Intelence Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES ......................................................................................... 2

TABLE OF CONTENTS ............................................................................................................... 2

PART I: HEALTH PROFESSIONAL INFORMATION .................................................................. 4

1 INDICATIONS ................................................................................................................... 4

1.1 Pediatrics .......................................................................................................... 4

1.2 Geriatrics ........................................................................................................... 4

2 CONTRAINDICATIONS ................................................................................................... 4

4 DOSAGE AND ADMINISTRATION .................................................................................. 5

4.1 Dosing Considerations ...................................................................................... 5

4.2 Recommended Dose and Dosage Adjustment ................................................. 5

4.4 Administration ................................................................................................... 6

4.5 Missed Dose ..................................................................................................... 6

5 OVERDOSAGE ................................................................................................................ 6

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ......................... 7

7 WARNINGS AND PRECAUTIONS .................................................................................. 7

7.1 Special Populations ........................................................................................... 9

7.1.1 Pregnant Women ...................................................................................... 9

7.1.2 Breast-feeding ......................................................................................... 10

7.1.3 Pediatrics ................................................................................................ 10

7.1.4 Geriatrics ................................................................................................. 10

8 ADVERSE REACTIONS ................................................................................................. 10

8.1 Adverse Reaction Overview ............................................................................ 10

8.2 Clinical Trial Adverse Reactions ..................................................................... 11

8.2.1 Clinical Trial Adverse Reactions - Pediatrics .......................................... 13

8.3 Less Common Clinical Trial Adverse Reactions ............................................. 13

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ............................................................................................................ 14

8.5 Post-Market Adverse Reactions ...................................................................... 15

9 DRUG INTERACTIONS .................................................................................................. 16

9.2 Drug Interactions Overview ............................................................................. 16

9.4 Drug-Drug Interactions .................................................................................... 16

9.5 Drug-Food Interactions ................................................................................... 28

9.6 Drug-Herb Interactions .................................................................................... 28

9.7 Drug-Laboratory Test Interactions .................................................................. 28

10 CLINICAL PHARMACOLOGY ....................................................................................... 28

10.1 Mechanism of Action ....................................................................................... 28

10.3 Pharmacokinetics ............................................................................................ 29

11 STORAGE, STABILITY AND DISPOSAL ...................................................................... 33

12 SPECIAL HANDLING INSTRUCTIONS ......................................................................... 33

PART II: SCIENTIFIC INFORMATION ....................................................................................... 34

13 PHARMACEUTICAL INFORMATION ............................................................................ 34

14 CLINICAL TRIALS ......................................................................................................... 34

14.1 Clinical Trials by Indication .............................................................................. 34

Treatment-Experienced Adult Patients ........................................................... 34

Treatment-Experienced Pediatric Patients ...................................................... 39

14.2 Comparative Bioavailability Studies ................................................................ 39

15 MICROBIOLOGY ............................................................................................................ 40

16 NON-CLINICAL TOXICOLOGY ..................................................................................... 43

PATIENT MEDICATION INFORMATION .................................................................................. 45

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

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 and pediatric (from 6 to <18 years of age and weighing ≥30 kg) patients who have failed prior therapy and have HIV-1 strains resistant to multiple antiretroviral agents, including NNRTIs (see 4 DOSAGE AND ADMINISTRATION).

The adult indication is based on safety and efficacy data at 48 weeks from two Phase III, 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 14 CLINICAL TRIALS for description of studies).

1.1 Pediatrics

Pediatrics (<6 years of age)

The safety and efficacy of Intelence in pediatric patients <6 years of age have not been established. Treatment with Intelence is not indicated for pediatric patients younger than 6 (see 7 WARNINGS AND PRECAUTIONS and 10.3 Pharmacokinetics)

Pediatrics (from 6 to <18 years of age)

Intelence, in combination with other antiretroviral agents, is indicated for the treatment of HIV-1 infection in antiretroviral treatment-experienced pediatric patients 6 years to <18 years of age and weighing ≥30 kg, including those with NNRTI resistance.

This indication is based on 24-week analyses of a single-arm, on-going Phase II trial evaluating safety, PK, and antiretroviral activity in Intelence in antiretroviral treatment-experienced pediatric subjects 6 years to less than 18 years of age. The results of 48 weeks analysis were similar to those of 24 weeks (see 7 WARNINGS AND PRECAUTIONS, 4 DOSAGE AND ADMINISTRATION, and 10 CLINICAL PHARMACOLOGY).

1.2 Geriatrics

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 7 WARNINGS AND PRECAUTIONS, 4 DOSAGE AND ADMINISTRATION, and 10 CLINICAL PHARMACOLOGY).

2 CONTRAINDICATIONS

• Co-administration of Intelence is contraindicated with the combination ombitasvir/paritaprevir/ritonavir and with drugs containing dasabuvir (see 9 DRUG INTERACTIONS)
• 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 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

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 14 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.
• The safety and efficacy of Intelence have not been established in treatment-naive adult/pediatric patients.
• Intelence must always be given in combination with 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.
• Patients should be instructed to swallow the tablet(s) whole with a liquid such as water (see 4.4 Administration).

4.2 Recommended Dose and Dosage Adjustment

Adults

The recommended oral dose of Intelence tablets is 200 mg (one 200 mg tablet or two 100 mg tablets) taken twice daily (b.i.d.) following a meal (see 10.3 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 1 INDICATIONS, 7 WARNINGS AND PRECAUTIONS and 10.3 Pharmacokinetics).

Pediatric Patients

Treatment-Experienced Pediatric Patients (from 6 to <18 years of age)

The recommended dose of Intelence for pediatric patients (6 years to <18 years of age and weighing at least 30 kg) is 200 mg (one 200 mg tablet or two 100 mg tablets) taken twice daily (b.i.d.). Intelence tablet(s) should be taken orally, following a meal.

Children (<6 years of age)

The safety and efficacy of Intelence in pediatric patients <6 years of age have not yet been established. Treatment with Intelence is not recommended in children younger than 6 (see 1 INDICATIONS, 7 WARNINGS AND PRECAUTIONS and 10.3 Pharmacokinetics).

Pregnancy

No dose adjustment is required during pregnancy and postpartum. Given the increased etravirine exposure during pregnancy, caution should be applied for those pregnant patients that require concomitant medications or have comorbidities that may further increase etravirine exposure.

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 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, and 10.3 Pharmacokinetics, Special Populations and Conditions, Hepatic insufficiency).

Renal Impairment

No dose adjustment is required in patients with renal impairment (see 7 WARNINGS AND PRECAUTIONS, Renal and 10.3 Pharmacokinetics, Special Populations and Conditions, Renal Insufficiency).

4.4 Administration

Patients should be instructed to swallow the Intelence tablet(s) whole with a liquid such as water. Patients who are unable to swallow the Intelence tablet(s) whole may disperse the tablet(s) in a glass of water. The patient should be instructed to do the following:

• place the tablet(s) in 5 ml (1 teaspoon) of water, or at least enough liquid to cover the medication,
• stir well for about 1 minute until the water looks milky,
• if desired, add up to 30 mL (2 tablespoons) more water or alternatively orange juice or milk (patients should not place the tablets in orange juice or milk without first adding water),
• drink it immediately,
• rinse the glass several times with water, orange juice, or milk and completely swallow the rinse each time to make sure the patient takes the entire dose.

The use of grapefruit juice, warm liquids (>40°C) or carbonated beverages should be avoided.

In case of any doubt that a child will take the entire dose of the tablet(s) dispersed in water, treatment with another antiretroviral product needs to be considered. For children who cannot swallow the tablet(s) whole, dispersion of the tablet(s) in water should only be considered if the child is likely to take the entire dose. The importance of consuming the entire dose needs to be highlighted to the child and their caregiver to avoid too low exposure and lack of virologic response.

It is recommended that Intelence tablet(s) dispersed in water be taken before other antiretroviral liquids that may need to be taken concomitantly.

4.5 Missed Dose

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.

5 OVERDOSAGE

There is no specific antidote for overdose with Intelence. Human experience of overdose with Intelence is limited. Treatment of overdose with Intelence consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Since etravirine is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1: Dosage Forms, Strengths, Composition and Packaging

Intelence 100 mg tablets

Intelence tablets are supplied as white to off-white oval tablets containing 100 mg of etravirine.

Each tablet is debossed with “T125” on one side and “100” on the other side. Intelence 100 mg tablets are packaged in bottles in the following configuration: 100 mg tablets—bottles of 120. Each bottle contains 3 desiccant pouches.

Intelence 200 mg tablets

Intelence 200 mg tablets are available as white to off-white, biconvex, oblong tablets containing 200 mg of etravirine.

Each tablet is debossed with “T200” on one side. Intelence 200 mg tablets are packaged in bottles in the following configuration: 200 mg tablets—bottles of 60. Each bottle contains 3 desiccant pouches.

7 WARNINGS AND PRECAUTIONS

General

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

Carcinogenesis and Mutagenesis

Etravirine was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. A statistically significant increase in the incidences of hepatocellular adenomas and carcinomas was observed in treated female mice. Administration of etravirine did not cause a statistically significant increase in the incidence of tumors in female or male rats. The relevance of the findings in mice to humans is not known. At the highest tested doses, the systemic exposures (based on AUC) to etravirine were lower than those in humans at the clinical therapeutic dose (200 mg b.i.d) with animal versus human AUC ratios being 0.6 (mice) and between 0.2 and 0.7 (rats) (see 16 NON-CLINICAL TOXICOLOGY, Carcinogenicity and Genotoxicity).

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 16 NON-CLINICAL TOXICOLOGY, Carcinogenicity and Genotoxicity).

Endocrine and Metabolism

Serum Lipids and Blood Glucose

Serum lipids and blood glucose may increase during antiretroviral therapy. Disease control and lifestyle changes may also be contributing factors. Consideration should be given to the measurement of serum lipids and blood glucose. Lipid disorders and blood glucose elevations should be managed as clinically appropriate.

Hepatic/Biliary/Pancreatic

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 4.2 Recommended Dosage and Dosage Adjustment, Hepatic Impairment and 10 CLINICAL PHARMACOLOGY, Special Populations and Conditions, Hepatic Insufficiency).

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 8 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

Immune Reconstitution

Immune reconstitution inflammatory 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.

Autoimmune disorders (such as Graves’ disease, and autoimmune hepatitis, polymyositis and Guillain-Barré syndrome) 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 and sometimes there can be an atypical presentation.

Renal

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 4 DOSAGE AND ADMINISTRATION and 10 CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal Insufficiency).

Skin

Severe, potentially life-threatening, and fatal skin reactions have been reported in patients taking Intelence (etravirine). During both clinical development and postmarket, cases of Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme have been reported. In a postmarketing epidemiologic study in HIV-1 infected children and adolescents receiving Intelence along with other antiretrovirals, Stevens Johnson Syndrome was reported at a higher incidence (1%) than has been reported in adult clinical trials (< 0.1%). Hypersensitivity reactions including DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) have also been reported and were characterized by rash, constitutional findings, and infrequently organ dysfunction, including hepatic failure.

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). 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 a life-threatening reaction.

In Phase III clinical trials, Grade 3 and 4 rashes were reported in 1.3% of subjects receiving Intelence compared to 0.2% of placebo subjects. A total of 2% of HIV-1-infected patients receiving Intelence discontinued from Phase III trials due to rash. Most frequently, rash was mild to moderate, occurred in the second week of therapy and was infrequent after week 4. Rash was mostly self-limiting and generally resolved within 1 to 2 weeks on continued therapy. The incidence of rash was higher in females (see 8 ADVERSE REACTIONS).

7.1 Special Populations

7.1.1 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 16 NON-CLINICAL TOXICOLOGY, Reproductive and Developmental Toxicity).

Intelence (200 mg b.i.d.), was evaluated in combination with other antiretroviral agents in an open-label study of 15 pregnant women during the second and third trimesters of pregnancy and postpartum. Etravirine pharmacokinetic data are available for 13 women in the second trimester, 10 women in the third trimester and 10 women postpartum. The exposure to total etravirine was generally higher during pregnancy compared with postpartum, and less so for unbound etravirine exposure. Given the increased etravirine exposure during pregnancy, caution should be applied for those pregnant patients that require concomitant medications or have comorbidities that may further increase etravirine exposure (see 10 CLINICAL PHARMACOLOGY, Special Populations and Conditions, Pregnancy and Postpartum). There were no relevant clinical findings in the mothers or in the newborns in this trial.

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.

7.1.2 Breast-feeding

Etravirine is excreted in human breast milk. 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.

7.1.3 Pediatrics

The safety assessment in children and adolescents is based on the Week 24 analysis of the single arm, Phase II PIANO trial in which 101 antiretroviral treatment-experienced HIV-1 infected pediatric subjects 6 years to less than 18 years of age and weighing at least 16 kg (35.2 lbs), received Intelence in combination with other antiretroviral agents (see 8 ADVERSE REACTIONS).

The safety and effectiveness of Intelence in pediatric patients less than 6 years of age or in treatment-naive patients have not been established.

7.1.4 Geriatrics

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.

8 ADVERSE REACTIONS

8.1 Adverse 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 52.3 and 51.0 weeks, respectively.

In total, 79.3% and 73.0% of the adult 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 22.2% and 17.2% of the Intelence- and placebo-treated subjects. The most commonly reported Grade 3 or 4 ADRs were hypertriglyceridemia (4.2% in the Intelence arm and 2.3% in the placebo arm), hypercholesterolemia (2.2% in the Intelence arm and 2.3% in the placebo arm), renal failure (2.0% in the Intelence arm and 1.2% in the placebo arm) and anemia (1.7% in the Intelence arm and 1.3% in the placebo arm). ADRs were reported as SAEs in 6.8% and 8.3% of subjects treated with Intelence and placebo, respectively. ADRs that led to permanent discontinuation of the investigational medication were reported in 5.2% of the Intelence-treated subjects and in 2.6% of the placebo-treated subjects. The most commonly reported ADRs (any grade) with Intelence identified from the pooled DUET trials were rash (any type), reported by 19.2% of Intelence-treated subjects and by 10.9% of placebo-treated subjects, diarrhea (18.0% and 23.5%), and nausea (14.9% and 12.8%).

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Adverse drug reactions (ADRs) of moderate intensity or greater (≥Grade 2) and reported in ≥1% of adult subjects treated with Intelence (200 mg b.i.d.) in the DUET-1 and DUET-2 trials are presented in Table 2. Laboratory abnormalities considered ADRs are included in Table 4.

Table 2: Treatment-Emergent Adverse Reactions¹ of at Least Moderate Intensity (Grades 2-4) in ≥1% of Adult Subjects in the Intelence Treatment Groups

N = total number of subjects per treatment group

BR = background regimen

1. 1. Includes adverse reactions at least possibly, probably, or very likely related to the drug

Skin Rash

The most frequently reported adverse drug reaction of at least Grade 2 in severity in the Phase III studies was rash (10%). Stevens-Johnson syndrome, severe hypersensitivity reaction, and erythema multiforme were reported in <0.1% of adult subjects during clinical development with Intelence. A total of 2% of HIV-1-infected subjects receiving Intelence discontinued from Phase III trials due to rash. In general, rash was mild to moderate, macular to maculopapular or erythematous, occurred primarily in the second week of therapy and was infrequent after Week 4. Rash generally resolved within 1-2 weeks on continued therapy. In Phase III studies, the incidence of rash was higher in women compared to men in the Intelence arm (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). Patients with a history of NNRTI-related rash did not appear to be at increased risk for the development of Intelence-related rash compared to patients without a history of NNRTI-related rash. See Table 3 for a summary of rash events.

Table 3: Rash (Any Type) – Week 48 DUET Analysis

N = number of subjects, n = number of subjects with observations

8.2.1 Clinical Trial Adverse Reactions - Pediatrics

Clinical Trial Experience in Pediatric Patients (6 years to <18 years)

The safety assessment in children and adolescents is based on the Week 24 analysis of the single arm, Phase II PIANO trial (TMC125-C213) in which 101 antiretroviral treatment-experienced HIV-1 infected pediatric subjects 6 years to <18 years of age and weighing at least 16 kg (35.2 lbs), received Intelence in combination with other antiretroviral agents (see 14 CLINICAL TRIALS). The frequency, type and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adults. Adverse Reactions with at least Grade 2 in severity and occurred more than 2% in pediatric subjects were rash (14.9%), diarrhea (5.9%), vomiting (4.0%), headache (4.0%), bronchospasm (3.0%), and hypercholesterolemia (3.0%). Rash was reported more frequently in female subjects than in male subjects (rash ≥Grade 2 was reported in 13/64 [20.3%] females versus 2/37 [5.4%] males; discontinuations due to rash were reported in 4/64 [6.3%] females versus 0/37 [0%] males). Rash was mostly mild to moderate and self-limiting, of macular/papular type, and occurred in the second week of therapy. Rash was generally resolved within 1 week on continued therapy. Rash including serious (Grade 3 or 4) events and discontinuations were more frequently observed in female subjects compared to male subjects. The safety profile for subjects who completed 48 weeks of treatment was similar to the safety profile of subjects who completed 24 weeks of treatment.

8.3 Less Common Clinical Trial Adverse Reactions

Treatment-emergent adverse drug reactions in the DUET-1 and DUET-2 trials (n=599) occurring in less than 1% of adult 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

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: cytolytic hepatitis, hepatic steatosis, hepatitis, hepatomegaly

Immune system disorders: drug hypersensitivity, immune reconstitution inflammatory syndrome

Metabolism and nutrition disorders: anorexia, dyslipidemia

Nervous system disorders: convulsion, disturbance in attention, 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, prurigo, swelling face

Additional ADRs observed in other trials 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:

Metabolism and nutrition disorders: acquired lipodystrophy

Nervous system disorders: haemorrhagic stroke

Skin and subcutaneous tissue disorders: angioneurotic edema, erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis

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.

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Treatment-emergent clinical laboratory abnormalities (Grade 3 or 4) observed in adult 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 4: Treatment Emergent Grade 3 to 4 Laboratory Abnormalities Reported in ≥2% of Adult Subjects

BR = Background regimen

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 adult subjects (139) 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 (12.5% of 72 subjects) compared to co-infected subjects in the placebo group (9.0% of 67 subjects). No specific pattern or type of event was observed.

Among co-infected subjects:

• Grade 3 or 4 elevations in AST developed in 9.7% of subjects in the Intelence arm compared to 6.0% of subjects in the placebo arm;
• Grade 3 or 4 elevations in ALT developed in 11.1% of subjects in the Intelence arm compared to 7.5% 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.

8.5 Post-Market Adverse Reactions

Immune system disorders: Immune reconstitution inflammatory syndrome, Severe hypersensitivity reactions including DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) with cases of hepatic failure (see 7 WARNINGS AND PRECAUTIONS, Immune).

Skin and subcutaneous tissue disorders: Fatal cases of toxic epidermal necrolysis (see 7 WARNINGS AND PRECAUTIONS, Skin).

Musculoskeletal and connective tissue disorders: Myopathy, Rhabdomyolysis

Post Marketing Studies in Pediatric Patients:

In a pharmacovigilance postmarketing epidemiologic study to define the long-term safety profile of etravirine in HIV-1-infected children and adolescents receiving etravirine with other HIV-1 antiretrovirals (N=182), Stevens-Johnson Syndrome was reported at a higher incidence (1%) than has been reported in adult clinical trials (<0.1%).

9 DRUG INTERACTIONS

9.2 Drug Interactions Overview

Etravirine is metabolized by cytochrome CYP3A4, CYP2C9 and CYP2C19 followed by glucuronidation of the metabolites by uridine diphosphate glucuronosyltransferase (UDPGT). Therefore, co-administration of Intelence with drugs that induce or inhibit CYP3A, CYP2C9, or CYP2C19 may result in altered plasma concentrations of etravirine and alter the therapeutic effect or adverse reaction profile of Intelence.

Etravirine is an inducer of CYP3A4, and an inhibitor of CYP2C9, CYP2C19 and P-glycoprotein. Therefore, co-administration of drugs that are substrates of CYP3A4, CYP2C9, CYP2C19 or that are transported by the P-glycoprotein with Intelence may result in altered plasma concentrations and alter the therapeutic effect or adverse reaction profile of the co-administered drug(s).

9.4 Drug-Drug Interactions

Co-adminitstration of Intelence is contraindicated with the combination ombitasvir/paritaprevir/ritonavir and with drugs containing dasabuvir because decrease in exposure (CYP3A induction by etravirine) may lead to a potential loss of therapeutic activity of ombitasvir/paritaprevir/ritonavir or dasabuvir (see 2 CONTRAINDICATIONS).

Drugs that are not recommended for co-administration with Intelence are included in Table 5. 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.

Table 5: Drugs That Should Not Be Co-administered With Intelence

Established and other potentially significant drug interactions with Intelence are included in Table 6. 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.

Table 6: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction

↑ = increases, ↓ = decreases, ↔ = no change

1. 1. The interaction between Intelence and the drug was evaluated in a clinical trial. All other drug interactions shown are predicted.
2. 2. The expected increase in systemic exposure of etravirine when co-administered with either lopinavir/ritonavir tablet (~85%), fluconazole (~194%) or voriconazole (~114%) is theoretical and is based on comparisons of etravirine exposures from drug-drug interaction studies to those in the pivotal Phase III trials (in which darunavir/ritonavir was co-administered as part of the background regimen).

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, C_max, and C_min values are summarized in Table 7 and Table 8. 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 7: Drug Interactions: Pharmacokinetic Parameters for Etravirine in the Presence of Co-administered Drugs¹

CI = Confidence Interval; N = maximum number of subjects with data; N.A. = not available; ↑ = increases; ↓ = decreases; ↔ = no change; q.d. = once daily; b.i.d. = twice daily; t.i.d. = three times daily; q.a.m. = once daily in the morning

1. 1. 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.
2. 2. Based on population pharmacokinetic analysis
3. 3. The systemic exposure of etravirine when co-administered with atazanavir/ritonavir in HIV infected patients is similar to exposures of etravirine observed in the Phase III trials after co-administration of Intelence and darunavir/ritonavir (as part of the background regimen).

Table 8: Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Etravirine¹

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; t.i.d. = three times daily; q.a.m. = once daily in the morning

1. 1. 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.

9.5 Drug-Food Interactions

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.

Grapefruit or grapefruit juice can inhibit CYP3A enzyme activity and should be avoided with Intelence.

9.6 Drug-Herb Interactions

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 9.4 Drug-Drug Interactions, Table 5).

Interactions with other herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

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 two 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 α, β, and γ.

Decreases in plasma viral load were typically observed as early as 1–2 days after the start of

Intelence administration in monotherapy trials.

Resistance

Development of resistance against etravirine in vitro typically required multiple NNRTI-resistances associated mutations (RAMs) of which the following were observed most frequently: L100I, E138K, E138G, V179I, Y181C and M230I.

In the Phase III trials, DUET-1 and DUET-2, mutations that developed most commonly in subjects with virologic failure to the Intelence-containing regimen were V179F, V179I and Y181C, generally within a background of other NNRTI RAMs (see 15 MICROBIOLOGY Resistance in treatment-experienced subjects).

Cross-Resistance

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 15 MICROBIOLOGY, Cross-Resistance In Vitro).

10.3 Pharmacokinetics

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.

Table 9: Population Pharmacokinetic Estimates of Etravirine 200 mg b.i.d. in HIV-1-Infected Adult Subjects¹ (Integrated Data from Phase III DUET Trials at Week 48)

1. 1. PK values are about 30% higher in healthy volunteers All HIV-infected subjects enrolled in Phase III clinical trials received darunavir/ritonavir 600/100 mg b.i.d. as part of their background regimen. Therefore, the pharmacokinetic parameter estimates account for reductions in the pharmacokinetic parameters of etravirine due to co-administration of Intelence with darunavir/ritonavir.

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

Maximum etravirine plasma concentrations are generally attained by 4 hours following single or multiple oral doses of 100 mg to 400 mg. Dose-proportional pharmacokinetics were observed for daily doses from 200-400 mg and steady-state plasma concentrations were reached in approximately 7 days.

The population pharmacokinetics derived geometric mean (SD) C_0h and AUC_12h for etravirine in 574 HIV-1-infected patients receiving Intelence is 4531.53 (±4543.69) ng.h/mL and 296.74 (±377.52) ng/mL, respectively.

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.

Effect of food on oral absorption

The exposure to etravirine is similar when taken following 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, exposure to etravirine was decreased by 51% in fasted conditions. Therefore, to achieve optimal exposure, Intelence should be taken following a meal. The caloric and fat content of the meal is irrelevant. (See 4 DOSAGE AND ADMINISTRATION and 9 DRUG INTERACTIONS; 9.5 Drug-Food Interactions).

Distribution

Etravirine is approximately 99.9% bound to plasma proteins, primarily to albumin (99.6%) and alpha1-acid glycoprotein (94.48-97.66%) in vitro. The distribution of etravirine into compartments other than plasma (e.g. cerebrospinal fluid, genital tract secretions) has not been evaluated in humans.

In rats, the highest concentrations of radiolabelled 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 radiolabelled 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

In vitro experiments with human liver microsomes (HLMs) indicate that etravirine primarily undergoes oxidative 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.

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 10,500 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.

Elimination

The terminal elimination half-life of etravirine is approximately 30-40 hours. After administration of a radiolabelled ¹⁴C-etravirine dose, 93.7% and 1.2% of the administered radioactivity could be retrieved in feces and urine, respectively. Unchanged etravirine accounted for 81.2%-86.4% of the administered dose in feces while no unchanged etravirine could be detected in urine.

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.

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.

Special Populations and Conditions

• Pediatrics

The pharmacokinetics of etravirine in 101 treatment-experienced HIV-1-infected pediatric subjects, 6 years to <18 years of age and weighing at least 16 kg (35.2 lbs), showed that the administered weight-based dosages resulted in etravirine exposure comparable to that in adults receiving Intelence 200 mg twice daily (see 4 DOSAGE AND ADMINISTRATION and 10 CLINICAL PHARMACOLOGY) when administered at a dose corresponding to 5.2 mg/kg twice daily. The population pharmacokinetic estimates for etravirine AUC_12h and C_0h are summarized in the table below.

Table 10: Population Pharmacokinetic Estimates for Etravirine (all doses combined) in Treatment-Experienced HIV-1-Infected Pediatric Subjects 6 years to <18 years of age (PIANO 24 and 48 weeks analysis)

The pharmacokinetics of etravirine in pediatric patients (<6 years of age) are under investigation. There are insufficient data at this time to recommend a dose in pediatric patients <6 years of age.

• 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 7.1.4 Geriatrics).

• Sex

A limited number of women were included in studies. The pharmacokinetics of etravirine in HIV-1-infected patients appears to be similar between men and women.

• Pregnancy and Breast-feeding

The total etravirine exposure after intake of Intelence 200 mg b.i.d. as part of an antiretroviral regimen was generally higher during pregnancy compared with postpartum (see Table 11). The differences were less pronounced for unbound etravirine exposure.

In women receiving Intelence 200 mg b.i.d., higher mean values for C_max, AUC_12h and C_min were observed during pregnancy compared to postpartum. During the 2^nd and 3^rd trimester of pregnancy mean values of these parameters were comparable.

Table 11: Pharmacokinetic results of total etravirine after administration of etravirine 200 mg b.i.d. as part of an antiretroviral regimen, during the 2^nd trimester of pregnancy, the 3^rd trimester of pregnancy, and postpartum.

1. 1. n=9 for AUC12h

Each subject served as her own control, and with an intra-individual comparison, the total etravirine C_min, C_max and AUC_12h values were 1.2-, 1.4- and 1.4-fold higher, respectively, during the 2^nd trimester of pregnancy as compared to postpartum, and 1.1-, 1.4- and 1.2-fold higher, respectively, based during the 3^rd trimester of pregnancy as compared to postpartum.

• Ethnic Origin

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

• Hepatic Insufficiency

Hepatic Impairment

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 7 WARNINGS AND PRECAUTIONS and 4 DOSAGE AND ADMINISTRATION).

Hepatitis B or Hepatitis C Virus Co-infection

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 7 WARNINGS AND PRECAUTIONS, Renal and 4 DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment, Renal Impairment).

11 STORAGE, STABILITY AND DISPOSAL

Store Intelence tablets between 15–30°C. Store in the original bottle. Keep the bottle tightly closed in order to protect from moisture. Do not remove the desiccant pouches.

Keep out of the reach and sight of children.

12 SPECIAL HANDLING INSTRUCTIONS

Not Applicable.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name:

etravirine

Chemical name:

4-[[6-amino-5-bromo-2-[(4-cyanophenyl)-amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile

Molecular formula and molecular mass:

Molecular formula: C₂₀H₁₅BrN₆O

Molecular mass: 435.28

Structural formula:

Physicochemical properties:

Etravirine is a white to slightly yellowish-brown powder with a solubility in water of <0.001 g/100 mL at 20^oC.

14 CLINICAL TRIALS

14.1 Clinical Trials by Indication

Treatment-Experienced Adult Patients

Trials TMC125-C206(DUET) and TMC125-216(DUET-2)

The evidence of efficacy of INTELENCE^® (etravirine) is based on the analyses of 48-week data from 2 randomized, double-blinded, placebo-controlled, Phase III trials DUET-1 and DUET-2. These trials were identical in design, and similar efficacy for Intelence was seen in each trial. The results below are pooled data from the two trials.

Treatment-experienced HIV-1-infected adult subjects who had plasma HIV-1 RNA >5000 copies/mL and had 1 or more NNRTI resistance-associated mutations at screening or from prior genotypic analysis (i.e., archived resistance) were enrolled. These subjects also had 3 or more of the following primary PI mutations: D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50L/V, V82A/F/L/S/T, I84V, N88S, or L90M at screening, and were on a stable antiretroviral regimen for at least 8 weeks. Randomization was stratified by the intended use of enfuvirtide in the BR, previous use of darunavir/ritonavir, and screening viral load. This analysis included 612 subjects in DUET-1 and 591 subjects in DUET-2 who had completed 48 weeks of treatment or discontinued earlier.

At 48 weeks, the virologic response rate was evaluated in subjects receiving Intelence (200 mg b.i.d.) in addition to a BR versus subjects receiving placebo in addition to a BR. The BR consisted of darunavir/ritonavir 600/100 mg b.i.d. and at least 2 other investigator-selected antiretroviral drugs (N[t]RTIs with or without enfuvirtide).

45.6% of subjects in the Intelence arm and 46.9% of subjects in the placebo arm used enfuvirtide in the underlying antiretroviral therapy. 25.5% of subjects in the Intelence arm used enfuvirtide for the first time (de novo), compared with 26.5% of subjects in the placebo arm. 20.0% of subjects in the Intelence arm re-used enfuvirtide, compared with 20.4% of subjects in the placebo arm. Virologic response was defined as achieving a confirmed undetectable viral load (<50 HIV-1 RNA copies/mL).

In the pooled analysis for DUET-1 and DUET-2, demographics and baseline characteristics were balanced between the Intelence arm and the placebo arm. Table 12 describes the demographic and baseline disease characteristics of the subjects in the Intelence arm and subjects in the placebo arm.

Table 12: Demographic and Baseline Disease Characteristics of Adult Subjects in the DUET-1 and DUET-2 Trials (Pooled Analysis)

RAMs = Resistance-Associated Mutations

FC = fold change in EC₅₀

1. 1. IAS-USA primary PI mutations [August/September 2007], D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50L/V, I54L/M, L76V, V82A/F/L/S/T, I84V, N88S, L90M
2. 2. Tibotec NNRTI RAMs [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
3. 3. 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.

Study results

Table 13 below presents the efficacy results at 48 weeks for adult patients in the Intelence arm and patients in the placebo arm from the pooled DUET-1 and DUET-2 trials.

At Week 24 a statistically significant interaction (p=0.0064, Breslow-Day test) between treatment and enfuvirtide use was seen. The interaction effect was still significant at Week 48 (p=0.1279). Therefore, the primary analysis at Week 48 was performed for each enfuvirtide stratum: “Re-Used/Not Used Enfuvirtide” [patients re-using or not using enfuvirtide] and “De novo Enfuvirtide use”.

Table 13: Outcomes of Treatment at Week 48 of the DUET-1² and DUET-2² Trials (pooled analysis)

¹ Imputations according to the TLOVR algorithm

NS: p>0.05, *: p<0.0001; p-values Intelence vs. placebo

BR – background regimen consisting of DRV/rtv + minimum of 2 commercially available ARVs consisting of NRTI(s) with or without ENFUVIRTIDE.

1. 1. p-value vs. placebo from CMH test controlling for previous DRV use and baseline viral load.
2. 2. DUET 1 & 2 are ongoing 96-week clinical trials.

At Week 48, AIDS-defining illness or death occurred in 5.8% of Intelence-treated subjects and 9.8% of placebo-treated subjects.

The proportion of virologic responders (viral load <50 HIV-1 RNA copies/mL) by the Phenotypic Sensitivity Score (PSS) of the background therapy, including enfuvirtide, is shown in Table 14.

Table 14: Virologic Response (Viral Load <50 HIV-1 RNA copies/mL) at Week 48 by Phenotypic Sensitivity Score (PSS) in the Non-Viral Failure Excluded Population of TMC125-C206 and TMC125-C216 Trials (Pooled Analysis)

1. 1. In the calculation of the PSS, darunavir was counted as a sensitive antiretroviral if the FC ≤ 10; enfuvirtide was counted as a sensitive antiretroviral if it had not been used previously. Intelence was not included in this calculation.

Trial TMC125-C227

Trial TMC125-C227 was a randomized, exploratory, active-controlled, open-label, Phase IIb trial. Eligible adult subjects were treatment-experienced, PI-naïve HIV-1-infected patients 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 (n=59) or an investigator-selected PI (n=57), each given with 2 investigator-selected N(t)RTIs. Compared to the control PI-treated subjects, Intelence-treated subjects had lower antiviral responses associated with reduced susceptibility to the N(t)RTIs and to Intelence.

Treatment-Experienced Pediatric Patients

(6 years to <18 years of age)

PIANO (TMC-125-C213) is a single-arm, Phase II trial evaluating the pharmacokinetics, safety, tolerability, and efficacy of Intelence in 101 antiretroviral treatment-experienced HIV-1 infected pediatric subjects 6 years to < 18 years of age and weighing at least 16 kg (35.2 lbs). The study enrolled subjects on a stable but virologically failing antiretroviral treatment regimen, with a confirmed HIV-1 RNA plasma viral load ≥500 copies/mL. Sensitivity of the virus to Intelence at screening was required.

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

The virologic response rate was evaluated in pediatric subjects receiving Intelence in combination with other antiretroviral agents (see 4 DOSAGE AND ADMINISTRATION for dosage recommendations per body weight). Virologic response was defined as the percentage of subjects with plasma viral load <50 HIV-1 copies/mL at week 24 or Week 48 calculated according to the TLOVR imputation algorithm.

At Week 24, 51.5% of all pediatric subjects had an undetectable viral load <50 HIV-1 RNA copies/mL. The proportion of pediatric subjects with <400 HIV-1 RNA copies/mL was 65.3%. The mean change in plasma HIV-1 RNA from baseline to Week 24 was -1.51 log₁₀ copies/mL, and the mean CD4 cell count increase from baseline was 112 × 10⁶ cells/L.

At Week 48, 53.5% of all pediatric patients had a confirmed undetectable viral load <50 HIV-1 RNA copies/mL. The proportion of pediatric patients with <400 HIV-1 RNA copies/mL was 63.4%. The mean change in plasma HIV-1 RNA from baseline to Week 48 was -1.53 log₁₀ copies/mL, and the mean CD4 cell count increase from baseline was 156 × 10⁶ cells/L.

14.2 Comparative Bioavailability Studies

Pivotal Comparative Bioavailability Study

In a Phase I, open-label, randomized, 4-period crossover bioavailability trial, the relative oral bioavailability of etravirine administered as either two Intelence (etravirine) 100 mg non-coated tablets (Treatment A; F060), two etravirine 100 mg coated tablets (Treatment B; F069), one etravirine 200 mg non-coated tablet (Treatment C; F068), or one etravirine 200 mg coated tablet (Treatment D; F070) under fed conditions (21 g fat; 533 kcal) was assessed in 24 healthy male and female adult subjects

A summary of the results based on the comparison between the current marketed Intelence (etravirine)100 mg non-coated tablets (F060; Treatment A [n=24] and the proposed for marketed etravirine 200 mg non-coated tablets (F068); Treatment C [n=23]) is presented in Table 15.

Table 15: Summary Table of the Comparative Bioavailability Data Under Fed Conditions

1. 1. Due to the design of the study AUCI and T1/2 parameters could not be accurately estimated.
2. 2. Etravirine 200 mg non-coated tablets (F068) (Janssen Inc.)
3. 3. Intelence (etravirine) 100 mg non-coated tablets (F060) (Janssen Inc.)
4. 4. Expressed as the median (range) only.

15 MICROBIOLOGY

Antiviral Activity In Vitro

Etravirine exhibits activity against laboratory strains and clinical isolates of wild-type HIV-1 in acutely infected T-cell lines, human peripheral blood mononuclear cells, and human monocytes/macrophages with median EC₅₀ values ranging from 0.9 to 5.5 nM (i.e., 0.4 to 2.4 ng/mL).

Etravirine demonstrated antiviral activity in cell culture against a broad panel of HIV-1 group M isolates (subtype A, B, C, D, E, F, G) with EC₅₀ values ranging from 0.29 to 1.65 nM and EC₅₀ values ranging from 11.5 to 21.7 nM against group O primary isolates. These EC₅₀ values are well below the 50% cellular toxicity concentration range of 15 to >100 µM.

The EC₅₀ value of etravirine for HIV-1 increases by a median factor of 5.8 in the presence of human serum.

No antagonism is observed between etravirine and any of the studied antiretrovirals. Etravirine shows additive antiviral activity in combination with the PIs amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, tipranavir, and saquinavir; the N(t)RTIs zalcitabine, didanosine, stavudine, abacavir, and tenofovir; the NNRTIs efavirenz, delavirdine, and nevirapine; the fusion inhibitor enfuvirtide; the integrase inhibitor raltegravir and the CCR5 antagonist maraviroc. Etravirine shows additive to synergistic antiviral activity in combination with the NRTIs emtricitabine, lamivudine, and zidovudine.

Resistance In Vitro

Etravirine showed antiviral activity against 55 of 65 HIV-1 strains with single amino acid substitutions at RT positions associated with NNRTI resistance, including the K103N. The amino acid substitutions which led to the highest resistance to etravirine in cell culture are Y181I (13-fold change in EC₅₀ value) and Y181V (17-fold change in EC₅₀ value). The antiviral activity of etravirine in cell culture against 24 HIV-1 strains with multiple amino acid substitutions associated with resistance to N(t)RTIs and/or PIs is comparable to that observed against wild type HIV-1.

In vitro selection of etravirine-resistant strains originating from wild type HIV-1 of different origins and subtypes as well as NNRTI-resistant HIV-1 was performed at high and low virus inoculum. At high virus inoculum, emergence of resistant strains from wild type HIV-1 was delayed or prevented at concentrations of 40 nM or 200 nM. Regardless of the experimental design and the original HIV-1 strain, development of resistance against etravirine typically required multiple mutations in the RT of which the following were observed most frequently: L100I, E138K, E138G, V179I, Y181C, and M230I.

Resistance in treatment-experienced subjects

In the Phase III trials DUET-1 and DUET-2, mutations that developed most commonly in subjects with virologic failure to the Intelence-containing regimen were V179F, V179I and Y181C which usually emerged in a background of multiple other NNRTI resistance-associated mutations (RAMs). In all the trials conducted with Intelence in HIV-1 infected subjects, the following mutations emerged most commonly: L100I, E138G, V179F, V179I, Y181C and H221Y.

Cross-Resistance In Vitro

The single amino acid substitutions associated with an etravirine reduction in susceptibility >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 values) and Y181V (17-fold change in EC₅₀ value). Mutant strains containing a single NNRTI resistance associated substitution (K101P, K101Q, E138Q, or M230L) had cross-resistance between etravirine and efavirenz. The majority (39 of 61; 64%) of the NNRTI mutant viruses with 2 or 3 amino acid substitutions associated with NNRTI resistance had decreased susceptibility to etravirine (fold-change >3). The highest levels of resistance to etravirine were observed for HIV-1 harbouring a combination of substitutions V179F + Y181C (181 fold-change), V179 + Y181I (123 fold-change), or V179F + Y181C + F227C (888 fold-change). Etravirine retains an EC₅₀ value <10 nM against 83% of 6171 clinical isolates resistant to delavirdine, efavirenz and/or nevirapine. The treatment of patients with delavirdine, efavirenz or nevirapine following virologic failure of an etravirine-containing regimen is not recommended.

Baseline Genotype/Phenotype and Virologic Outcome Analyses

In DUET-1 and DUET-2, the presence at baseline of three or more of the following mutations: V90I, A98G, L100I, K101E, K101P, V106I, V179D, V179F, Y181C, Y181I, Y181V, G190A, and G190S (Intelence-RAMs) was associated with a decreased virologic response to Intelence (see Table 16). These individual mutations mainly occurred in the presence of other NNRTI RAMs. V179F was never present without Y181C.

K103N, which was the most prevalent NNRTI mutation in DUET-1 and DUET-2 at baseline, was not identified as a mutation associated with resistance to Intelence. The presence of this mutation did not affect the response in the Intelence arm.

Table 16: Proportion of Subjects with <50 HIV-1 RNA copies/mL at Week 48 by Baseline Number of TMC125 Resistance Associated Mutations (RAMs) in the non-Viral Failure excluded Population of the Pooled DUET Studies

1. 1. TMC125 RAMs = V90I, A98G, L100I, K101E/P, V106I, V179D/F, Y181C/I/V, G190A/S

Conclusions regarding the relevance of particular mutations or mutational patterns are subject to change pending additional data.

Response rates assessed by baseline etravirine phenotype are shown in Table 17. These baseline phenotype groups are based on the select subject populations in DUET-1 and DUET-2 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 17: Proportion of Subjects with <50 HIV-1 RNA copies/mL at Week 48 by Baseline Phenotype and Enfuvirtide Use in the Pooled DUET studies¹

1. 1. non-VF Excluded Population

In deciding on a new regimen for patients who have failed an antiretroviral regimen, careful consideration should be given to the treatment history and to resistance testing results where available.

16 NON-CLINICAL TOXICOLOGY

General Toxicology:

Acute Toxicity

In mice and rats, there were no relevant effects following oral or subcutaneous administration of etravirine at doses up to 1000 and 320 mg/kg, respectively. Similarly, in dogs there was no effect of etravirine treatment following oral administration at doses up to 160 mg/kg.

Chronic Toxicity

Chronic repeat dose toxicity studies were conducted in mice (3 month duration), rats (6 month duration) and dogs (12 month duration). In mice the key target organs identified were the liver and the coagulation system. Haemorrhagic cardiomyopathy was only observed in male mice and was considered to be secondary to severe coagulopathy mediated via the vitamin K pathway. This is considered not relevant to humans. In the rat, the key target organs identified were the liver, the thyroid, and the coagulation system. Exposure in mice was equivalent to human exposure while in rats it was below the clinical exposure at the recommended dose (200 mg b.i.d.).

In the dog, changes in the liver and gall bladder were seen at exposures approximately 8-fold higher than human exposure observed at the recommended dose (200 mg b.i.d.).

Carcinogenicity: Etravirine was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. A statistically significant increase in the incidences of hepatocellular adenomas and carcinomas was observed in treated female mice. Administration of etravirine did not cause a statistically significant increase in the incidence of tumors in female or male rats. The relevance of the findings in mice to humans is not known. At the highest tested doses, the systemic exposures (based on AUC) to etravirine were lower than those in humans at the clinical therapeutic dose (200 mg b.i.d.) with animal versus human AUC ratios being 0.6 (mice) and between 0.2 and 0.7 (rats).

Genotoxicity: In a range of mutagenicity studies, etravirine tested negative in the in vitro Ames reverse mutation assay, in vitro chromosomal aberration assay in human lymphocytes, and in vitro clastogenicity mouse lymphoma assay, in the absence and presence of a metabolic activation system. Etravirine did not induce chromosomal damage in the in vivo micronucleus test in mice.

Reproductive and Developmental Toxicology: In a study conducted in rats, there were no effects on mating or fertility with etravirine treatment up to 500 mg/kg/day and exposure levels equivalent to those in humans at the clinically recommended dose.

There was no teratogenicity with etravirine in rats (1000 mg/kg) and rabbits (375 mg/kg) at exposures equivalent to those observed in humans at the recommended clinical dose. In a pre- and postnatal development assessment in rats, etravirine had no effect on offspring development during lactation or post-weaning when the mother was dosed up to 500 mg/kg and at exposures equivalent to those observed at the recommended clinical dose.

Local Tolerance: Etravirine was classified as “nonsensitizing” based on an in vivo guinea pig skin sensitization study and was also found to be unlikely to cause skin sensitization in a mouse local lymph node assay. Etravirine was also classified as “nonirritant” based on an in vivo rabbit skin irritation study. In an in vitro eye irritation assay, etravirine was considered as a “mild” eye irritant. No effects were observed in an in vitro phototoxicity study.

Immunotoxicity: Immunotoxicity has been evaluated in rats. Etravirine was administered at a dose of 600 mg/kg/day for 4 weeks and effects on lymphoid organs (lymph nodes, spleen and thymus) were evaluated. There were no relevant effects of treatment with etravirine, and the immune response, as measured by IgM production, was not affected by treatment.