reactions of moderate to severe intensity (at least 2%) which occurred at higher rate than placebo in adults are rash and peripheral neuropathy. (6.1)The most common adverse drug reactions in at least 2% of pediatric patients are rash and diarrhea. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Janssen Products, LP at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 AdultsThe safety assessment is based on all data from 1203 subjects in the Phase placebo-controlled trials, TMC125-C206 and TMC125-C216, conducted in antiretroviral treatment-experienced HIV-1-infected adult subjects, 599 of whom received INTELENCE (200 mg twice daily). In these pooled trials, the median exposure for subjects in the INTELENCE arm and placebo arm was 52.3 and 51.0 weeks, respectively. Discontinuations due to adverse drug reactions (ADRs) were 5.2% in the INTELENCE arm and 2.6% in the placebo arm.The most frequently reported ADR at least Grade 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 INTELENCE [see Warnings and Precautions (5.1)]. total of 2.2% of HIV-1-infected subjects in Phase trials receiving INTELENCE discontinued due to rash. In general, in clinical trials, rash was mild to moderate, occurred primarily in the second week of therapy, and was infrequent after Week 4. Rash generally resolved within to weeks on continued therapy. The incidence of rash was higher in women compared to men in the INTELENCE arm in the Phase trials (rash >= Grade 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 history of NNRTI-related rash did not appear to be at increased risk for the development of INTELENCE-related rash compared to patients without history of NNRTI-related rash.. Common Adverse ReactionsClinical ADRs of moderate intensity or greater (greater than or equal to Grade 2) and reported in at least 2% of subjects treated with INTELENCE and occurring at 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 to 4) in at Least 2% of Adult Subjects (Pooled TMC125-C206 and TMC125-C216 Trials)Preferred TermINTELENCE BRN=599%Placebo BRN=604%N=total number of subjects per treatment group; BR=background regimen Rash10%3% Peripheral neuropathy4%2%. Less Common Adverse ReactionsTreatment-emergent ADRs occurring in less than 2% of subjects (599 subjects) receiving INTELENCE 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 fibrillationEar and Labyrinth Disorders: vertigoEye Disorders: blurred visionGastrointestinal Disorders: gastroesophageal reflux disease, flatulence, gastritis, abdominal distension, pancreatitis, constipation, dry mouth, hematemesis, retching, stomatitisGeneral Disorders and Administration Site Conditions: sluggishnessHematologic Disorders: hemolytic anemiaHepatobiliary Disorders: hepatic failure, hepatomegaly, cytolytic hepatitis, hepatic steatosis, hepatitisImmune System Disorders: drug hypersensitivity, immune reconstitution syndromeMetabolism and Nutrition Disorders: diabetes mellitus, anorexia, dyslipidemiaNervous System Disorders: paresthesia, somnolence, convulsion, hypoesthesia, amnesia, syncope, disturbance in attention, hypersomnia, tremorPsychiatric Disorders: anxiety, sleep disorders, abnormal dreams, confusional state, disorientation, nervousness, nightmaresRenal and Urinary Disorders: acute renal failureReproductive System and Breast Disorders: gynecomastiaRespiratory, Thoracic and Mediastinal Disorders: exertional dyspnea, bronchospasmSkin and Subcutaneous Tissue Disorders: night sweats, lipohypertrophy, prurigo, hyperhidrosis, dry skin, swelling faceAdditional 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 PatientsSelected Grade to Grade laboratory abnormalities that represent worsening from baseline observed in adult subjects treated with INTELENCE are presented in Table 3.Table 3:Selected Grade to Laboratory Abnormalities Observed in Treatment-Experienced Subjects (Pooled TMC125-C206 and TMC125-C216 Trials)Laboratory ParameterDAIDS Toxicity RangeINTELENCE BRN=599%Placebo BRN=604%ULN=Upper Limit of Normal; BR=background regimenGENERAL BIOCHEMISTRY Pancreatic amylase Grade 2> 1.5-2 ULN7%8% Grade 3> 2-5 ULN7%8% Grade 4> x ULN2%1% Lipase Grade 2> 1.5-3 ULN4%6% Grade 3> 3-5 ULN2%2% Grade 4> x ULN1%< 1% Creatinine Grade 2> 1.4-1.8 ULN6%5% Grade 3> 1.9-3.4 ULN2%1% Grade 4> 3.4 ULN0%< 1%HEMATOLOGY Decreased hemoglobin Grade 290-99 g/L2%4% Grade 370-89 g/L< 1%< 1% Grade 4< 70 g/L< 1%< 1% White blood cell count Grade 21,500-1,999/mm3 2%3% Grade 31,000-1,499/mm3 1%4% Grade 4< 1,000/mm3 1%< 1% Neutrophils Grade 2750-999/mm3 5%6% Grade 3500-749/mm3 4%4% Grade 4< 500/mm3 2%3% Platelet count Grade 250,000-99,999/mm3 3%5% Grade 325,000-49,999/mm3 1%1% Grade 4< 25,000/mm3 1%< 1%LIPIDS AND GLUCOSE Total cholesterol Grade 2> 6.20-7.77 mmol/L240-300 mg/dL20%17% Grade 3> 7.77 mmol/L> 300 mg/dL8%5% Low density lipoprotein Grade 24.13-4.9 mmol/L160-190 mg/dL13%12% Grade 3> 4.9 mmol/L> 190 mg/dL7%7% Triglycerides Grade 25.65-8.48 mmol/L500-750 mg/dL9%7% Grade 38.49-13.56 mmol/L751-1200 mg/dL6%4% Grade 4> 13.56 mmol/L> 1200 mg/dL4%2% Elevated glucose levels Grade 26.95-13.88 mmol/L161-250 mg/dL15%13% Grade 313.89-27.75 mmol/L251-500 mg/dL4%2% Grade 4> 27.75 mmol/L> 500 mg/dL0%< 1%HEPATIC PARAMETERS Alanine amino transferase Grade 22.6-5 ULN6%5% Grade 35.1-10 ULN3%2% Grade 4> 10 ULN1%< 1% Aspartate amino transferase Grade 22.6-5 ULN6%8% Grade 35.1-10 ULN3%2% Grade 4> 10 ULN< 1%< 1%. Patients Co-Infected With Hepatitis and/or Hepatitis VirusIn Phase trials TMC125-C206 and TMC125-C216, 139 subjects (12.3%) with chronic hepatitis and/or hepatitis virus co-infection out of 1129 subjects were permitted to enroll. AST and ALT abnormalities occurred more frequently in hepatitis and/or hepatitis virus co-infected subjects for both treatment groups. Grade or higher laboratory abnormalities that represent worsening from baseline of AST, ALT or total bilirubin occurred in 27.8%, 25.0% and 7.1% respectively, of INTELENCE-treated co-infected subjects as compared to 6.7%, 7.5% and 1.8% of non-co-infected INTELENCE-treated subjects. In general, adverse events reported by INTELENCE-treated subjects with hepatitis and/or hepatitis virus co-infection were similar to INTELENCE-treated subjects without hepatitis and/or hepatitis virus co-infection.. Clinical Trials Experience in Pediatric Subjects (2 Years to Less Than 18 years of age)The safety assessment in pediatric subjects is based on two single-arm trials. TMC125-C213 is Phase trial in which 101 antiretroviral treatment-experienced HIV-1 infected pediatric subjects years to less than 18 years of age received INTELENCE in combination with other antiretroviral agents (Week 24 analysis). TMC125-C234/IMPAACT P1090 is Phase 1/2 trial in which 20 antiretroviral treatment-experienced HIV-1 infected pediatric subjects years to less than years of age received INTELENCE 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 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 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 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 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 years to less than 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 or Grade rash and no subjects discontinued prematurely due to rash. One subject discontinued etravirine due to asymptomatic lipase elevation.. 6.2Postmarketing Experience. The following events have been identified during postmarketing use of INTELENCE. Because these events are reported voluntarily from population of unknown size, it is not always possible to reliably estimate their frequency or establish 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: rhabdomyolysisSkin and Subcutaneous Tissue Disorders: Fatal cases of toxic epidermal necrolysis and Stevens-Johnson syndrome have been reported [see Warnings and Precautions (5.1)].

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisEtravirine 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).. MutagenesisEtravirine 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 metabolic activation system. Etravirine did not induce chromosomal damage in the in vivo micronucleus test in mice.. Impairment of FertilityNo 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).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Etravirine is an antiretroviral drug [see Microbiology (12.4)].. 12.2 Pharmacodynamics. Cardiac ElectrophysiologyIn thorough QT/QTc study in 41 healthy subjects, INTELENCE 200 mg twice daily or 400 mg once daily did not affect the QT/QTc interval.. 12.3 Pharmacokinetics. The pharmacokinetic properties of INTELENCE 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 Trials at Week 48)All HIV-1-infected subjects enrolled in Phase clinical trials received darunavir/ritonavir 600/100 mg twice daily as part of their background regimen. Therefore, the pharmacokinetic parameter estimates shown in Table account for reductions in the pharmacokinetic parameters of etravirine due to co-administration of INTELENCE with darunavir/ritonavir. ParameterEtravirineN=575AUC12h (ngh/mL) Geometric mean +- standard deviation4522 +- 4710 Median (range)4380 (458-59084)C0h (ng/mL) Geometric mean +- standard deviation297 +- 391 Median (range)298 (2-4852)Note: The median protein binding adjusted EC50 for MT4 cells infected with HIV-1/IIIB in vitro equals ng/mL.. Absorption and BioavailabilityFollowing oral administration, etravirine was absorbed with Tmax of about 2.5 to hours. The absolute oral bioavailability of INTELENCE is unknown.In healthy subjects, the absorption of etravirine is not affected by co-administration of oral ranitidine or omeprazole, drugs that increase gastric pH.. Effects of Food on Oral AbsorptionThe systemic exposure (AUC) to etravirine was decreased by about 50% when INTELENCE was administered under fasting conditions, as compared to when INTELENCE was administered following 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).. DistributionEtravirine 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.. MetabolismIn 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.. EliminationAfter 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 PatientsPopulation 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 PatientsThe pharmacokinetics of etravirine in 115 treatment-experienced HIV-1-infected pediatric subjects, 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 INTELENCE 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 Years to Less Than 18 Years of Age (TMC125-C213 [Population PK] and TMC125-C234/P1090)StudyTMC125-C213TMC125-C234/IMPAACT P1090Age Range (years)(6 years to less than 18 years)(2 years to less than years)ParameterN=101N=14AUC12h (ngh/mL) Geometric mean +- standard deviation3742 +- 43143504 +- 2923 Median (range)4499 (62-28865)3579 (1221-11815)C0h (ng/mL) Geometric mean +- standard deviation205 +- 342183 +- 240 Median (range)287 (2-2276)162 (54-908)The pharmacokinetics and dose of etravirine in pediatric subjects less than years of age have not been established [see Use in Specific Populations (8.4)]. Male and Female PatientsNo significant pharmacokinetic differences have been observed between males and females.. Racial or Ethnic GroupsPopulation pharmacokinetic analysis of etravirine in HIV-infected subjects did not show an effect of race on exposure to etravirine.. Patients with Renal ImpairmentThe pharmacokinetics of etravirine have not been studied in patients with renal impairment. The results from 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 ImpairmentEtravirine is primarily metabolized by the liver. The steady state pharmacokinetic parameters of etravirine were similar after multiple dose administration of INTELENCE to subjects with normal hepatic function (16 subjects), mild hepatic impairment (Child-Pugh Class A, subjects), and moderate hepatic impairment (Child-Pugh Class B, 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 PostpartumAfter intake of INTELENCE 200 mg twice daily in combination with other antiretroviral agents (13 subjects with NRTIs, subject with NRTIs lopinavir ritonavir, subject with NRTIs raltegravir), based on intra-individual comparison, the Cmax and AUC12h of total etravirine were 23 to 42% higher during pregnancy compared with postpartum (6-12 weeks). The Cmin of total etravirine was 78 to 125% higher during pregnancy compared with postpartum (6-12 weeks), while two subjects had Cmin <10 ng/mL in the postpartum period (6-12 weeks) [Cmin of total etravirine was 11 to 16% higher when these 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.ParameterMean +- SD (median)PostpartumN=102nd TrimesterN=133rd TrimesterN=10n=9 for AUC12h Cmin, ng/mL269 +- 182 (284)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). 383 +- 210 (346)349 +- 103 (371)Cmax, ng/mL569 +- 261 (528)774 +- 300 (828)785 +- 238 (694)AUC12h, ngh/mL5004 +- 2521 (5246)6617 +- 2766 (6836)6846 +- 1482 (6028). Patients with Hepatitis and/or Hepatitis Virus Co-InfectionPopulation pharmacokinetic analysis of the TMC125-C206 and TMC125-C216 trials showed reduced clearance for etravirine in HIV-1-infected subjects with hepatitis and/or virus co-infection. Based upon the safety profile of INTELENCE [see Adverse Reactions (6)], no dose adjustment is necessary in patients co-infected with hepatitis and/or virus.. Drug InteractionsEtravirine is substrate of CYP3A, CYP2C9, and CYP2C19. Therefore, co-administration of INTELENCE with drugs that induce or inhibit CYP3A, CYP2C9, and CYP2C19 may alter the therapeutic effect or adverse reaction profile of INTELENCE.Etravirine is an inducer of CYP3A and inhibitor of CYP2C9, CYP2C19 and P-gp. Therefore, co-administration of drugs that are substrates of CYP3A, CYP2C9 and CYP2C19 or are transported by P-gp with INTELENCE may alter the therapeutic effect or adverse reaction profile of the co-administered drug(s).Drug interaction studies were performed with INTELENCE and other drugs likely to be co-administered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of other drugs on the AUC, Cmax, and Cmin values of etravirine are summarized in Table (effect of other drugs on INTELENCE). The effect of co-administration of INTELENCE on the AUC, Cmax, and Cmin values of other drugs are summarized in Table (effect of INTELENCE 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 DrugsCo-administered DrugDose/Schedule of Co-administered DrugNExposureMean Ratio of Etravirine Pharmacokinetic Parameters90% CI; No Effect 1.00Cmax AUCCmin CI Confidence Interval; = number of subjects with data; N.A. not available; increase; decrease; <-> no changeCo-administration with HIV protease inhibitors (PIs)Atazanavir400 mg once daily141.47(1.36-1.59)1.50(1.41-1.59)1.58(1.46-1.70)Atazanavir/ritonavirThe systemic exposure of etravirine when co-administered with atazanavir/ritonavir in HIV infected subjects is similar to exposures of etravirine observed in the Phase trials after co-administration of INTELENCE and darunavir/ritonavir (as part of the background regimen). 300/100 mg once daily141.30(1.17-1.44)1.30(1.18-1.44)1.26(1.12-1.42)Darunavir/ritonavir600/100 mg twice daily140.68(0.57-0.82)0.63(0.54-0.73)0.51(0.44-0.61)Lopinavir/ritonavir(tablet)400/100 mg twice daily160.70(0.64-0.78)0.65(0.59-0.71)0.55(0.49-0.62)Ritonavir600 mg twice daily110.68(0.55-0.85)0.54(0.41-0.73)N.A.Saquinavir/ritonavir1000/100 mg twice daily140.63(0.53-0.75)0.67(0.56-0.80)0.71(0.58-0.87)Tipranavir/ritonavir500/200 mg twice daily190.29(0.22-0.40)0.24(0.18-0.33)0.18(0.13-0.25)Co-administration with nucleoside reverse transcriptase inhibitors (NRTIs)Didanosine400 mg once daily15<->1.16(1.02-1.32)1.11(0.99-1.25)1.05(0.93-1.18)Tenofovir disoproxil fumarate300 mg once daily230.81(0.75-0.88)0.81(0.75-0.88)0.82(0.73-0.91)Co-administration with CCR5 antagonistsMaraviroc300 mg twice daily14<->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)The reference for etravirine exposure is the pharmacokinetic parameters of etravirine in the presence of darunavir/ritonavir. 150/600/100 mg twice daily10<->1.08(0.98-1.20)1.00(0.86-1.15)0.81(0.65-1.01)Co-administration with integrase strand transfer inhibitorsRaltegravir400 mg twice daily19<->1.04(0.97-1.12)1.10(1.03-1.16)1.17(1.10-1.26)Co-administration with other drugsArtemether/lumefantrine80/480 mg, doses at 0, 8, 24, 36, 48, and 60 hours14<->1.11(1.06-1.17)1.10(1.06-1.15)1.08(1.04-1.14)Atorvastatin40 mg once daily16<->0.97(0.93-1.02)1.02(0.97-1.07)1.10(1.02-1.19)Clarithromycin500 mg twice daily151.46(1.38-1.56)1.42(1.34-1.50)1.46(1.36-1.58)Fluconazole200 mg once daily in the morning161.75(1.60-1.91)1.86(1.73-2.00)2.09(1.90-2.31)Omeprazole40 mg once daily181.17(0.96-1.43)1.41(1.22-1.62)N.A.Paroxetine20 mg once daily16<->1.05(0.96-1.15)1.01(0.93-1.10)1.07(0.98-1.17)Ranitidine150 mg twice daily180.94(0.75-1.17)0.86(0.76-0.97)N.A.Rifabutin300 mg once daily120.63(0.53-0.74)0.63(0.54-0.74)0.65(0.56-0.74)Voriconazole200 mg twice daily161.26(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 INTELENCECo-administered DrugDose/Schedule of Co-administered DrugNExposureMean Ratio of Co-administered Drug Pharmacokinetic Parameters90% CI; No effect 1.00Cmax AUCCmin CI Confidence Interval; = number of subjects with data; N.A. not available; increase; decrease; <-> no changeCo-administration with HIV protease inhibitors (PIs)Atazanavir400 mg once daily140.97(0.73-1.29)0.83(0.63-1.09)0.53(0.38-0.73)Atazanavir/ritonavir300/100 mg once daily130.97(0.89-1.05)0.86(0.79-0.93)0.62(0.55-0.71)Atazanavir/ritonavirHIV-infected subjects 300/100 mg once daily200.96(0.80-1.16)0.96(0.76-1.22)0.82(0.55-1.22)Darunavir/ritonavir600/100 mg twice daily15<->1.11(1.01-1.22)1.15(1.05-1.26)1.02(0.90-1.17)Fosamprenavir/ritonavir700/100 mg twice daily81.62(1.47-1.79)1.69(1.53-1.86)1.77(1.39-2.25)Lopinavir/ritonavir(tablet)400/100 mg twice daily16<->0.89(0.82-0.96)0.87(0.83-0.92)0.80(0.73-0.88)Saquinavir/ritonavir1000/100 mg twice daily15<->1.00(0.70-1.42)0.95(0.64-1.42)0.80(0.46-1.38)Tipranavir/ritonavir500/200 mg twice daily191.14(1.02-1.27)1.18(1.03-1.36)1.24(0.96-1.59)Co-administration with nucleoside reverse transcriptase inhibitors (NRTIs)Didanosine400 mg once daily14<->0.91(0.58-1.42)0.99(0.79-1.25)N.A.Tenofovir disoproxil fumarate300 mg once daily19<->1.15(1.04-1.27)1.15(1.09-1.21)1.19(1.13-1.26)Co-administration with CCR5 antagonistsMaraviroc300 mg twice daily140.40(0.28-0.57)0.47(0.38-0.58)0.61(0.53-0.71)Maraviroc (when co-administered with darunavir/ritonavir) compared to maraviroc 150 mg twice daily 150/600/100 mg twice daily101.77(1.20-2.60)3.10(2.57-3.74)5.27(4.51-6.15)Co-administration with integrase strand transfer inhibitorsDolutegravir50 mg once daily160.48(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 daily90.88(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/ritonavir50 mg once daily 400/100 mg twice daily8<->1.07(1.02 to 1.13)1.11(1.02 to 1.20)1.28(1.13 to 1.45)Raltegravir400 mg twice daily190.89(0.68-1.15)0.90(0.68-1.18)0.66(0.34-1.26)Co-administration with other drugsArtemether80/480 mg, doses at 0, 8, 24, 36, 48, and 60 hours150.72(0.55-0.94)0.62(0.48-0.80)0.82(0.67-1.01)Dihydroartemisinin150.84(0.71-0.99)0.85(0.75-0.97)0.83(0.71-0.97)Lumefantrine151.07(0.94-1.23)0.87(0.77-0.98)0.97(0.83-1.15)Atorvastatin40 mg once daily161.04(0.84-1.30)0.63(0.58-0.68)N.A.2-hydroxy-atorvastatin161.76(1.60-1.94)1.27(1.19-1.36)N.A.BuprenorphineIndividual dose regimen ranging from 4/1 mg to 16/4 mg once daily160.89(0.76-1.05)0.75(0.66-0.84)0.60(0.52-0.68)Norbuprenorphine16<->1.08(0.95-1.23)0.88(0.81-0.96)0.76(0.67-0.87)Clarithromycin500 mg twice daily150.66(0.57-0.77)0.61(0.53-0.69)0.47(0.38-0.57)14-hydroxy-clarithromycin151.33(1.13-1.56)1.21(1.05-1.39)1.05(0.90-1.22)Digoxin0.5 mg single dose161.19(0.96-1.49)1.18(0.90-1.56)N.A.Ethinylestradiol0.035 mg once daily161.33(1.21-1.46)1.22(1.13-1.31)1.09(1.01-1.18)Norethindrone1 mg once daily16<->1.05(0.98-1.12)0.95(0.90-0.99)0.78(0.68-0.90)Fluconazole200 mg once daily in the morning15<->0.92(0.85-1.00)0.94(0.88-1.01)0.91(0.84-0.98)R(-) MethadoneIndividual dose regimen ranging from 60 to 130 mg/day16<->1.02(0.96-1.09)1.06(0.99-1.13)1.10(1.02-1.19)S(+) Methadone16<->0.89(0.83-0.97)0.89(0.82-0.96)0.89(0.81-0.98)Paroxetine20 mg once daily16<->1.06(0.95-1.20)1.03(0.90-1.18)0.87(0.75-1.02)Rifabutin300 mg once daily120.90(0.78-1.03)0.83(0.75-0.94)0.76(0.66-0.87)25-O-desacetylrifabutin300 mg once daily120.85(0.72-1.00)0.83(0.74-0.92)0.78(0.70-0.87)Sildenafil50 mg single dose150.55(0.40-0.75)0.43(0.36-0.51)N.A.N-desmethyl-sildenafil150.75(0.59-0.96)0.59(0.52-0.68)N.A.Voriconazole200 mg twice daily140.95(0.75-1.21)1.14(0.88-1.47)1.23(0.87-1.75). 12.4 Microbiology. Mechanism of ActionEtravirine 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 disruption of the enzymes catalytic site. Etravirine does not inhibit the human DNA polymerases , and .. Antiviral Activity in Cell CultureEtravirine 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 broad panel of HIV-1 group 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 primary isolates. Etravirine did not show antagonism when studied in combination with the following antiretroviral drugs--the NNRTIs delavirdine, efavirenz, and nevirapine; the N(t)RTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, 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 CultureEtravirine-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 SubjectsIn the Phase trials TMC125-C206 and TMC125-C216, substitutions that developed most commonly in subjects with virologic failure at Week 48 to the INTELENCE-containing regimen were V179F, V179I, and Y181C which usually emerged in background of multiple other NNRTI resistance-associated substitutions. In all the trials conducted with INTELENCE in HIV-1 infected subjects, the following substitutions emerged most commonly: L100I, E138G, V179F, V179I, Y181C and H221Y. Other NNRTI-resistance-associated substitutions which emerged on etravirine treatment in 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 median fold-change in etravirine susceptibility of 40-fold from reference and median fold-change of 6-fold from baseline.. Cross-ResistanceCross-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 rilpivirine-containing regimen with development of rilpivirine resistance is likely to result in cross-resistance to etravirine (see Treatment-Naive HIV-1-Infected Subjects in the Phase Trials for EDURANT (rilpivirine) below). Cross-resistance to etravirine has been observed after virologic failure on 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 VirusEtravirine 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 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 or 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 combination of substitutions V179F Y181C (187 fold-change), V179F Y181I (123 fold-change), or V179F Y181C F227C (888 fold-change).. Clinical IsolatesEtravirine retained fold-change less than or equal to 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 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-Naive HIV-1-Infected Subjects in the Phase Trials for EDURANT (Rilpivirine)There are currently no clinical data available on the use of etravirine in subjects who experienced virologic failure on 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 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 AnalysesIn TMC125-C206 and TMC125-C216, the presence at baseline of the substitutions L100I, E138A, I167V, V179D, V179F, Y181I, Y181V, or G190S was associated with decreased virologic response to etravirine. Additional substitutions associated with decreased virologic response to etravirine when in the presence of or more additional 2008 IAS-USA defined NNRTI substitutions include A98G, K101H, K103R, V106I, V179T, and Y181C. The presence of K103N, which was the most prevalent NNRTI substitution in TMC125-C206 and TMC125-C216 at baseline, did not affect the response in the INTELENCE arm. Overall, response rates to etravirine decreased as the number of baseline NNRTI substitutions increased (shown as the proportion of subjects achieving viral load 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 Substitutions2008 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 in the Non-VF Excluded Population of the Pooled TMC125-C206 and TMC125-C216ENF: enfuvirtide IAS-USA-Defined NNRTI substitutions EtravirineN=561Re-used/not used ENFde novo ENFAll ranges61% (254/418)76% (109/143)068% (52/76)95% (20/21)167% (72/107)77% (24/31)264% (75/118)86% (38/44)355% (36/65)62% (16/26)>= 437% (19/52)52% (11/21)PlaceboN=592All ranges34% (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 INTELENCE. The data are provided to give clinicians information on the likelihood of virologic success based on pre-treatment susceptibility to etravirine in treatment-experienced patients.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-C216Non-VF excluded analysis ENF: enfuvirtideFold ChangeEtravirineN=559Re-used/not used ENFde novo ENFClinical response rangeAll ranges61% (253/416)76% (109/143)Overall Response0-369% (188/274)83% (75/90)Higher than Overall Response> 3-1350% (39/78)66% (25/38)Lower than Overall Response> 1341% (26/64)60% (9/15)Lower than Overall ResponsePlaceboN=583All ranges34% (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-C216PSSThe phenotypic susceptibility score (PSS) was defined as the total number of active antiretroviral drugs in the background therapy to which subjects baseline viral isolate showed sensitivity in phenotypic resistance tests. Each drug in the background therapy was scored as 1 or 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 sensitive antiretroviral if the FC was less than or equal to 10; ENF was counted as sensitive antiretroviral if it had not been used previously. INTELENCE was not included in this calculation. INTELENCE BRN=559Placebo BRN=586043% (40/93)5% (5/95)161% (125/206)28% (64/226)277% (114/149)59% (97/165)>= 375% (83/111)72% (72/100).

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Treatment-Experienced Adult Subjects. The clinical efficacy of INTELENCE is derived from the analyses of 48-week data from ongoing, randomized, double-blinded, placebo-controlled, Phase trials, TMC125-C206 and TMC125-C216 (DUET-1 and DUET-2) in subjects with 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 studies designed to evaluate the safety and antiretroviral activity of INTELENCE in combination with background regimen (BR) as compared to placebo in combination with 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 weeks. In addition, subjects had or more NNRTI resistance-associated substitutions at screening or from prior genotypic analysis, and 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 other investigator-selected antiretroviral drugs (N[t]RTIs with or without ENF). Of INTELENCE-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 INTELENCE arm and the placebo arm (Table 13). Table 13 displays selected demographic and baseline disease characteristics of the subjects in the INTELENCE and placebo arms.Table 13: Demographic and Baseline Disease Characteristics of Subjects(Pooled Analysis TMC125-C206 and TMC125-C216)--INTELENCE BRN=599Placebo BRN=604RASs Resistance-Associated Substitutions, BR=background regimen, FC fold change in EC50 Demographic characteristicsMedian age, years (range)46(18-77)45(18-72)Sex Male90.0%88.6% Female10.0%11.4%Race White70.1%69.8% Black13.2%13.0% Hispanic11.3%12.2% Asian1.3%0.6% Other4.1%4.5%Baseline disease characteristicsMedian baseline plasma HIV-1 RNA (range), log10 copies/mL4.8(2.7-6.8)4.8(2.2-6.5)Percentage of subjects with baseline viral load: 30,000 copies/mL27.5%28.8% >= 30,000 copies/mL and 100,000 copies/mL34.4%35.3% >= 100,000 copies/mL38.1%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 35.6%34.7% >= 50 cells/mm3 and 200 cells/mm3 34.8%34.5% >= 200 cells/mm3 29.6%30.8%Median (range) number of primary PI substitutionsIAS-USA primary PI substitutions [August/September 2007]: D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50L/V, I54L/M, L76V, V82A/F/L/S/T, I84V, N88S, L90M 4(0-7)4(0-8)Percentage of subjects with previous use of NNRTIs: 08.2%7.9% 146.9%46.7% 144.9%45.4%Percentage of subjects with previous use of the following NNRTIs: Efavirenz70.3%72.5% Nevirapine57.1%58.6% Delavirdine13.7%12.6%Median (range) number of NNRTI RASsTibotec 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 2(0-8)2(0-7)Median fold change of the virus for the following NNRTIs: Delavirdine27.326.1 Efavirenz63.945.4 Etravirine1.61.5 Nevirapine74.374.0Percentage of subjects with previous use of fusion inhibitor39.6%42.2%Percentage of subjects with Phenotypic Sensitivity Score (PSS) for the background therapy 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. INTELENCE is not included in this calculation. of: 017.0%16.2% 136.5%38.7% 226.9%27.8% >= 319.7%17.3%Efficacy at Week 48 for subjects in the INTELENCE 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)INTELENCE BRN=599Placebo BRN=604BR=background regimenVirologic responders at Week 48Viral Load 50 HIV-1 RNA copies/mL359 (60%)232 (38%)Virologic failures at Week 48Viral Load >= 50 HIV-1 RNA copies/mL123 (21%)201 (33%)Death11 (2%)19 (3%)Discontinuations before Week 48: due to virologic failures58 (10%)110 (18%) due to adverse events31 (5%)14 (2%) due to other reasons17 (3%)28 (5%)At Week 48, 70.8% of INTELENCE-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 INTELENCE-treated subjects and -1.46 log10 copies/mL for placebo-treated subjects. The mean CD4+ cell count increase from baseline for INTELENCE-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 INTELENCE-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 INTELENCE-treated subjects and 57.2% of placebo-treated subjects achieved HIV-1 RNA less than 50 copies/mL.Treatment-emergent CDC category events occurred in 4% of INTELENCE-treated subjects and 8.4% of placebo-treated subjects.Study TMC125-C227 was randomized, exploratory, active-controlled, open-label, Phase 2b trial. Eligible subjects were treatment-experienced, PI-naive 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 INTELENCE (59 subjects) or an investigator-selected PI (57 subjects), each given with investigator-selected N(t)RTIs. INTELENCE-treated subjects had lower antiviral responses associated with reduced susceptibility to the N(t)RTIs and to INTELENCE 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 INTELENCE for treatment-experienced pediatric subjects is based on two Phase trials, TMC125-C213 and TMC125-C234/IMPAACT P1090.. Pediatric Subjects (6 Years to Less Than 18 Years of Age [TMC125-C213])TMC125-C213, single-arm, Phase trial evaluating the pharmacokinetics, safety, tolerability, and efficacy of INTELENCE enrolled 101 antiretroviral treatment-experienced HIV-1 infected pediatric subjects 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 INTELENCE 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 Than Years of Age [TMC125-C234/IMPAACT P1090])TMC125-C234/IMPAACT P1090 is Phase 1/2 trial evaluating the pharmacokinetics, safety, tolerability, and efficacy of INTELENCE in 20 antiretroviral treatment-experienced HIV-1 infected pediatric subjects years to less than years of age. The study enrolled subjects who had virologic failure on an antiretroviral treatment regimen after at least weeks of treatment, or who had interrupted treatment for at least weeks. Enrolled subjects had history of virologic failure while on an antiretroviral regimen, with 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 ritonavir-boosted protease inhibitor in combination with or 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.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None.

DESCRIPTION SECTION.

11 DESCRIPTION. INTELENCE (etravirine) is non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type (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:Etravirine is white to slightly yellowish-brown powder. Etravirine is practically insoluble in water over wide pH range. It is very slightly soluble in propylene glycol and slightly soluble in ethanol. Etravirine is soluble in polyethylene glycol (PEG)400 and freely soluble in some organic solvents (e.g., N,N-dimethylformamide and tetrahydrofuran).INTELENCE 25 mg tablets are available as white to off-white, oval scored tablets for oral administration. Each 25 mg tablet contains 25 mg of etravirine and the inactive ingredients colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate and microcrystalline cellulose.INTELENCE 100 mg tablets are available as white to off-white, oval tablets for oral administration. Each 100 mg tablet contains 100 mg of etravirine and the inactive ingredients colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate and microcrystalline cellulose.INTELENCE 200 mg tablets are available as white to off-white, biconvex, oblong tablets for oral administration. Each 200 mg tablet contains 200 mg of etravirine and the inactive ingredients colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose and silicified microcrystalline cellulose.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Adult patients: 200 mg (one 200 mg tablet or two 100 mg tablets) taken twice daily following meal. (2.1, 2.2, 2.4)Pregnant patients: 200 mg (one 200 mg tablet or two 100 mg tablets) taken twice daily following meal. (2.2)Pediatric patients (2 years to less than 18 years of age and weighing at least 10 kg): dosage of INTELENCE is based on body weight and should not exceed the recommended adult dose. INTELENCE tablets should be taken following meal. (2.3). Adult patients: 200 mg (one 200 mg tablet or two 100 mg tablets) taken twice daily following meal. (2.1, 2.2, 2.4). Pregnant patients: 200 mg (one 200 mg tablet or two 100 mg tablets) taken twice daily following meal. (2.2). Pediatric patients (2 years to less than 18 years of age and weighing at least 10 kg): dosage of INTELENCE is based on body weight and should not exceed the recommended adult dose. INTELENCE tablets should be taken following meal. (2.3). 2.1Recommended Dosage in Adult Patients. The recommended oral dosage of INTELENCE for adult patients is 200 mg (one 200 mg tablet or two 100 mg tablets) taken twice daily following meal. The type of food does not affect the exposure to INTELENCE [see Clinical Pharmacology (12.3)].. 2.2Recommended Dosage During Pregnancy. The recommended oral dosage of INTELENCE for pregnant individuals is 200 mg (one 200 mg tablet or two 100 mg tablets) taken twice daily following meal [see Use in Specific Populations (8.1)].. 2.3Recommended Dosage in Pediatric Patients (2 Years to Less Than 18 Years of Age). The recommended dosage of INTELENCE for pediatric patients 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. INTELENCE should be taken orally, following meal. The type of food does not affect the exposure to INTELENCE [see Clinical Pharmacology (12.3)].Table 1:Recommended Dosage of INTELENCE for Pediatric Patients Years to Less Than 18 Years of AgeBody Weightkilograms (kg)Dosegreater than or equal to 10 kg to less than 20 kg100 mg twice dailygreater than or equal to 20 kg to less than 25 kg125 mg twice dailygreater than or equal to 25 kg to less than 30 kg150 mg twice dailygreater than or equal to 30 kg200 mg twice daily. 2.4Method of Administration. Instruct patients to swallow the INTELENCE tablet(s) whole with liquid such as water. Patients who are unable to swallow the INTELENCE tablet(s) whole may disperse the tablet(s) in water. Instruct the patient to do the following:place the tablet(s) in 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 104F [greater than 40C]) 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.. place the tablet(s) in 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 104F [greater than 40C]) 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.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. 25 mg white to off-white, oval, scored tablets debossed with TMC on one side.100 mg white to off-white oval tablets debossed with TMC125 on one side and 100 on the other side.200 mg white to off-white, biconvex, oblong tablets debossed with T200 on one side.. 25 mg white to off-white, oval, scored tablets debossed with TMC on one side.. 100 mg white to off-white oval tablets debossed with TMC125 on one side and 100 on the other side.. 200 mg white to off-white, biconvex, oblong tablets debossed with T200 on one side.. Tablets: 25 mg, 100 mg, and 200 mg (3). Tablets: 25 mg, 100 mg, and 200 mg (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Co-administration of INTELENCE with other drugs can alter the concentrations of other drugs and other drugs may alter the concentrations of etravirine. The potential drug-drug interactions must be considered prior to and during therapy. (7, 12.3). 7.1Potential for Other Drugs to Affect INTELENCE. Etravirine is substrate of CYP3A, CYP2C9, and CYP2C19. Therefore, co-administration of INTELENCE with drugs that induce or inhibit CYP3A, CYP2C9, and CYP2C19 may alter the therapeutic effect or adverse reaction profile of INTELENCE (see Table 4) [see Clinical Pharmacology (12.3)]. 7.2Potential for INTELENCE 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 INTELENCE may alter the therapeutic effect or adverse reaction profile of the co-administered drug(s) (see Table 4) [see Clinical Pharmacology (12.3)]. 7.3Significant Drug Interactions. Table shows significant drug interactions based on which, alterations in dose or regimen of INTELENCE and/or co-administered drug may be recommended. Drugs that are not recommended for co-administration with INTELENCE are also included in Table [see Clinical Pharmacology (12.3)].Table 4:Significant Drug InteractionsConcomitant Drug Class:Drug NameEffect on Concentration of Etravirine or Concomitant Drug Clinical Comment increase; decrease; <-> no changeHIV-antiviral agents: integrase strand inhibitorsdolutegravirThe interaction between INTELENCE and the drug was evaluated in clinical study. All other drug interactions shown are predicted. dolutegravir<-> etravirineEtravirine 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<-> etravirineThe 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 should only be used with INTELENCE when co-administered with atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir.dolutegravir/lopinavir/ritonavir <-> dolutegravir<-> etravirineHIV-antiviral agents: non-nucleoside reverse transcriptase inhibitors (NNRTIs)efavirenz nevirapine etravirineCombining two NNRTIs has not been shown to be beneficial. Concomitant use of INTELENCE with efavirenz or nevirapine may cause significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE. Co-administration of INTELENCE and other NNRTIs is not recommended.delavirdine etravirineCombining two NNRTIs has not been shown to be beneficial. INTELENCE and delavirdine should not be co-administered.rilpivirine rilpivirine<-> etravirineCombining two NNRTIs has not been shown to be beneficial. Co-administration of INTELENCE and rilpivirine is not recommended.HIV-antiviral agents: protease inhibitors (PIs)atazanavir (without ritonavir) atazanavirCo-administration of INTELENCE and atazanavir without low-dose ritonavir is not recommended.atazanavir/ritonavir atazanavir<-> etravirineConcomitant use of INTELENCE with atazanavir/ritonavir decreased atazanavir Cmin but it is not considered clinically relevant. The mean systemic exposure (AUC) of etravirine after co-administration of INTELENCE with atazanavir/ritonavir in HIV-infected subjects was similar to the mean systemic exposure of etravirine observed in the Phase trials after co-administration of INTELENCE and darunavir/ritonavir (as part of the background regimen). INTELENCE and atazanavir/ritonavir can be co-administered without dose adjustments.atazanavir/cobicistat atazanavir cobicistatCo-administration of INTELENCE with atazanavir/cobicistat is not recommended because it may result in loss of therapeutic effect and development of resistance to atazanavir.darunavir/ritonavir etravirineThe mean systemic exposure (AUC) of etravirine was reduced when INTELENCE was co-administered with darunavir/ritonavir. Because all subjects in the Phase trials received darunavir/ritonavir as part of the background regimen and etravirine exposures from these trials were determined to be safe and effective, INTELENCE and darunavir/ritonavir can be co-administered without dose adjustments.darunavir/cobicistat cobicistatdarunavir: effect unknownCo-administration of INTELENCE with darunavir/cobicistat is not recommended because it may result in loss of therapeutic effect and development of resistance to darunavir.fosamprenavir(without ritonavir) amprenavirConcomitant use of INTELENCE with fosamprenavir without low-dose ritonavir may cause significant alteration in the plasma concentration of amprenavir. Co-administration of INTELENCE and fosamprenavir without low-dose ritonavir is not recommended.fosamprenavir/ritonavir amprenavirDue to significant increase in the systemic exposure of amprenavir, the appropriate doses of the combination of INTELENCE and fosamprenavir/ritonavir have not been established. Co-administration of INTELENCE and fosamprenavir/ritonavir is not recommended.indinavir (without ritonavir) indinavirConcomitant use of INTELENCE with indinavir without low-dose ritonavir may cause significant alteration in the plasma concentration of indinavir. Co-administration of INTELENCE and indinavir without low-dose ritonavir is not recommended.lopinavir/ritonavir etravirineThe mean systemic exposure (AUC) of etravirine was reduced after co-administration of INTELENCE with lopinavir/ritonavir (tablet). Because the reduction in the mean systemic exposures of etravirine in the presence of lopinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE and lopinavir/ritonavir can be co-administered without dose adjustments.nelfinavir(without ritonavir) nelfinavirConcomitant use of INTELENCE with nelfinavir without low-dose ritonavir may cause significant alteration in the plasma concentration of nelfinavir. Co-administration of INTELENCE and nelfinavir without low-dose ritonavir is not recommended.ritonavir etravirineConcomitant use of INTELENCE with ritonavir 600 mg twice daily may cause significant decrease in the plasma concentration of etravirine and loss of therapeutic effect of INTELENCE. Co-administration of INTELENCE and ritonavir 600 mg twice daily is not recommended.saquinavir/ritonavir etravirineThe mean systemic exposure (AUC) of etravirine was reduced when INTELENCE was co-administered with saquinavir/ritonavir. Because the reduction in the mean systemic exposures of etravirine in the presence of saquinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE and saquinavir/ritonavir can be co-administered without dose adjustments.tipranavir/ritonavir etravirineConcomitant use of INTELENCE with tipranavir/ritonavir may cause significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE. Co-administration of INTELENCE and tipranavir/ritonavir is not recommended.CCR5 antagonistsmaraviroc <-> etravirine maravirocWhen INTELENCE is co-administered with maraviroc in the absence of potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 600 mg twice daily. No dose adjustment of INTELENCE is needed.maraviroc/darunavir/ritonavir The reference for etravirine exposure is the pharmacokinetic parameters of etravirine in the presence of darunavir/ritonavir. <-> etravirine maravirocWhen INTELENCE is co-administered with maraviroc in the presence of potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 150 mg twice daily. No dose adjustment of INTELENCE is needed.Other agentsAntiarrhythmics: digoxin<-> etravirine digoxinFor patients who are initiating combination of INTELENCE and digoxin, the lowest dose of digoxin should initially be prescribed. For patients on stable digoxin regimen and initiating INTELENCE, no dose adjustment of either INTELENCE or digoxin is needed. The serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.amiodaronebepridildisopyramideflecainidelidocaine (systemic)mexiletinepropafenonequinidine antiarrhythmicsConcentrations of these antiarrhythmics may be decreased when co-administered with INTELENCE. INTELENCE and antiarrhythmics should be co-administered with caution. Drug concentration monitoring is recommended, if available.Anticoagulant: warfarin anticoagulantsWarfarin concentrations may be increased when co-administered with INTELENCE. The international normalized ratio (INR) should be monitored when warfarin is combined with INTELENCE.Anticonvulsants:carbamazepinephenobarbitalphenytoin etravirineCarbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. INTELENCE should not be used in combination with carbamazepine, phenobarbital, or phenytoin as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE.Antifungals:fluconazole etravirine<-> fluconazoleCo-administration of etravirine and fluconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and fluconazole should be co-administered with caution. No dose adjustment of INTELENCE or fluconazole is needed.voriconazole voriconazoleCo-administration of etravirine and voriconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and voriconazole should be co-administered with caution. No dose adjustment of INTELENCE or voriconazole is needed.Antifungals:itraconazoleketoconazoleposaconazole etravirine itraconazole ketoconazole<-> posaconazolePosaconazole, potent inhibitor of CYP3A4, may increase plasma concentrations of etravirine. Itraconazole and ketoconazole are potent inhibitors as well as substrates of CYP3A4. Concomitant systemic use of itraconazole or ketoconazole and INTELENCE may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of itraconazole or ketoconazole may be decreased by INTELENCE. Dose adjustments for itraconazole, ketoconazole or posaconazole may be necessary depending on the other co-administered drugs.Antiinfective:clarithromycin etravirine clarithromycin 14-OH-clarithromycinClarithromycin exposure was decreased by INTELENCE; 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 lumefantrineCaution is warranted when co-administering INTELENCE 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 INTELENCE.Antimycobacterials:rifampinrifapentine etravirineRifampin and rifapentine are potent inducers of CYP450 enzymes. INTELENCE should not be used with rifampin or rifapentine as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE.Antimycobacterial:rifabutin etravirine rifabutin 25-O-desacetylrifabutinIf INTELENCE is NOT co-administered with protease inhibitor/ritonavir, then rifabutin at dose of 300 mg once daily is recommended.If INTELENCE is co-administered with darunavir/ritonavir, lopinavir/ritonavir or saquinavir/ritonavir, then rifabutin should not be co-administered due to the potential for significant reductions in etravirine exposure.Benzodiazepine:diazepam diazepamConcomitant use of INTELENCE with diazepam may increase plasma concentrations of diazepam. decrease in diazepam dose may be needed.Corticosteroid:dexamethasone (systemic) etravirineSystemic dexamethasone induces CYP3A and can decrease etravirine plasma concentrations. This may result in loss of therapeutic effect of INTELENCE. Systemic dexamethasone should be used with caution or alternatives should be considered, particularly for long-term use.Herbal products:St. Johns wort (Hypericum perforatum) etravirineConcomitant use of INTELENCE with products containing St. Johns wort may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE. INTELENCE and products containing St. Johns wort should not be co-administered.Hepatitis virus (HCV) direct-acting antivirals:daclatasvir daclatasvirCo-administration of INTELENCE with daclatasvir may decrease daclatasvir concentrations. Increase the daclatasvir dose to 90 mg once daily.elbasvir/grazoprevir elbasvir grazoprevirCo-administration of INTELENCE with elbasvir/grazoprevir may decrease elbasvir and grazoprevir concentrations, leading to reduced therapeutic effect of elbasvir/grazoprevir. Co-administration is not recommended.simeprevir simeprevirCo-administration of INTELENCE with simeprevir may decrease simeprevir concentrations. Co-administration is not recommended.HMG-CoA reductase inhibitors:atorvastatin<-> etravirine atorvastatin 2-OH-atorvastatinThe combination of INTELENCE and atorvastatin can be given without dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response.pravastatinrosuvastatin<-> etravirine<-> pravastatin<-> rosuvastatinNo interaction between pravastatin, rosuvastatin and INTELENCE is expected.lovastatinsimvastatin lovastatin simvastatin Lovastatin and simvastatin are CYP3A substrates and co-administration with INTELENCE may result in lower plasma concentrations of the HMG-CoA reductase inhibitor. fluvastatinpitavastatin fluvastatin pitavastatinFluvastatin and pitavastatin are metabolized by CYP2C9 and co-administration with INTELENCE may result in higher plasma concentrations of the HMG-CoA reductase inhibitor. Dose adjustments for these HMG-CoA reductase inhibitors may be necessary.Immunosuppressants:cyclosporinesirolimustacrolimus immunosuppressantINTELENCE 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:buprenorphinebuprenorphine/naloxonemethadone<-> etravirine buprenorphine<-> norbuprenorphine<-> methadoneINTELENCE 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.INTELENCE and methadone can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as methadone maintenance therapy may need to be adjusted in some patients.Phosphodiesterase type (PDE-5) inhibitors:sildenafiltadalafilvardenafil sildenafil N-desmethyl-sildenafilINTELENCE 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) metaboliteActivation of clopidogrel to its active metabolite may be decreased when clopidogrel is co-administered with INTELENCE. Alternatives to clopidogrel should be considered.. 7.4Drugs Without Clinically Significant Interactions with INTELENCE. In addition to the drugs included in Table 4, the interaction between INTELENCE 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.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of INTELENCE did not include sufficient numbers of subjects aged 65 years of age and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].

HEPATIC IMPAIRMENT SUBSECTION.

8.6Hepatic Impairment. No dose adjustment of INTELENCE is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. The pharmacokinetics of INTELENCE have not been evaluated in patients with severe hepatic impairment (Child-Pugh Class C) [see Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. INTELENCE 25 mg tablets are supplied as white to off-white, oval, scored tablets containing 25 mg of etravirine. Each tablet is debossed with TMC on one side.INTELENCE 100 mg tablets are supplied as white to off-white, oval tablets containing 100 mg of etravirine. Each tablet is debossed with TMC125 on one side and 100 on the other side.INTELENCE 200 mg tablets are supplied as white to off-white, biconvex, oblong tablets containing 200 mg of etravirine. Each tablet is debossed with T200 on one side.INTELENCE tablets are packaged in bottles in the following configuration:25 mg tablets--bottles of 120 (NDC 59676-572-01). Each bottle contains desiccant pouches.100 mg tablets--bottles of 120 (NDC 59676-570-01). Each bottle contains desiccant pouches.200 mg tablets--bottles of 60 (NDC 59676-571-01). Each bottle contains desiccant pouches.. 25 mg tablets--bottles of 120 (NDC 59676-572-01). Each bottle contains desiccant pouches.. 100 mg tablets--bottles of 120 (NDC 59676-570-01). Each bottle contains desiccant pouches.. 200 mg tablets--bottles of 60 (NDC 59676-571-01). Each bottle contains desiccant pouches.. Store INTELENCE tablets at 25C (77F); with excursions permitted to 15 to 30C (59 to 86F) [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.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. INTELENCE(R), in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus type (HIV-1) infection in antiretroviral treatment-experienced adult patients and pediatric patients years of age and older [see Microbiology (12.4) and Clinical Studies (14)].. INTELENCE is human immunodeficiency virus type (HIV-1) non-nucleoside reverse transcriptase inhibitor (NNRTI) indicated for treatment of HIV-1 infection in treatment-experienced patients years of age and older. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).. AdministrationAdvise patients to take INTELENCE following meal twice day on 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 INTELENCE or discontinue therapy with INTELENCE without consulting their physician. INTELENCE must always be used in combination with other antiretroviral drugs [see Dosage and Administration (2.4)]. Advise patients to swallow the INTELENCE tablet(s) whole with liquid such as water. Instruct patients not to chew the tablets. Patients who are unable to swallow the INTELENCE tablet(s) whole may disperse the tablet(s) in water. The patient should be instructed to do the following:place the tablet(s) in 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 104F [greater than 40C]) 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.. place the tablet(s) in 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 104F [greater than 40C]) or carbonated beverages should be avoided.. drink the mixture immediately,. rinse the glass several times with orange juice, milk or water and completely swallow the rinse each time to make sure the patient takes the entire dose.. Severe Skin ReactionsInform patients that severe and potentially life-threatening rash has been reported with INTELENCE. Rash has been reported most commonly in the first weeks of therapy. Advise patients to immediately contact their healthcare provider if they develop rash. Instruct patients to immediately stop taking INTELENCE and seek medical attention if they develop rash associated with any of the following symptoms as it may be sign of 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 InteractionsINTELENCE 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. Johns wort [see Warnings and Precautions (5.2)].. Immune Reconstitution SyndromeAdvise 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 RedistributionInform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy, including INTELENCE, 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 RegistryInform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant individuals exposed to INTELENCE [see Use in Specific Populations (8.1)].. LactationInstruct 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)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryThe Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV.Based on limited data, etravirine has been shown to be present in human breast milk. There are no data on the effects of etravirine on the breastfed infant, or the effects of etravirine on milk production.Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants) and (3) adverse reactions in breastfed infants similar to those seen in adults, instruct mothers not to breastfeed if they are receiving INTELENCE.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Etravirine is an antiretroviral drug [see Microbiology (12.4)].

MICROBIOLOGY SECTION.

12.4 Microbiology. Mechanism of ActionEtravirine 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 disruption of the enzymes catalytic site. Etravirine does not inhibit the human DNA polymerases , and .. Antiviral Activity in Cell CultureEtravirine 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 broad panel of HIV-1 group 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 primary isolates. Etravirine did not show antagonism when studied in combination with the following antiretroviral drugs--the NNRTIs delavirdine, efavirenz, and nevirapine; the N(t)RTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, 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 CultureEtravirine-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 SubjectsIn the Phase trials TMC125-C206 and TMC125-C216, substitutions that developed most commonly in subjects with virologic failure at Week 48 to the INTELENCE-containing regimen were V179F, V179I, and Y181C which usually emerged in background of multiple other NNRTI resistance-associated substitutions. In all the trials conducted with INTELENCE in HIV-1 infected subjects, the following substitutions emerged most commonly: L100I, E138G, V179F, V179I, Y181C and H221Y. Other NNRTI-resistance-associated substitutions which emerged on etravirine treatment in 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 median fold-change in etravirine susceptibility of 40-fold from reference and median fold-change of 6-fold from baseline.. Cross-ResistanceCross-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 rilpivirine-containing regimen with development of rilpivirine resistance is likely to result in cross-resistance to etravirine (see Treatment-Naive HIV-1-Infected Subjects in the Phase Trials for EDURANT (rilpivirine) below). Cross-resistance to etravirine has been observed after virologic failure on 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 VirusEtravirine 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 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 or 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 combination of substitutions V179F Y181C (187 fold-change), V179F Y181I (123 fold-change), or V179F Y181C F227C (888 fold-change).. Clinical IsolatesEtravirine retained fold-change less than or equal to 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 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-Naive HIV-1-Infected Subjects in the Phase Trials for EDURANT (Rilpivirine)There are currently no clinical data available on the use of etravirine in subjects who experienced virologic failure on 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 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 AnalysesIn TMC125-C206 and TMC125-C216, the presence at baseline of the substitutions L100I, E138A, I167V, V179D, V179F, Y181I, Y181V, or G190S was associated with decreased virologic response to etravirine. Additional substitutions associated with decreased virologic response to etravirine when in the presence of or more additional 2008 IAS-USA defined NNRTI substitutions include A98G, K101H, K103R, V106I, V179T, and Y181C. The presence of K103N, which was the most prevalent NNRTI substitution in TMC125-C206 and TMC125-C216 at baseline, did not affect the response in the INTELENCE arm. Overall, response rates to etravirine decreased as the number of baseline NNRTI substitutions increased (shown as the proportion of subjects achieving viral load 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 Substitutions2008 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 in the Non-VF Excluded Population of the Pooled TMC125-C206 and TMC125-C216ENF: enfuvirtide IAS-USA-Defined NNRTI substitutions EtravirineN=561Re-used/not used ENFde novo ENFAll ranges61% (254/418)76% (109/143)068% (52/76)95% (20/21)167% (72/107)77% (24/31)264% (75/118)86% (38/44)355% (36/65)62% (16/26)>= 437% (19/52)52% (11/21)PlaceboN=592All ranges34% (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 INTELENCE. The data are provided to give clinicians information on the likelihood of virologic success based on pre-treatment susceptibility to etravirine in treatment-experienced patients.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-C216Non-VF excluded analysis ENF: enfuvirtideFold ChangeEtravirineN=559Re-used/not used ENFde novo ENFClinical response rangeAll ranges61% (253/416)76% (109/143)Overall Response0-369% (188/274)83% (75/90)Higher than Overall Response> 3-1350% (39/78)66% (25/38)Lower than Overall Response> 1341% (26/64)60% (9/15)Lower than Overall ResponsePlaceboN=583All ranges34% (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-C216PSSThe phenotypic susceptibility score (PSS) was defined as the total number of active antiretroviral drugs in the background therapy to which subjects baseline viral isolate showed sensitivity in phenotypic resistance tests. Each drug in the background therapy was scored as 1 or 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 sensitive antiretroviral if the FC was less than or equal to 10; ENF was counted as sensitive antiretroviral if it had not been used previously. INTELENCE was not included in this calculation. INTELENCE BRN=559Placebo BRN=586043% (40/93)5% (5/95)161% (125/206)28% (64/226)277% (114/149)59% (97/165)>= 375% (83/111)72% (72/100).

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisEtravirine 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).. MutagenesisEtravirine 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 metabolic activation system. Etravirine did not induce chromosomal damage in the in vivo micronucleus test in mice.. Impairment of FertilityNo 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).

OVERDOSAGE SECTION.

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

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 100 mg Tablet Bottle Label. 120 Tablets NDC 59676-570-01INTELENCE(R) (etravirine) tablets 100 mgEach tablet contains100 mg of etravirine.Rx onlyjanssenALERT: Find out about medicines thatshould NOT be taken with INTELENCE(R) from your healthcare provider.. PRINCIPAL DISPLAY PANEL 100 mg Tablet Bottle Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of INTELENCE have been established for the treatment of HIV-infected pediatric patients from years of age to less than 18 years [see Indications and Usage (1) and Dosage and Administration (2.3)]. Use of INTELENCE in pediatric patients years to less than 18 years of age is supported by evidence from adequate and well-controlled studies of INTELENCE in adults with additional data from two Phase trials in treatment-experienced pediatric subjects, TMC125-C213, years to less than 18 years of age (N=101) and TMC125-C234/IMPAACT P1090, years to less than years of age (N=20). Both studies were open-label, single arm trials of etravirine plus an optimized background regimen. In clinical trials, the safety, pharmacokinetics, and efficacy were comparable to that observed in adults except for rash (greater than or equal to Grade 2) which was observed more frequently in pediatric subjects [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)]. Postmarketing reports of Stevens-Johnson syndrome in pediatric patients receiving INTELENCE have been reported [see Warnings and Precautions (5.1), and Adverse Reactions (6.2)]. Treatment with INTELENCE is not recommended in pediatric patients less than years of age [see Clinical Pharmacology (12.3)]. Five HIV-infected subjects from year to 2 years of age were enrolled in TMC125-C234/IMPAACT P1090. Etravirine exposure was lower than reported in HIV-infected adults (AUC12h geometric mean ratio [90% CI] was 0.59 [0.34, 1.01] for pediatric subjects from year to 2 years of age compared to adults). Virologic failure at Week 24 (confirmed HIV-RNA greater than or equal to 400 copies/mL) occurred in of evaluable subjects who discontinued before or had reached Week 24. Genotypic and phenotypic resistance to etravirine developed in of the subjects who experienced virologic failure.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Cardiac ElectrophysiologyIn thorough QT/QTc study in 41 healthy subjects, INTELENCE 200 mg twice daily or 400 mg once daily did not affect the QT/QTc interval.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetic properties of INTELENCE 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 Trials at Week 48)All HIV-1-infected subjects enrolled in Phase clinical trials received darunavir/ritonavir 600/100 mg twice daily as part of their background regimen. Therefore, the pharmacokinetic parameter estimates shown in Table account for reductions in the pharmacokinetic parameters of etravirine due to co-administration of INTELENCE with darunavir/ritonavir. ParameterEtravirineN=575AUC12h (ngh/mL) Geometric mean +- standard deviation4522 +- 4710 Median (range)4380 (458-59084)C0h (ng/mL) Geometric mean +- standard deviation297 +- 391 Median (range)298 (2-4852)Note: The median protein binding adjusted EC50 for MT4 cells infected with HIV-1/IIIB in vitro equals ng/mL.. Absorption and BioavailabilityFollowing oral administration, etravirine was absorbed with Tmax of about 2.5 to hours. The absolute oral bioavailability of INTELENCE is unknown.In healthy subjects, the absorption of etravirine is not affected by co-administration of oral ranitidine or omeprazole, drugs that increase gastric pH.. Effects of Food on Oral AbsorptionThe systemic exposure (AUC) to etravirine was decreased by about 50% when INTELENCE was administered under fasting conditions, as compared to when INTELENCE was administered following 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).. DistributionEtravirine 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.. MetabolismIn 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.. EliminationAfter 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 PatientsPopulation 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 PatientsThe pharmacokinetics of etravirine in 115 treatment-experienced HIV-1-infected pediatric subjects, 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 INTELENCE 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 Years to Less Than 18 Years of Age (TMC125-C213 [Population PK] and TMC125-C234/P1090)StudyTMC125-C213TMC125-C234/IMPAACT P1090Age Range (years)(6 years to less than 18 years)(2 years to less than years)ParameterN=101N=14AUC12h (ngh/mL) Geometric mean +- standard deviation3742 +- 43143504 +- 2923 Median (range)4499 (62-28865)3579 (1221-11815)C0h (ng/mL) Geometric mean +- standard deviation205 +- 342183 +- 240 Median (range)287 (2-2276)162 (54-908)The pharmacokinetics and dose of etravirine in pediatric subjects less than years of age have not been established [see Use in Specific Populations (8.4)]. Male and Female PatientsNo significant pharmacokinetic differences have been observed between males and females.. Racial or Ethnic GroupsPopulation pharmacokinetic analysis of etravirine in HIV-infected subjects did not show an effect of race on exposure to etravirine.. Patients with Renal ImpairmentThe pharmacokinetics of etravirine have not been studied in patients with renal impairment. The results from 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 ImpairmentEtravirine is primarily metabolized by the liver. The steady state pharmacokinetic parameters of etravirine were similar after multiple dose administration of INTELENCE to subjects with normal hepatic function (16 subjects), mild hepatic impairment (Child-Pugh Class A, subjects), and moderate hepatic impairment (Child-Pugh Class B, 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 PostpartumAfter intake of INTELENCE 200 mg twice daily in combination with other antiretroviral agents (13 subjects with NRTIs, subject with NRTIs lopinavir ritonavir, subject with NRTIs raltegravir), based on intra-individual comparison, the Cmax and AUC12h of total etravirine were 23 to 42% higher during pregnancy compared with postpartum (6-12 weeks). The Cmin of total etravirine was 78 to 125% higher during pregnancy compared with postpartum (6-12 weeks), while two subjects had Cmin <10 ng/mL in the postpartum period (6-12 weeks) [Cmin of total etravirine was 11 to 16% higher when these 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.ParameterMean +- SD (median)PostpartumN=102nd TrimesterN=133rd TrimesterN=10n=9 for AUC12h Cmin, ng/mL269 +- 182 (284)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). 383 +- 210 (346)349 +- 103 (371)Cmax, ng/mL569 +- 261 (528)774 +- 300 (828)785 +- 238 (694)AUC12h, ngh/mL5004 +- 2521 (5246)6617 +- 2766 (6836)6846 +- 1482 (6028). Patients with Hepatitis and/or Hepatitis Virus Co-InfectionPopulation pharmacokinetic analysis of the TMC125-C206 and TMC125-C216 trials showed reduced clearance for etravirine in HIV-1-infected subjects with hepatitis and/or virus co-infection. Based upon the safety profile of INTELENCE [see Adverse Reactions (6)], no dose adjustment is necessary in patients co-infected with hepatitis and/or virus.. Drug InteractionsEtravirine is substrate of CYP3A, CYP2C9, and CYP2C19. Therefore, co-administration of INTELENCE with drugs that induce or inhibit CYP3A, CYP2C9, and CYP2C19 may alter the therapeutic effect or adverse reaction profile of INTELENCE.Etravirine is an inducer of CYP3A and inhibitor of CYP2C9, CYP2C19 and P-gp. Therefore, co-administration of drugs that are substrates of CYP3A, CYP2C9 and CYP2C19 or are transported by P-gp with INTELENCE may alter the therapeutic effect or adverse reaction profile of the co-administered drug(s).Drug interaction studies were performed with INTELENCE and other drugs likely to be co-administered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of other drugs on the AUC, Cmax, and Cmin values of etravirine are summarized in Table (effect of other drugs on INTELENCE). The effect of co-administration of INTELENCE on the AUC, Cmax, and Cmin values of other drugs are summarized in Table (effect of INTELENCE 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 DrugsCo-administered DrugDose/Schedule of Co-administered DrugNExposureMean Ratio of Etravirine Pharmacokinetic Parameters90% CI; No Effect 1.00Cmax AUCCmin CI Confidence Interval; = number of subjects with data; N.A. not available; increase; decrease; <-> no changeCo-administration with HIV protease inhibitors (PIs)Atazanavir400 mg once daily141.47(1.36-1.59)1.50(1.41-1.59)1.58(1.46-1.70)Atazanavir/ritonavirThe systemic exposure of etravirine when co-administered with atazanavir/ritonavir in HIV infected subjects is similar to exposures of etravirine observed in the Phase trials after co-administration of INTELENCE and darunavir/ritonavir (as part of the background regimen). 300/100 mg once daily141.30(1.17-1.44)1.30(1.18-1.44)1.26(1.12-1.42)Darunavir/ritonavir600/100 mg twice daily140.68(0.57-0.82)0.63(0.54-0.73)0.51(0.44-0.61)Lopinavir/ritonavir(tablet)400/100 mg twice daily160.70(0.64-0.78)0.65(0.59-0.71)0.55(0.49-0.62)Ritonavir600 mg twice daily110.68(0.55-0.85)0.54(0.41-0.73)N.A.Saquinavir/ritonavir1000/100 mg twice daily140.63(0.53-0.75)0.67(0.56-0.80)0.71(0.58-0.87)Tipranavir/ritonavir500/200 mg twice daily190.29(0.22-0.40)0.24(0.18-0.33)0.18(0.13-0.25)Co-administration with nucleoside reverse transcriptase inhibitors (NRTIs)Didanosine400 mg once daily15<->1.16(1.02-1.32)1.11(0.99-1.25)1.05(0.93-1.18)Tenofovir disoproxil fumarate300 mg once daily230.81(0.75-0.88)0.81(0.75-0.88)0.82(0.73-0.91)Co-administration with CCR5 antagonistsMaraviroc300 mg twice daily14<->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)The reference for etravirine exposure is the pharmacokinetic parameters of etravirine in the presence of darunavir/ritonavir. 150/600/100 mg twice daily10<->1.08(0.98-1.20)1.00(0.86-1.15)0.81(0.65-1.01)Co-administration with integrase strand transfer inhibitorsRaltegravir400 mg twice daily19<->1.04(0.97-1.12)1.10(1.03-1.16)1.17(1.10-1.26)Co-administration with other drugsArtemether/lumefantrine80/480 mg, doses at 0, 8, 24, 36, 48, and 60 hours14<->1.11(1.06-1.17)1.10(1.06-1.15)1.08(1.04-1.14)Atorvastatin40 mg once daily16<->0.97(0.93-1.02)1.02(0.97-1.07)1.10(1.02-1.19)Clarithromycin500 mg twice daily151.46(1.38-1.56)1.42(1.34-1.50)1.46(1.36-1.58)Fluconazole200 mg once daily in the morning161.75(1.60-1.91)1.86(1.73-2.00)2.09(1.90-2.31)Omeprazole40 mg once daily181.17(0.96-1.43)1.41(1.22-1.62)N.A.Paroxetine20 mg once daily16<->1.05(0.96-1.15)1.01(0.93-1.10)1.07(0.98-1.17)Ranitidine150 mg twice daily180.94(0.75-1.17)0.86(0.76-0.97)N.A.Rifabutin300 mg once daily120.63(0.53-0.74)0.63(0.54-0.74)0.65(0.56-0.74)Voriconazole200 mg twice daily161.26(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 INTELENCECo-administered DrugDose/Schedule of Co-administered DrugNExposureMean Ratio of Co-administered Drug Pharmacokinetic Parameters90% CI; No effect 1.00Cmax AUCCmin CI Confidence Interval; = number of subjects with data; N.A. not available; increase; decrease; <-> no changeCo-administration with HIV protease inhibitors (PIs)Atazanavir400 mg once daily140.97(0.73-1.29)0.83(0.63-1.09)0.53(0.38-0.73)Atazanavir/ritonavir300/100 mg once daily130.97(0.89-1.05)0.86(0.79-0.93)0.62(0.55-0.71)Atazanavir/ritonavirHIV-infected subjects 300/100 mg once daily200.96(0.80-1.16)0.96(0.76-1.22)0.82(0.55-1.22)Darunavir/ritonavir600/100 mg twice daily15<->1.11(1.01-1.22)1.15(1.05-1.26)1.02(0.90-1.17)Fosamprenavir/ritonavir700/100 mg twice daily81.62(1.47-1.79)1.69(1.53-1.86)1.77(1.39-2.25)Lopinavir/ritonavir(tablet)400/100 mg twice daily16<->0.89(0.82-0.96)0.87(0.83-0.92)0.80(0.73-0.88)Saquinavir/ritonavir1000/100 mg twice daily15<->1.00(0.70-1.42)0.95(0.64-1.42)0.80(0.46-1.38)Tipranavir/ritonavir500/200 mg twice daily191.14(1.02-1.27)1.18(1.03-1.36)1.24(0.96-1.59)Co-administration with nucleoside reverse transcriptase inhibitors (NRTIs)Didanosine400 mg once daily14<->0.91(0.58-1.42)0.99(0.79-1.25)N.A.Tenofovir disoproxil fumarate300 mg once daily19<->1.15(1.04-1.27)1.15(1.09-1.21)1.19(1.13-1.26)Co-administration with CCR5 antagonistsMaraviroc300 mg twice daily140.40(0.28-0.57)0.47(0.38-0.58)0.61(0.53-0.71)Maraviroc (when co-administered with darunavir/ritonavir) compared to maraviroc 150 mg twice daily 150/600/100 mg twice daily101.77(1.20-2.60)3.10(2.57-3.74)5.27(4.51-6.15)Co-administration with integrase strand transfer inhibitorsDolutegravir50 mg once daily160.48(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 daily90.88(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/ritonavir50 mg once daily 400/100 mg twice daily8<->1.07(1.02 to 1.13)1.11(1.02 to 1.20)1.28(1.13 to 1.45)Raltegravir400 mg twice daily190.89(0.68-1.15)0.90(0.68-1.18)0.66(0.34-1.26)Co-administration with other drugsArtemether80/480 mg, doses at 0, 8, 24, 36, 48, and 60 hours150.72(0.55-0.94)0.62(0.48-0.80)0.82(0.67-1.01)Dihydroartemisinin150.84(0.71-0.99)0.85(0.75-0.97)0.83(0.71-0.97)Lumefantrine151.07(0.94-1.23)0.87(0.77-0.98)0.97(0.83-1.15)Atorvastatin40 mg once daily161.04(0.84-1.30)0.63(0.58-0.68)N.A.2-hydroxy-atorvastatin161.76(1.60-1.94)1.27(1.19-1.36)N.A.BuprenorphineIndividual dose regimen ranging from 4/1 mg to 16/4 mg once daily160.89(0.76-1.05)0.75(0.66-0.84)0.60(0.52-0.68)Norbuprenorphine16<->1.08(0.95-1.23)0.88(0.81-0.96)0.76(0.67-0.87)Clarithromycin500 mg twice daily150.66(0.57-0.77)0.61(0.53-0.69)0.47(0.38-0.57)14-hydroxy-clarithromycin151.33(1.13-1.56)1.21(1.05-1.39)1.05(0.90-1.22)Digoxin0.5 mg single dose161.19(0.96-1.49)1.18(0.90-1.56)N.A.Ethinylestradiol0.035 mg once daily161.33(1.21-1.46)1.22(1.13-1.31)1.09(1.01-1.18)Norethindrone1 mg once daily16<->1.05(0.98-1.12)0.95(0.90-0.99)0.78(0.68-0.90)Fluconazole200 mg once daily in the morning15<->0.92(0.85-1.00)0.94(0.88-1.01)0.91(0.84-0.98)R(-) MethadoneIndividual dose regimen ranging from 60 to 130 mg/day16<->1.02(0.96-1.09)1.06(0.99-1.13)1.10(1.02-1.19)S(+) Methadone16<->0.89(0.83-0.97)0.89(0.82-0.96)0.89(0.81-0.98)Paroxetine20 mg once daily16<->1.06(0.95-1.20)1.03(0.90-1.18)0.87(0.75-1.02)Rifabutin300 mg once daily120.90(0.78-1.03)0.83(0.75-0.94)0.76(0.66-0.87)25-O-desacetylrifabutin300 mg once daily120.85(0.72-1.00)0.83(0.74-0.92)0.78(0.70-0.87)Sildenafil50 mg single dose150.55(0.40-0.75)0.43(0.36-0.51)N.A.N-desmethyl-sildenafil150.75(0.59-0.96)0.59(0.52-0.68)N.A.Voriconazole200 mg twice daily140.95(0.75-1.21)1.14(0.88-1.47)1.23(0.87-1.75).

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to INTELENCE during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.. Risk SummaryProspective pregnancy data from clinical trials and the APR are not sufficient to adequately assess the risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Etravirine use during pregnancy has been evaluated in limited number of individuals as reported by the APR, and available data show birth defect in 66 first trimester exposures to etravirine-containing regimens (see Data).The estimated background rate for major birth defects is 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15-20%. The background risk of major birth defects and miscarriage for the indicated population is unknown.In animal reproduction studies, no adverse developmental effects were observed with orally administered etravirine at exposures equivalent to those at the maximum recommended human dose (MRHD) of 400 mg daily (see Data).. Data. Human DataBased on prospective reports to the APR of 116 live births following exposure to etravirine-containing regimens during pregnancy (including 66 exposed in the first trimester and 38 exposed in the second/third trimester), the number of birth defects in live births for etravirine was out of 66 with first trimester exposure and out of 38 with second/third trimester exposure. Prospective reports from the APR of overall major birth defects in pregnancies exposed to INTELENCE is compared with U.S. background major birth defect rate. Methodological limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease; these limitations preclude an accurate comparison of outcomes.INTELENCE (200 mg twice daily) in combination with other antiretroviral agents was evaluated in clinical trial enrolling 15 pregnant subjects during the second and third trimesters of pregnancy and postpartum. Thirteen subjects completed the trial through postpartum period (6-12 weeks after delivery). The pharmacokinetic data demonstrated that exposure to total etravirine was generally higher during pregnancy compared with postpartum [see Clinical Pharmacology (12.3)].Among subjects who were virologically suppressed (HIV-1 RNA less than 50 copies/mL) at baseline (9/13), virologic suppression was maintained through the third trimester and postpartum period. Among subjects with HIV-1 RNA greater than 50 copies/mL and less than 400 copies/mL at baseline (3/13), viral loads remained less than 400 copies/mL. In one subject with HIV-1 RNA greater than 1,000 copies/mL at baseline (1/13), HIV-1 RNA remained greater than 1,000 copies/mL during the study period. Thirteen infants were born to 13 HIV-infected pregnant individuals in this study. HIV-1 test results were not available for infants. Among the eleven infants with HIV-1 test results available, who were born to 11 HIV-infected pregnant individuals who completed the study, all had test results that were negative for HIV-1 at the time of delivery. No unexpected safety findings were observed compared with the known safety profile of INTELENCE in non-pregnant adults.. Animal DataReproductive and developmental toxicity studies were performed in rats (at 250, 500 and 1,000 mg/kg/day) and rabbits (at 125, 250 and 375 mg/kg/day) administered etravirine on gestation days through 16, and through 19, respectively. In both species, no treatment-related embryo-fetal effects were observed. In addition, no treatment-related effects were observed in pre- and postnatal development study performed in rats administered oral doses up to 500 mg/kg/day on gestation days through lactation day 7. The systemic drug exposures achieved at the high dose in these animal studies were equivalent to those at the MRHD.

RECENT MAJOR CHANGES SECTION.

Indications and Usage (1)11/2018Dosage and Administration:Recommended Dosage During Pregnancy (2.2)11/2018Warnings and Precautions:Severe Skin and Hypersensitivity Reactions (5.1)07/2019Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions (5.2)11/2018Immune Reconstitution Syndrome (5.3)07/2019.

RENAL IMPAIRMENT SUBSECTION.

8.7Renal Impairment. Since the renal clearance of etravirine is negligible (less than 1.2%), decrease in total body clearance is not expected in patients with renal impairment. No dose adjustments are required in patients with renal impairment. As etravirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis [see Clinical Pharmacology (12.3)].

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Revised July 2019PATIENT INFORMATIONINTELENCE(R) (in-tel-ence)(etravirine)tabletsImportant: Ask your healthcare provider or pharmacist about medicines that should not be taken with INTELENCE. For more information, see the section What should tell my healthcare provider before taking INTELENCEWhat is INTELENCEINTELENCE is 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 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).INTELENCE is not recommended for use in children less than years of age.What should tell my healthcare provider before taking INTELENCEBefore taking INTELENCE tell your healthcare provider about all of your medical conditions, including if you:have liver problems, including hepatitis or C.are pregnant or plan to become pregnant. Tell your healthcare provider if you become pregnant during treatment with INTELENCE. Pregnancy Registry: There is pregnancy registry for people who take INTELENCE 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 INTELENCE.You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby. INTELENCE 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 INTELENCE. Keep list of your medicines and show it to your healthcare provider and pharmacist when you get new medicine.You can ask your healthcare provider or pharmacist for list of medicines that interact with INTELENCE.Do not start new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take INTELENCE with other medicines.How should take INTELENCEStay under the care of your healthcare provider during treatment with INTELENCE.Take INTELENCE tablets every day exactly as prescribed by your healthcare provider.Your healthcare provider will tell you how many INTELENCE tablets to take and when to take them. Talk to your healthcare provider if you have questions about when to take INTELENCE.Take INTELENCE times each day.If your child takes INTELENCE, your healthcare provider will prescribe the right dose based on your childs weight.Always take INTELENCE following meal. Do not take INTELENCE on an empty stomach. INTELENCE may not work as well if you take it on an empty stomach.Do not change your dose or stop taking INTELENCE without first talking with your healthcare provider.Swallow INTELENCE tablets whole, with liquid, such as water. Do not chew the tablet(s).If you are unable to swallow INTELENCE tablets whole, you may take your dose of INTELENCE as follows:Step 1: Measure approximately mL (1 teaspoon) of water and pour into cup.Step 2: Place the tablets in the cup containing 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 small amount (approximately 15 mL or 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 104F or 40C) 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 INTELENCE.It is important that you do not miss or skip doses of INTELENCE during treatment.When your supply of INTELENCE starts to run low, get more from your healthcare provider or pharmacy. It is important not to run out of INTELENCE. The amount of HIV in your blood may increase if the medicine is stopped even for short time.If you take too much INTELENCE, call your healthcare provider or go to the nearest emergency room right away.What are the possible side effects of INTELENCEINTELENCE can cause serious side effects including:Severe skin rash and allergic reactions. Skin rash is common side effect of INTELENCE. The risk of getting 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 INTELENCE in combination with other HIV-1 medicines than in adults. Call your healthcare provider right away if rash develops; severe cases may need to be treated in hospital. If you get rash with any of the following symptoms, stop taking INTELENCE and call your healthcare provider or get medical help right away:fevergenerally ill feelingextreme tirednessmuscle or joint achesblisters or sores in mouthblisters or peeling of the skinredness or swelling of the eyesswelling of the mouth, lips, or faceproblems breathingSometimes 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 eyesdark or tea colored urinepale colored stools (bowel movements)nausea or vomitingloss of appetitepain, aching, or tenderness on the right side of your stomach areaChanges 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 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 INTELENCE in adults include rash as well as numbness, tingling or pain in the hands or feet.The most common side effects of INTELENCE in children include rash and diarrhea.These are not all the possible side effects of INTELENCE.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store INTELENCEStore INTELENCE tablets at room temperature between 68F to 77F (20C to 25C).Keep INTELENCE in the original bottle.Keep the bottle tightly closed to protect INTELENCE from moisture.The INTELENCE bottle contains desiccant packet to help keep your medicine dry (protect it from moisture). The bottle of 25 mg tablets contains desiccant packets. The bottles of 100 mg and 200 mg tablets contain desiccant packets. Keep the desiccant packets in the bottle. Do not eat the desiccant packets. Keep INTELENCE and all medicines out of the reach of children.General information about the safe and effective use of INTELENCEMedicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use INTELENCE for condition for which it was not prescribed. Do not give INTELENCE 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 INTELENCE that is written for health professionals.What are the ingredients in INTELENCEActive ingredient: etravirine.25 mg and 100 mg INTELENCE tablets contain the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate and microcrystalline cellulose.200 mg INTELENCE tablets contain the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, and silicified microcrystalline cellulose.Product of BelgiumFinished Product Manufactured by:Janssen Cilag S.p.A., Latina, ITOrJanssen Ortho LLC, Gurabo, PR 00778Manufactured for:Janssen Therapeutics, Division of Janssen Products, LP, Titusville NJ 08560(C) 2008, 2018 Janssen Pharmaceutical CompaniesFor more information, call Janssen Products, LP at 1-800-526-7736.. have liver problems, including hepatitis or C.. are pregnant or plan to become pregnant. Tell your healthcare provider if you become pregnant during treatment with INTELENCE. Pregnancy Registry: There is pregnancy registry for people who take INTELENCE 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 INTELENCE.You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby. INTELENCE can pass to your baby in your breast milk.Talk with your healthcare provider about the best way to feed your baby. You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby. INTELENCE can pass to your baby in your breast milk.. Talk with your healthcare provider about the best way to feed your baby.. You can ask your healthcare provider or pharmacist for list of medicines that interact with INTELENCE.. Do not start new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take INTELENCE with other medicines.. Stay under the care of your healthcare provider during treatment with INTELENCE.. Take INTELENCE tablets every day exactly as prescribed by your healthcare provider.. Your healthcare provider will tell you how many INTELENCE tablets to take and when to take them. Talk to your healthcare provider if you have questions about when to take INTELENCE.. Take INTELENCE times each day.. If your child takes INTELENCE, your healthcare provider will prescribe the right dose based on your childs weight.. Always take INTELENCE following meal. Do not take INTELENCE on an empty stomach. INTELENCE may not work as well if you take it on an empty stomach.. Do not change your dose or stop taking INTELENCE without first talking with your healthcare provider.. Swallow INTELENCE tablets whole, with liquid, such as water. Do not chew the tablet(s).. If you are unable to swallow INTELENCE tablets whole, you may take your dose of INTELENCE as follows:Step 1: Measure approximately mL (1 teaspoon) of water and pour into cup.Step 2: Place the tablets in the cup containing 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 small amount (approximately 15 mL or 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 104F or 40C) 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 INTELENCE.. It is important that you do not miss or skip doses of INTELENCE during treatment.. When your supply of INTELENCE starts to run low, get more from your healthcare provider or pharmacy. It is important not to run out of INTELENCE. The amount of HIV in your blood may increase if the medicine is stopped even for short time.. If you take too much INTELENCE, call your healthcare provider or go to the nearest emergency room right away.. Severe skin rash and allergic reactions. Skin rash is common side effect of INTELENCE. The risk of getting 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 INTELENCE in combination with other HIV-1 medicines than in adults. Call your healthcare provider right away if rash develops; severe cases may need to be treated in hospital. fever. generally ill feeling. extreme tiredness. muscle or joint aches. blisters or sores in mouth. blisters or peeling of the skin. redness or swelling of the eyes. swelling of the mouth, lips, or face. problems breathing. yellowing of your skin or whites of your eyes. dark or tea colored urine. pale colored stools (bowel movements). nausea or vomiting. loss of appetite. 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 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.. Store INTELENCE tablets at room temperature between 68F to 77F (20C to 25C).. Keep INTELENCE in the original bottle.. Keep the bottle tightly closed to protect INTELENCE from moisture.. The INTELENCE bottle contains desiccant packet to help keep your medicine dry (protect it from moisture). The bottle of 25 mg tablets contains desiccant packets. The bottles of 100 mg and 200 mg tablets contain desiccant packets. Keep the desiccant packets in the bottle. Do not eat the desiccant packets.

SPL UNCLASSIFIED SECTION.

2.1Recommended Dosage in Adult Patients. The recommended oral dosage of INTELENCE for adult patients is 200 mg (one 200 mg tablet or two 100 mg tablets) taken twice daily following meal. The type of food does not affect the exposure to INTELENCE [see Clinical Pharmacology (12.3)].