SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 7 DRUG INTERACTIONS 12 DOSAGE AND ADMINISTRATION 22 OVERDOSAGE 23 ACTION AND CLINICAL PHARMACOLOGY 23 STORAGE AND STABILITY 27 DOSAGE FORMS, COMPOSITION AND PACKAGING 27

PART II: SCIENTIFIC INFORMATION 28

PHARMACEUTICAL INFORMATION 28 CLINICAL TRIALS 29 DETAILED PHARMACOLOGY 33 MICROBIOLOGY 34 TOXICOLOGY 37 REFERENCES 39

PART III: CONSUMER INFORMATION. 41

PrINTELENCE * etravirine tablets 100 mg Human Immunodeficiency Virus (HIV) non-nucleoside reverse transcriptase inhibitor

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

INTELENCE (etravirine), in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in treatment-experienced adult patients who have failed prior therapy and have HIV-1 strains resistant to multiple antiretroviral agents, including NNRTIs. This indication is based on safety and efficacy data at 24 weeks from two Phase 3, double- blinded, placebo-controlled trials in treatment-experienced patients who had a least one NNRTI resistance-associated mutation and multiple primary protease inhibitor mutations (see CLINICAL TRIALS for description of studies). The following points should be considered when initiating therapy with INTELENCE: Do not use INTELENCE with only N[t]RTIs in the setting of previous NNRTI failure. This is based on an analysis of an exploratory Phase 2 clinical trial in patients who had experienced virologic failure on an NNRTI- and N[t]RTI-containing regimen (See Clinical Trials for Description of Studies). The use of other active antiretroviral agents with INTELENCE is associated with an increased likelihood of treatment response. Treatment history and, when available, resistance testing, should guide the use of INTELENCE.

Geriatrics (> 65 years of age):

Clinical studies of INTELENCE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised when administering INTELENCE in elderly patients, reflecting the greater frequency of decreased hepatic, renal or cardiac function, concomitant disease or other drug therapy (see WARNINGS AND PRECAUTIONS, DOSAGE AND ADMINISTRATION, and ACTION AND CLINICAL PHARMACOLOGY).

Pediatrics (< 18 years of age):

Safety and effectiveness of INTELENCE in pediatric patients have not been established. Treatment with INTELENCE is not recommended in children and adolescents (see WARNINGS AND PRECAUTIONS, DOSAGE AND ADMINISTRATION, and ACTION AND CLINICAL PHARMACOLOGY).

CONTRAINDICATIONS

INTELENCE (etravirine) is contraindicated in patients who are hypersensitive to etravirine or to any ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph.

WARNINGS AND PRECAUTIONS

Severe and potentially life-threatening skin reactions have occurred in patients taking INTELENCE (etravirine), including Stevens-Johnson syndrome, hypersensitivity reaction and erythema multiforme. These reactions have been reported in <0.1% of subjects taking INTELENCE. Treatment with INTELENCE should be discontinued and appropriate therapy initiated if severe rash develops (see ADVERSE REACTIONS). In the Phase III DUET trials, rash was most frequently mild to moderate, generally macular to maculopapular, mostly occurred in the second week of therapy and was infrequent after week 4. The median time to onset for rash was 12 days and median duration was 11 days. Discontinuations due to rash occurred in 2.2% of patients treated with INTELENCE. Rash was mostly self-limiting and generally resolved within 1-2 weeks on continued therapy. The incidence of rash was higher in women compared to men in the INTELENCE arm. There was no gender difference in severity or treatment discontinuation due to rash. In patients with a history of NNRTI-related rash, there was no apparent increased risk for the development of INTELENCE-related rash compared to patients without a history of NNRTI-related rash.

Patients with hereditary problems of lactose intolerance should not take this medicine.

Long-term carcinogenicity studies of etravirine have not been completed (see Product Monograph Part II: TOXICOLOGY, Carcinogenesis and Mutagenesis). Etravirine tested negative in the in vitro Ames reverse mutation assay, in vitro chromosomal aberration assay in human lymphocyte, and in vitro clastogenicity mouse lymphoma assay, tested in the presence and absence of the metabolic activation system. Etravirine did not induce chromosomal damage in the in vivo micronucleus test in mice (see Product Monograph Part II: TOXICOLOGY, Carcinogenesis and Mutagenesis).

Fat Redistribution

Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Hepatic Impairment

No dose adjustment is required in patients with mild or moderate hepatic impairment. The pharmacokinetics of INTELENCE have not been studied in patients with severe hepatic impairment (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Hepatic Insufficiency and DOSAGE AND ADMINISTRATION, Recommended Dosage and Dosage Adjustment, Hepatic Impairment).

Pancreatitis

Pancreatitis has been reported infrequently (<1%) during clinical trials with INTELENCE. In the placebo-controlled Phase III DUET-1 and DUET-2 trials, the rate of clinical pancreatitis was similar in patients receiving INTELENCE 4/599 (0.7%) and placebo 2/604 (0.3%). Pancreatitis has been reported in one healthy volunteer (1/1093, 0.09%). In the DUET trials asymptomatic grade 3 or 4 increases in serum amylase levels were observed in a similar number of patients treated with INTELENCE (7.5%) and placebo (7.9%) (see ADVERSE REACTIONS; Laboratory Abnormalities). Grade 3 or 4 elevated lipase levels were reported in 2.7% patients receiving INTELENCE compared to 1.7% of patients receiving placebo.

Immune Reconstitution

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including INTELENCE. During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as MAC, CMV, PCP and TB), which may necessitate further evaluation and treatment.

Renal Impairment

Since the renal clearance of etravirine is minimal (< 1.2%), a decrease in total body clearance is not expected in patients with renal impairment. No special precautions or 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 haemodialysis or peritoneal dialysis (see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal Insufficiency).

Pregnant Women:

There are no adequate and well-controlled studies with etravirine in pregnant women. Studies in animals have not shown evidence of developmental toxicity or effect on reproductive function and fertility (see Product Monograph Part II: TOXICOLOGY, Reproductive and Developmental Toxicity). INTELENCE should be used during pregnancy only if the potential benefit justifies the potential risk.

Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to INTELENCE, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

Nursing Women:

There were indirect indications of the presence of etravirine in the milk of lactating rats. It is not yet known if etravirine is excreted in human milk and whether there is potential for adverse events in nursing infants. Because of both the potential for HIV transmission and the potential for adverse events in nursing infants, mothers should be instructed not to breast-feed if they are receiving INTELENCE (see Product Monograph Part II: TOXICOLOGY, Reproductive and Developmental Toxicity).

Pediatrics (< 18 years of age):

The safety and effectiveness of INTELENCE in pediatric patients have not been established.

Geriatrics (> 65 years of age):

There were insufficient numbers of subjects aged 65 and over in the clinical studies to determine whether they respond differently from younger subjects. In general, caution should be exercised when administering INTELENCE in elderly patients, reflecting the greater frequency of decreased hepatic, renal or cardiac function, concomitant disease or other drug therapy.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

The safety assessment is based on all data from 1203 patients in the ongoing Phase III placebo- controlled trials in antiretroviral treatment-experienced HIV-1-infected adult patients [DUET-1 (TMC125-C206) and DUET-2 (TMC125-C216)], 599 of whom received INTELENCE (etravirine), 200 mg b.i.d. In these pooled trials, the median exposure for subjects in the INTELENCE arm and placebo arm was 30.0 and 29.1 weeks, respectively. In the pooled DUET trials, 92.5% of both INTELENCE-treated subjects and placebo-treated subjects experienced adverse events. The most commonly (>10%) reported adverse events of all intensities and regardless of causality that occurred at a higher rate in INTELENCE-treated subjects as compared to placebo-treated subjects were rash (any type) in 17.0% and 9.4%, and nausea 13.9% and 11.1% of INTELENCE-treated subjects and placebo-treated subjects, respectively. In total, 71.0% and 66.9% of the subjects experienced adverse drug reactions (ADRs; i.e. adverse events considered related to INTELENCE) with INTELENCE and placebo, respectively. The majority of the ADRs reported during treatment with INTELENCE were grade 1 to 2 in severity. Grade 3 or 4 ADRs were reported in 16.9% and 12.7% of the INTELENCE- and placebo-treated subjects. ADRs were reported as SAEs in 5.0% and 6.5% of subjects treated with INTELENCE and placebo, respectively. ADRs that led to permanent discontinuation of the investigational medication were reported in 4.5% of the INTELENCE-treated subjects and in 2.2% of the placebo-treated subjects. The most commonly reported ADRs with INTELENCE identified from the pooled DUET trials were rash (any type), reported by 17.0% of INTELENCE-treated subjects and by 9.4% of placebo-treated subjects, diarrhea (15.0% and 20.4%), and nausea (13.9% and 11.1%).

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug- related adverse events and for approximating rates.

ADRs of moderate intensity or greater (>= Grade 2) and reported in >= 1% of subjects treated with INTELENCE (200 mg b.i.d.) in the DUET-1 and DUET-2 trials are presented in Table 1. Laboratory abnormalities considered ADRs are included in Table 2.

Table 1: Treatment-Emergent Adverse Reactions * of at least Moderate Intensity (Grades 2-4) in >= 1% of Adult Subjects in the INTELENCE Treatment Groups
System Organ Class, Preferred Term, %	DUET-1 and DUET-2 Trials
System Organ Class, Preferred Term, %	INTELENCE + BR N=599	Placebo + BR N=604
Blood and Lymphatic System Disorders
Anemia	3.5%	3.6%
Thrombocytopenia	1.3%	1.3%
Gastrointestinal Disorders
Diarrhea	5.2%	9.6%
Nausea	4.7%	3.5%
Abdominal pain	3.0%	2.5%
Vomiting	2.3%	2.0%
Gastroesophageal reflux disease	1.5%	1.0%
Flatulence	1.0%	1.0%
Gastritis	1.0%	0.7%
General Disorders and Administration Site Conditions
Fatigue	3.3%	4.0%
Metabolism and Nutrition Disorders
Hypertriglyceridemia	4.7%	3.0%
Hypercholesterolemia	3.5%	2.2%
Hyperlipidemia	1.5%	0.7%
Hyperglycemia	1.2%	0.5%
Diabetes mellitus	1.0%	0.2%
Dyslipidemia	1.0%	0.3%
Nervous System Disorders
Peripheral neuropathy	2.8%	1.8%
Headache	2.7%	4.1%
Psychiatric Disorders
Insomnia	1.8%	2.2%
Anxiety	1.2%	1.7%
Renal and Urinary Disorders
Renal failure	1.5%	1.5%
Skin and Subcutaneous Tissue Disorders
Rash	9.0%	3.1%
Vascular Disorders
Hypertension	2.8%	2.2%
*Includes adverse reactions at least possibly, probably, or very likely related to the drug N=total number of subjects per treatment group BR=background regimen

Skin Rash

The most frequently reported adverse drug reaction that was at least grade 2 in severity was rash (9.0% and 3.1% of INTELENCE-treated subjects and placebo-treated subjects, respectively). Stevens-Johnson syndrome, hypersensitivity reaction and erythema multiforme were reported in <0.1% of subjects during clinical development with INTELENCE. See Table 2 for a summary of rash events.

Table 2: Rash (Any Type)
Rash Summary, n (%)	Placebo N = 604	Pooled DUET Trials N = 599
Rash (any type)	57 (9.4)	102 (17.0)
Grade 1	40 (6.6)	56 (9.3)
Grade 2	19 (3.1)	47 (7.8)
Grade 3	0	8 (1.3)
Onset in days, median	45.0	12.0
Duration in days, median	17.0	11.0
Leading to permanent stop	0	13 (2.2)
Vesicular Rash	1 (0.2)	0
N = number of subjects, n = number of subjects with observations

Less Common Clinical Trial Adverse Drug Reactions (< 1%)

Treatment-emergent adverse drug reactions in the DUET-1 and DUET-2 trials (n=599) occurring in less than 1% of patients receiving INTELENCE (200 mg b.i.d. ), and of at least moderate intensity (>= Grade 2) are listed below by body system:

Cardiac disorders:

angina pectoris, atrial fibrillation, myocardial infarction

Ear and labyrinth disorders:

vertigo

Eye disorders:

blurred vision

Gastrointestinal disorders:

abdominal distension, constipation, dry mouth, hematemesis, pancreatitis, retching, stomatitis

General disorders and administration site conditions:

sluggishness

Hepatobiliary disorders: Immune system disorders: Metabolism and nutrition disorders:

cytolytic hepatitis, hepatic steatosis, hepatitis, hepatomegaly

drug hypersensitivity, immune reconstitution syndrome

anorexia

Nervous system disorders:

convulsion, hypoesthesia, syncope, amnesia, hypersomnia, paraesthesia, somnolence, tremor

Psychiatric disorders:

abnormal dreams, confusional state, disorientation, nervousness, nightmares, sleep disorders

Reproductive system and breast disorders:

gynecomastia

Respiratory, thoracic and mediastinal disorders:

bronchospasm, exertional dyspnea

Skin and subcutaneous tissue disorders:

dry skin, hyperhidrosis, lipohypertrophy, night sweats, prurigo, swelling face

Additional ADRs of at least moderate intensity observed in other trials were acquired lipodystrophy, angioneurotic edema, erythema multiforme and haemorrhagic stroke, each reported in no more than 0.5% of subjects. Stevens-Johnson Syndrome has been reported rarely (< 0.1%) during clinical development with INTELENCE.

Abnormal Hematologic and Clinical Chemistry Findings

Laboratory Abnormalities

Treatment-emergent clinical laboratory abnormalities (Grade 3 or 4) observed in patients and reported in greater than or equal to 2% of INTELENCE-treated subjects are presented in the table below. All other grade 3 or 4 abnormal laboratory parameters were observed in less than 2% of the INTELENCE-treated subjects.

Table 3: Treatment Emergent Grade 3 to 4 Laboratory Abnormalities Reported in >= 2% of Subjects
Pooled DUET-1 and DUET-2 Trials
Laboratory Parameter Preferred Term, n (%)	INTELENCE + BR N=599	Placebo + BR N=604
GENERAL BIOCHEMISTRY
Pancreatic amylase	44 (7.5)	48 (7.9)
Grade 3	37 (6.3)	42 (7.0)
Grade 4	7 (1.2)	6 (1.0)
Lipase	16 (2.7)	10 (1.7)
Grade 3	10 (1.7)	7 (1.2)
Grade 4	6 (1.0)	3 (0.5)
HEMATOLOGY DIFFERENTIAL COUNTS
Neutrophils	22 (3.7)	38 (6.3)
Grade 3	16 (2.7)	21 (3.5)
Grade 4	6 (1.0)	17 (2.8)
LIPIDS AND GLUCOSE
Total cholesterol	34 (5.8)	25 (4.1)
Grade 3	34 (5.8)	25 (4.1)
Low density lipoprotein	30 (5.2)	32 (5.4)
Grade 3	30 (5.2)	32 (5.4)
Elevated glucose levels	15 (2.5)	12 (2.0)
Grade 3	15 (2.5)	11 (1.8)
Grade 4	0 (0)	1 (0.2)
Triglycerides	41 (7.0)	26 (4.3)
Grade 3	24 (4.1)	18 (3.0)
Grade 4	17 (2.9)	8 (1.3)
HEPATIC PARAMETERS	0 (0)	0 (0)
Alanine amino transferase	15 (2.5)	10 (1.7)
Grade 3	11 (1.9)	8 (1.3)
Grade 4	4 (0.7)	2 (0.3)
Aspartate amino transferase	15 (2.5)	10 (1.7)
Grade 3	12 (2.0)	8 (1.3)
Grade 4	3 (0.5)	2 (0.3)

Patients Co-infected with Hepatitis B and/or Hepatitis C Virus

In the pooled analysis for DUET-1 and DUET-2, the safety profile in co-infected subjects (n=140) was generally comparable between subjects receiving INTELENCE and subjects receiving placebo. There was a higher incidence of hepatic and biliary system disorders in co- infected subjects treated with INTELENCE (6.9% of 72 subjects) compared to co-infected subjects in the placebo group (1.5% of 68 subjects). No specific pattern or type of event was observed. Among co-infected subjects:

Grade 3 or 4 elevations in AST developed in 5.7% of subjects in the INTELENCE arm compared to 4.4% of subjects in the placebo arm;
Grade 3 or 4 elevations in ALT developed in 7.1% of subjects in the INTELENCE arm compared to 5.9% of subjects in the placebo arm;
Grade 3 or 4 elevations in bilirubin developed in 5.7% of subjects in the INTELENCE arm compared to 1.5% of subjects in the placebo arm.

DRUG INTERACTIONS

Etravirine is a substrate of CYP3A4, CYP2C9 and CYP2C19. Therefore, co-administration of INTELENCE (etravirine) with drugs that induce or inhibit CYP3A4, CYP2C9 and CYP2C19 may alter the therapeutic effect or adverse reaction profile of INTELENCE. Etravirine is an inducer of CYP3A4, and an inhibitor of CYP2C9 and CYP2C19. Therefore, co- administration of drugs that are substrates of CYP3A4, CYP2C9 and CYP2C19 with INTELENCE may alter the therapeutic effect or adverse reaction profile of the co-administered drug(s).

Drugs that are not recommended for co-administration with INTELENCE are included in Table 4. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy.

Established and other potentially significant drug interactions with INTELENCE are included in Table 5. These recommendations are based on either drug interaction studies or predicated interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy.

Drug interaction studies were performed with etravirine and other drugs likely to be co- administered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of etravirine on the AUC, Cmax, and Cmin values are summarized in Table 6 and Table 7. Different formulations and/or doses were used which led to similar exposures and, therefore, interactions relevant for one formulation are relevant for the other.

Table 6: Drug Interactions: Pharmacokinetic Parameters for Etravirine in the Presence of Co- administered Drugsa

CI = Confidence Interval; N = maximum number of subjects with data; N.A. = not available; | = increases; | = decreases; - = no change;

In drug-drug interaction studies, different formulations and/or doses of INTELENCE were used which led to similar exposures, and, therefore, interactions relevant for one formulation are relevant for the other.

Table 7: Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Etravirinea

Atazanavir/ ritonavir Darunavir/ ritonavir Fosamprenavir/ ritonavir Lopinavir/ ritonavir

The systemic exposure (AUC) to etravirine was decreased by about 50% when INTELENCE was administered under fasting conditions, as compared to when INTELENCE was administered following a meal. Therefore, INTELENCE should always be taken following a meal. The caloric and fat content of the meal is irrelevant.

Concomitant use of INTELENCE and St. John's Wort (Hypericum perforatum), or products containing St. John's Wort, is not recommended. Co-administration of etravirine with St. John's Wort may cause significant decreases in etravirine plasma concentrations, which may result in loss of therapeutic effect of INTELENCE (see Drug-Drug Interactions, Table 4). Interactions with other herbal products have not been established.

DOSAGE AND ADMINISTRATION

INTELENCE must always be given in combination other antiretroviral medicinal products. It is recommended that the dosage of INTELENCE be taken following a meal. The type of food does not affect the exposure to etravirine.

Adults:

The recommended oral dose of INTELENCE tablets is 200 mg (two 100 mg tablets) taken twice daily (b.i.d.) following a meal (see ACTION AND CLINICAL PHARMACOLOGY, - Pharmacokinetics).

Geriatric Patients:

In general, caution should be exercised in the administration of INTELENCE in elderly patients, reflecting the greater frequency of decreased hepatic, renal or cardiac function, concomitant disease or other drug therapy. (see INDICATIONS AND CLINICAL USE, WARNINGS AND PRECAUTIONS and ACTION AND CLINICAL PHARMACOLOGY).

Pediatric Patients:

The safety and efficacy of INTELENCE in pediatric patients have not yet been established. Treatment with INTELENCE is not recommended in children and adolescents (see INDICATIONS AND CLINICAL USE, WARNINGS AND PRECAUTIONS and ACTION AND CLINICAL PHARMACOLOGY).

Hepatic Impairment:

No dose adjustment is required in patients with mild or moderate hepatic impairment. The pharmacokinetics of INTELENCE has not been studied in patients with severe hepatic impairment (see WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Hepatic insufficiency).

Renal Impairment:

No dose adjustment is required in patients with renal impairment (see WARNINGS AND PRECAUTIONS, Renal and ACTION AND CLINICAL PHARMACOLOGY,

If the patient misses a dose of INTELENCE within 6 hours of the time it is usually taken, the patient should be told to take INTELENCE following a meal as soon as possible, and then take the next dose of INTELENCE at the regularly scheduled time. If a patient misses a dose of INTELENCE by more than 6 hours of the time it is usually taken, the patient should be told not to take the missed dose and simply resume the usual dosing schedule.

OVERDOSAGE

There is no specific antidote for overdose with INTELENCE. Treatment of overdose with INTELENCE consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Administration of activated charcoal may be used to aid in removal of unabsorbed active substance. Since etravirine is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance. For management of a suspected drug overdose, contact your regional Poison Control Centre

ACTION AND CLINICAL PHARMACOLOGY

Etravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1). Etravirine binds directly to reverse transcriptase (RT) and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme's catalytic site. Etravirine can bind in at least 2 conformationally distinct modes. Within a given binding mode, torsional flexibility of etravirine permits access to numerous conformational variants, while the compact design of etravirine permits significant repositioning and reorientation (translation and rotation) within the pocket. Etravirine does not inhibit the human DNA polymerases a, b, and g. Decreases in plasma viral load were typically observed as early as 1-2 days after the start of INTELENCE administration in monotherapy trials.

Development of resistance against etravirine in vitro typically required multiple NNRTI- resistance associated mutations (RAMs) of which the following were observed most frequently: L100I, E138K, E138G, V179I, Y181C and M230I. In the Phase 3 trials, DUET 1 and DUET 2, mutations that developed most commonly in subjects with virologic failure to the INTELENCE-containing regimen were V179F, V179I, Y181C and Y181I, generally within a background of other NNRTI RAMs (see MICROBIOLOGY).

Limited cross-resistance between etravirine and efavirenz was observed in vitro in 3 of the 65 site directed HIV-1 mutant strains containing an NNRTI resistance associated mutation. Cross- resistance to delavirdine, efavirenz and/or nevirapine is expected after virologic failure with an etravirine-containing regimen for the virologic failure isolates. Therefore, the treatment of patients with delavirdine, efavirenz or nevirapine following virologic failure of an etravirine- containing regimen is not recommended (see MICROBIOLOGY).

The pharmacokinetic properties of etravirine have been evaluated in adult healthy subjects and in adult treatment-experienced HIV-1-infected patients. Exposure to etravirine was slightly lower in HIV-1-infected patients than in healthy subjects.

When INTELENCE was administered for 8 days to healthy volunteers, the increase in exposure to etravirine was generally dose proportional between total daily doses of 200 and 400 mg, and the total exposure to etravirine was similar irrespective of whether the total daily dose was administered in a once-daily or twice-daily regimen.

Absorption:

An intravenous formulation of etravirine is unavailable: thus, the absolute bioavailability of INTELENCE is unknown. After oral administration with food, the maximum plasma concentration of etravirine is generally achieved within 4 hours. In healthy subjects, the absorption of etravirine is not affected by co-administration of oral ranitidine or omeprazole, drugs that are known to increase gastric pH.

The exposure to etravirine is similar when taken after a standard normal caloric meal (561 kcal) or high-fat high caloric meal (1160 kcal). When compared to administration following a standard normal caloric meal, exposures decreased when etravirine was taken before a standard normal caloric meal (17%), following a croissant (20%), or fasted (51%). Therefore, to achieve optimal exposure, INTELENCE should be taken following a meal.

Distribution:

Etravirine is about 99.9% bound to plasma proteins, primarily to albumin (99.6%) and a1-acid glycoprotein (94.48%-97.66%) in vitro. In rats, the highest concentrations of radiolabeled etravirine and its metabolites were measured in the gastrointestinal tract, liver and adrenal gland and the lowest levels were associated with blood, plasma, brain, lung and bone. There was no evidence of undue retention or accumulation. The elimination of radioactivity was complete in rats within 96 hours of etravirine oral administration. In pregnant rats, there was distribution of radiolabeled etravirine and its metabolites to the placenta, vagina, uterus, mammary glands and fetus. Total radioactivity levels in placenta and fetus were about twice the levels observed in maternal blood.

Metabolism:

experiments with human liver microsomes (HLMs) indicate that etravirine primarily undergoes oxidative metabolism by CYP3A4, 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.

Etravirine is not a substrate for P-glycoprotein in in vitro studies. Etravirine is an inhibitor of P- glycoprotein in vitro with a 50% inhibitory concentration (IC50) value of 10500 ng/mL for the probe paclitaxel. This value is approximately 20-fold higher than the average maximum plasma concentration observed in HIV-1 infected patients and is unlikely to have a clinically relevant impact. The extent of first-pass metabolism of etravirine has not been evaluated due to the absence of a suitable intravenous formulation. Etravirine has no pharmacologically active metabolites in the presence of NNRTI-resistant strains of HIV. No dose-dependent changes in metabolism have been observed for etravirine over the daily dose range of 200-400 mg.

Excretion:

After administration of a radiolabelled 14C-etravirine dose in human subjects, 93.7% and 1.2% of the administered dose of 14C-etravirine could be retrieved in 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 terminal elimination half-life of etravirine was approximately 30-40 hours.

Effects on Electrocardiogram:

In a randomized, double-blind, active- and placebo-controlled crossover study, 41 healthy male and female volunteers were administered INTELENCE 200 mg b.i.d., INTELENCE 400 mg q.d., placebo and moxifloxacin 400 mg. After 8 days of dosing, etravirine did not prolong the QT interval. The placebo-adjusted mean maximum increases in QTcF from baseline after 200 mg b.i.d. and 400 mg q.d. of etravirine were 0.1 msec and -0.2 msec, respectively, and 10.1 msec for moxifloxacin 400 mg q.d. No subject in any group had an increase in QTcF of >60 msec. No subject experienced an interval exceeding the potentially clinically relevant threshold of 500 msec.

Pediatrics:

The pharmacokinetics of etravirine in paediatric patients are under investigation. There are insufficient data at this time to recommend a dose.

Geriatrics:

Population pharmacokinetic analysis in HIV-infected subjects showed that etravirine pharmacokinetics are not considerably different in the age range (18 to 77 years) evaluated (see WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics).

Gender:

Race:

Population pharmacokinetic analysis of etravirine in HIV-infected patients indicated that race had no apparent effect on the exposure to etravirine.

Hepatic Insufficiency:

Etravirine is primarily metabolized and eliminated by the liver. In a study comparing 8 patients with mild hepatic impairment to 8 matched controls and 8 patients with moderate hepatic impairment to 8 matched controls, the multiple dose pharmacokinetic disposition of etravirine was not altered in patients with mild to moderate hepatic impairment. No dosing adjustment is required in patients with mild or moderate hepatic impairment. INTELENCE has not been studied in patients with severe hepatic impairment (see WARNINGS AND PRECAUTIONS, and DOSAGE AND ADMINISTRATION).

Population pharmacokinetic analysis of the DUET-1 and DUET-2 trials showed reduced clearance for INTELENCE in HIV-1-infected subjects with hepatitis B and/or C virus co- infection. Based upon the safety profile, no dose adjustment is necessary in patients co-infected with hepatitis B and/or C virus.

Renal Insufficiency:

The pharmacokinetics of etravirine have not been studied in patients with renal insufficiency. Results from a mass balance study with radioactive 14C-etravirine showed that <1.2% of the administered dose of etravirine is excreted in the urine. No unchanged drug was detected in urine so the impact of renal impairment on etravirine elimination is expected to be minimal. As etravirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis (see WARNINGS AND PRECAUTIONS, Renal and DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment, Renal Impairment).

STORAGE AND STABILITY

Store INTELENCE tablets between 15 - 30degC. Store in the original bottle. Keep the bottle tightly closed in order to protect from moisture. Do not remove the desiccant pouches.

DOSAGE FORMS, COMPOSITION AND PACKAGING

INTELENCE tablets are supplied as white to off-white oval tablets containing 100 mg of etravirine. Each tablet contains the inactive ingredients hypromellose, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate and lactose monohydrate. Each tablet is debossed with "T125" on one side and "100" on the other side. INTELENCE tablets are packaged in bottles in the following configuration: 100 mg tablets--bottles of 120. Each bottle contains 3 desiccant pouches.

Route of Administration	Pharmaceutical Form/Strength	Clinically Relevant Nonmedicinal Ingredients
oral	tablet, 100 mg	lactose monohydrate For a complete listing see DOSAGE FORMS, COMPOSITION AND PACKAGING section.

Table 4: Drugs That Should Not Be Co-administered With INTELENCE
Concomitant Drug Class: Drug Name	Clinical Comment
HIV-Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
efavirenz neviripine delavirdine	Combining two NNRTIs has not been shown to be beneficial. Concomitant use of INTELENCE with efavirenz or nevirapine may cause a decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE. INTELENCE and other NNRTIs should not be co-administered. Combining two NNRTIs has not been shown to be beneficial. INTELENCE and delavirdine should not be co-administered.
HIV-Antiviral Agents: Protease Inhibitors (PIs)--Unboosted (i.e., without co-administration of low-dose ritonavir)
ritonavir	Concomitant use of INTELENCE with full-dose ritonavir (600 mg b.i.d.) may cause a significant decrease in the plasma concentration of etravirine. This may result in loss of therapeutic effect of INTELENCE. It is not recommended to co-administer full-dose ritonavir (600 mg b.i.d.) with INTELENCE.
atazanavir nelfinavir indinavir	Concomitant use of INTELENCE without co-administration of low-dose ritonavir may cause a significant alteration in the plasma concentrations of the PI. INTELENCE should not be co- administered with PIs without low-dose ritonavir.
HIV-Antiviral Agents: Protease Inhibitors (PIs)--Boosted (with co-administration of low-dose ritonavir)
atazanavir/ritonavir fosamprenavir/ritonavir tipranavir/ritonavir	Concomitant use of INTELENCE with atazanivir/ritonavir may cause a significant decrease in atazanavir C m in by about 38%. INTELENCE and atazanavir/ritonavir should not be co- administered. An increase of 69% for amprenavir exposure was observed when fosamprenavir/ritonavir was co-administered in the presence of etravirine. Appropriate doses of the combination of INTELENCE and fosamprenavir/ritonavir have not been established. INTELENCE and fosamprenavir/ritonavir should not be co- administered. Concomitant use of INTELENCE with tipranavir/low-dose ritonavir may cause a significant decrease in the plasma concentration of etravirine and loss of therapeutic effect of INTELENCE. Tipranavir/low-dose ritonavir and INTELENCE should not be co-administered.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin	Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. INTELENCE should not be used in combination with carbamazepine, phenobarbital, or phenytoin as co- administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE.
Table 4: Drugs That Should Not Be Co-administered With INTELENCE
Concomitant Drug Class: Drug Name	Clinical Comment
Antimycobacterials: rifampin,	Rifampin is a potent inducer of CYP450 enzymes. INTELENCE should not be used in combination with rifampin as co- administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE.
Herbal Products: St. John's Wort ( Hypericum perforatum )	INTELENCE should not be used concomitantly with products containing St. John's Wort because co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE.

Table 5: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
Concomitant Drug Class: Drug Name	Effect on Concentration of Etravirine or Concomitant Drug	Clinical Comment
HIV-Antiviral Agents: Nucleoside or Nucleotide Reverse Transcriptase Inhibitors (NRTIs/N[t]RTIs)
didanosine *	etravirine didanosine	The combination of INTELENCE and didanosine can be used without dose adjustments. As didanosine is administered on an empty stomach, didanosine should be administered one hour before or two hours after INTELENCE (which should be administered following a meal).
tenofovir disoproxil fumarate *	\| etravirine - tenofovir	The combination of INTELENCE and tenofovir disoproxil fumarate can be used without dose adjustments.
Other NRTIs: Based on the primarily renal elimination route for other NRTIs (e.g., abacavir, emtricitabine, lamivudine, stavudine, and zidovudine), no drug interactions are expected between these drugs and INTELENCE.
HIV-Antiviral Agents: Protease Inhibitors (PIs)--Boosted (with co-administration of low-dose ritonavir)
darunavir/ritonavir *	\| etravirine - darunavir	The mean systemic exposure (AUC) of etravirine was reduced by 37% when INTELENCE was co-administered with darunavir/ritonavir. However, the combination of darunavir/ritonavir and etravirine was used safely and effectively in the Phase 3 trials, therefore, INTELENCE and darunavir/ritonavir can be co-administered without any dose adjustments.
lopinavir/ritonavir (soft gel capsule) *	\| etravirine \| lopinavir	The mean systemic exposure (AUC) of etravirine after co- administration of INTELENCE with lopinavir/ritonavir is anticipated to be about 85% higher than the mean AUC of etravirine observed in the Phase 3 trials. The amount of safety data at these increased etravirine exposures is limited, therefore, INTELENCE and lopinavir/ritonavir should be co- administered with caution.
Table 5: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
Concomitant Drug Class: Drug Name	Effect on Concentration of Etravirine or Concomitant Drug	Clinical Comment
saquinavir/ritonavir *	\| etravirine - saquinavir	The mean systemic exposure (AUC) of etravirine was reduced by about 33% after co-administration of INTELENCE and saquinavir/ritonavir. 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, therefore, INTELENCE and saquinavir/ritonavir can be co-administered without any dose adjustments.
HIV-Antiviral Agents: Dual Boosted Protease Inhibitors
lopinavir/saquinavir/ ritonavir *	- etravirine \| lopinavir \| saquinavir	The combination of INTELENCE and lopinavir/saquinavir/ritonavir can be used without dose adjustments.
HIV-Antiviral Agents: Fusion Inhibitors
enfuvirtide	etravirine enfuvirtide	No interaction is expected for either INTELENCE or enfuvirtide when co-administered.
HIV-Antiviral Agents: Integrase Strand Transfer Inhibitors
raltegravir *	- etravirine \| raltegravir	The combination of INTELENCE and raltegravir can be used without dose adjustments.
Other Agents
Antiarrhythmics: amiodarone, bepridil, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine	\| antiarrhythmics	Concentrations of these antiarrhythmics may be decreased when co-administered with INTELENCE. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when co- administered with INTELENCE.
Anticoagulants: Warfarin	\| warfarin	Warfarin concentrations may be affected when co- administered with INTELENCE. Co-administration of INTELENCE and warfarin is anticipated to cause an increase in warfarin exposures, while etravirine exposures are not expected to change. It is recommended that the international normalized ratio (INR) be monitored when warfarin is combined with INTELENCE.
Table 5: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
Concomitant Drug Class: Drug Name	Effect on Concentration of Etravirine or Concomitant Drug	Clinical Comment
Anti-infectives: azithromycin Clarithromycin *	etravirine azithromycin \| etravirine \| clarithromycin \| 14-OH- clarithromycin	Based on the renal elimination pathway of azithromycin, no drug interactions are expected between azithromycin and INTELENCE. Clarithromycin exposure was decreased by etravirine; 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; therefore, alternatives to clarithromycin, such as azithromycin, should be considered for the treatment of MAC.
Antifungals:	\| etravirine	Posaconazole is a potent inhibitor of CYP3A4 and fluconazole
fluconazole	- fluconazole	is a potent inhibitor of CYP2C9; both may increase plasma
itraconazole	\| itraconazole	concentrations of etravirine. Itraconazole and ketoconazole are
voriconazole	\| voriconazole	potent inhibitors as well as substrates of CYP3A4.
posaconazole	- posaconazole	Concomitant systemic use of itraconazole or ketoconazole and
ketoconazole	\| ketoconazole	INTELENCE may increase plasma concentrations of
		etravirine. Simultaneously, plasma concentrations of
		itraconazole or ketoconazole may be decreased by
		INTELENCE. Voriconazole is a CYP2C19 substrate and
		CYP3A4, CYP2C9 and CYP2C19 inhibitor. Concomitant use
		of voriconazole and INTELENCE may increase plasma
		concentrations of both drugs. Dose adjustments for
		itraconazole, ketoconazole or voriconazole may be necessary
		depending on other co-administered drugs.
Antimycobacterials: rifabutin *	\| etravirine \| rifabutin \| 25-O- desacetylrifabutin	If INTELENCE is co-administered with darunavir/ritonavir or saquinavir/ritonavir, then rifabutin should not be co-administered due to the potential for significant reductions in etravirine exposure. If INTELENCE is NOT co-administered with a protease inhibitor/ritonavir, then rifabutin at a dose of 300 mg q.d. is recommended.
Antivirals: ribavirin	etravirine ribavirin	Based on the renal elimination pathway of ribavirin, no drug interactions are expected between ribavirin and INTELENCE.
Benzodiazepines: diazepam	\| diazepam	Concomitant use of INTELENCE with diazepam may increase plasma concentrations of diazepam. A decrease in diazepam dose may be needed.
Table 5: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
Concomitant Drug Class: Drug Name	Effect on Concentration of Etravirine or Concomitant Drug	Clinical Comment
Corticosteroids: dexamethasone (systemic)	\| etravirine	Systemic dexamethasone induces CYP3A4 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.
Estrogen-based Contraceptives: ethinylestradiol * norethindrone *	etravirine norethindrone \| ethinylestradiol	The combination of estrogen-and/or progesterone-based contraceptives and INTELENCE can be used without dose adjustment.
HMG-CoA Reductase Inhibitors: atorvastatin * fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin	etravirine etravirine pravastatin, rosuvastatin, \| atorvastatin \| 2-OH- atorvastatin \| fluvastatin, \| lovastatin, \| simvastatin	Atorvastatin plasma concentrations are decreased 37% and plasma concentrations of the active metabolite, 2-hydroxy- atorvastatin, are increased by 27% when combined with INTELENCE. Dose adjustment of atorvastatin may be necessary to tailor the clinical response when combined with INTELENCE. No interaction between pravastatin and INTELENCE is expected. Lovastatin, rosuvastatin, and simvastatin are CYP3A4 substrates and co-administration with INTELENCE may result in lower plasma concentrations of the HMG-CoA reductase inhibitor. Fluvastatin and rosuvastatin are metabolized by CYP2C9. Co- administration of fluvastatin with INTELENCE may result in higher plasma concentrations of the HMG-CoA reductase inhibitor. Dose adjustments for fluvastatin may be necessary. No interaction between rosuvastatin and INTELENCE is expected.
H 2 -Receptor Antagonists: ranitidine *	\| etravirine	INTELENCE can be co-administered with H 2 -receptor antagonists without dose adjustments.
Immunosuppressants: cyclosporine, sirolimus, tacrolimus	\| cyclosporine \| sirolimus \| tacrolimus	Co-administration with systemic immunosuppressants should be done with caution because plasma concentrations of cyclosporine, sirolimus, or tacrolimus may be affected when co-administered with INTELENCE.
Narcotic Analgesics: methadone *	etravirine R(-) methadone S(+) methadone	INTELENCE and methadone may 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.
Table 5: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
Concomitant Drug Class: Drug Name	Effect on Concentration of Etravirine or Concomitant Drug	Clinical Comment
Phosphodiesterase Type 5 (PDE-5) Inhibitors: sildenafil *, vardenafil, tadalafil	\| sildenafil \| N-desmethyl- sildenafil	Sildenafil plasma concentrations are decreased by 57% and plasma concentrations of the active metabolite, N-desmethyl- sildenafil, are decreased by 41% when combined with INTELENCE. Concomitant use of PDE-5 inhibitors with INTELENCE may require dose adjustment of the PDE-5 inhibitor to attain the desired clinical effect.
Proton Pump Inhibitors: omeprazole *	\| etravirine	INTELENCE can be co-administered with proton pump inhibitors without dose adjustments.
Selective Serotonin Reuptake Inhibitors (SSRIs): paroxetine *	etravirine paroxetine	INTELENCE can be co-administered with paroxetine without dose adjustments.
\| = increases, \| = decreases, - = no change * The interaction between INTELENCE and the drug was evaluated in a clinical trial. All other drug interactions shown are predicted.

Atazanavir	400 mg q.d.	14	\|	1.47	1.50	1.58
				(1.36-1.59)	(1.41-1.59)	(1.46-1.70)
Atazanavir/	300/100 mg q.d.	14	\|	1.30	1.30	1.26
Ritonavir				(1.17-1.44)	(1.18-1.44)	(1.12-1.42)
Darunavir/	600/100 mg b.i.d.	14	\|	0.68	0.63	0.51
Ritonavir				(0.57-0.82)	(0.54-0.73)	(0.44-0.61)
Fosamprenavir/	700/100 mg b.i.d.	8	-	N.A.	N.A.	N.A.
Ritonavir
Lopinavir/	400/100 mg b.i.d.	13	\|	1.15	1.17	1.23
ritonavir				(0.94-1.41)	(0.96-1.43)	(0.98-1.53)
(soft gel capsule)
Ritonavir	100 mg single dose	18	-	1.00	1.03	N.A.
				(0.89-1.12)	(0.91-1.17)
Ritonavir	600 mg b.i.d.	11	\|	0.68	0.54	N.A.
				(0.55-0.85)	(0.41-0.73)

Tipranavir/	500/200 mg b.i.d.	19	\|	0.29	0.24	0.18
Ritonavir				(0.22-0.40)	(0.18-0.33)	(0.13-0.25)

Didanosine	400 mg q.d.	15	-	1.16	1.11	1.05
				(1.02-1.32)	(0.99-1.25)	(0.93-1.18)
Tenofovir disoproxil	300 mg q.d.	23	\|	0.81	0.81	0.82
fumarate				(0.75-0.88)	(0.75-0.88)	(0.73-0.91)
Co-Administration With Fusion Inhibitors
Enfuvirtide	90 mg b.i.d.	2 61 - b N .A. N.A. N.A.


Co-Administration With Integrase Strand Transfer Inhibitors
Raltegravir	400 mg b.i.d.	19	-	1.04	1.10	1.17
				(0.97-1.12)	(1.03-1.16)	(1.10-1.26)
Co-Administration With Other Drugs
Atorvastatin	40 mg q.d.	16	-	0.97	1.02	1.10
				(0.93-1.02)	(0.97-1.07)	(1.02-1.19)
Clarithromycin	500 mg b.i.d.	15	\|	1.46	1.42	1.46
				(1.38-1.56)	(1.34-1.50)	(1.36-1.58)
Ethinylestradiol/	0.035 mg q.d./	16	-	N.A.	N.A.	N.A.
norethindrone	1 mg q.d.
Methadone	Individual dose regimen ranging from	16	-	N.A.	N.A.	N.A.
	60 to 130 mg/day
Omeprazole	40 mg q.d.	18	\|	1.17	1.41	N.A.
				(0.96-1.43)	(1.22-1.62)
Paroxetine	20 mg q.d.	16	-	1.05	1.01	1.07
				(0.96-1.15)	(0.93-1.10)	(0.98-1.17)
Ranitidine	150 mg b.i.d.	18	\|	0.94	0.86	N.A.
				(0.75-1.17)	(0.76-0.97)
Rifabutin	300 mg q.d.	12	\|	0.63	0.63	0.65
				(0.53-0.74)	(0.54-0.74)	(0.56-0.74)

Table 7: Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Etravirine a
Co-administered Drug	Dose/Schedule of Co-administered Drug	N	PK	Mean Ratio of Co-administered Drug Pharmacokinetic Parameters 90% CI; No effect = 1.00
Co-administered Drug	Dose/Schedule of Co-administered Drug	N	PK	C max	AUC	C min
Norethindrone	1 mg q.d.	16	-	1.05 (0.98-1.12)	0.95 (0.90-0.99)	0.78 (0.68-0.90)
R(-) methadone S(+) methadone	Individual dose regimen ranging from 60 to 130 mg/day	16 16	- -	1.02 (0.96-1.09) 0.89 (0.83-0.97)	1.06 (0.99-1.13) 0.89 (0.82-0.96)	1.10 (1.02-1.19) 0.89 (0.81-0.98)
Paroxetine	20 mg q.d.	16	-	1.06 (0.95-1.20)	1.03 (0.90-1.18)	0.87 (0.75-1.02)
Rifabutin 25- O - desacetylrifabutin	300 mg q.d. 300 mg q.d.	12 12	\| \|	0.90 (0.78-1.03) 0.85 (0.72-1.00)	0.83 (0.75-0.94) 0.83 (0.74-0.92)	0.76 (0.66-0.87) 0.78 (0.70-0.87)
Sildenafil N-desmethyl- sildenafil	50 mg single dose	15 15	\| \|	0.55 (0.40-0.75) 0.75 (0.59-0.96)	0.43 (0.36-0.51) 0.59 (0.52-0.68)	N.A. N.A.
CI = Confidence Interval; N = number of subjects with data; N.A. = not available; \| = increases; \| = decreases; - = no change; q.d. = once daily ; b.i.d. = twice daily a In drug-drug interaction studies, different formulations and/or doses of INTELENCE were used which led to similar exposures, and, therefore, interactions relevant for one formulation are relevant for the other.

Table 8: Population Pharmacokinetic Estimates of Etravirine 200 mg b.i.d. in HIV-1-Infected Subjects * (Integrated Data from Phase III DUET Trials at Week 24)
Parameter	Etravirine 200 mg b.i.d. N = 574
AUC 12h (ng *h/mL)
Geometric Mean +- Standard Deviation	4531.53 +- 4543.69
Median (Interquartile Range)	4450.7 (3091.3 - 6315.0)
C 0h (ng/mL)
Geometric Mean +- Standard Deviation	296.74 +- 377.52
Median (Interquartile Range)	298.8 (188.5 - 462.3)
*PK values are about 30% higher in healthy volunteers All HIV-infected subjects enrolled in Phase 3 clinical trials received darunavir/ritonavir 600/100 mg b.i.d. as part of their background regimen. Therefore, the pharmacokinetic parameter estimates in Table 8 account for reductions in the pharmacokinetic parameters of etravirine due to co- administration of INTELENCE with darunavir/ritonavir.

Submission Control Number: 113100

PART I: HEALTH PROFESSIONAL INFORMATION 3

PART II: SCIENTIFIC INFORMATION 28

PART III: CONSUMER INFORMATION. 41

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

Geriatrics (> 65 years of age):

Pediatrics (< 18 years of age):

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

Fat Redistribution

Hepatic Impairment

Pancreatitis

Immune Reconstitution

Renal Impairment

Pregnant Women:

Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to INTELENCE, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

Nursing Women:

Pediatrics (< 18 years of age):

Geriatrics (> 65 years of age):

ADVERSE REACTIONS

Skin Rash

Cardiac disorders:

Ear and labyrinth disorders:

Eye disorders:

Gastrointestinal disorders:

General disorders and administration site conditions:

Hepatobiliary disorders: Immune system disorders: Metabolism and nutrition disorders:

Nervous system disorders:

Psychiatric disorders:

Reproductive system and breast disorders:

Respiratory, thoracic and mediastinal disorders:

Skin and subcutaneous tissue disorders:

Laboratory Abnormalities

DRUG INTERACTIONS

DOSAGE AND ADMINISTRATION

Adults:

Geriatric Patients:

Pediatric Patients:

Hepatic Impairment:

Renal Impairment:

OVERDOSAGE

ACTION AND CLINICAL PHARMACOLOGY

Absorption:

Distribution:

Metabolism:

Excretion:

Effects on Electrocardiogram:

Pediatrics:

Geriatrics:

Gender:

Race:

Hepatic Insufficiency:

Renal Insufficiency:

STORAGE AND STABILITY

DOSAGE FORMS, COMPOSITION AND PACKAGING