Tablet White to off-white, oval, scored tablet, debossed with "TMC" on one side. The tablet can be divided into equal doses.

CLINICAL PARTICULARS

Posology and method of administration

Therapy should be initiated by a physician experienced in the management of HIV infection. INTELENCE must always be given in combination with other antiretroviral medicinal products.

The recommended dose of INTELENCE for adults is 200 mg (two 100 mg tablets) taken orally twice daily (b.i.d. ), following a meal (see section 5.2).

The recommended dose of INTELENCE for paediatric patients (6 years to less than 18 years of age and weighing at least 16 kg) is based on body weight (see table below). INTELENCE tablet(s) should be taken orally, following a meal (see section 5.2).

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

There is limited information regarding the use of INTELENCE in patients > 65 years of age (see section 5.2), therefore caution should be used in this population.

No dose adjustment is suggested in patients with mild or moderate hepatic impairment (Child-Pugh Class A or B); INTELENCE should be used with caution in patients with moderate hepatic impairment. The pharmacokinetics of etravirine have not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Therefore, INTELENCE is not recommended in patients with severe hepatic impairment (see sections 4.4 and 5.2).

No dose adjustment is required in patients with renal impairment (see section 5.2).

The safety and efficacy of INTELENCE in children less than 6 years of age or weighing less than 16 kg have not yet been established (see section 5.2). No data are available. Method of administration Oral use. Patients should be instructed to swallow the tablet(s) whole with a liquid such as water. Patients who are unable to swallow the tablet(s) whole may disperse the tablet(s) in a glass of water. For instructions on dispersion of the medicinal product before administration, see section 6.6.

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Special warnings and precautions for use

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines. INTELENCE should optimally be combined with other antiretrovirals that exhibit activity against the patient's virus (see section 5.1). A decreased virologic response to etravirine was observed in patients with viral strains harbouring 3 or more among the following mutations V90I, A98G, L100I, K101E/P, V106I, V179D/F, Y181C/I/V, and G190A/S (see section 5.1). Conclusions regarding the relevance of particular mutations or mutational patterns are subject to change with additional data, and it is recommended to always consult current interpretation systems for analysing resistance test results. No data other than drug-drug interaction data (see section 4.5) are available when etravirine is combined with raltegravir or maraviroc.

Severe cutaneous adverse drug reactions have been reported with INTELENCE; Stevens-Johnson Syndrome and erythema multiforme have been rarely (< 0.1%) reported. Treatment with INTELENCE should be discontinued if a severe cutaneous reaction develops. The clinical data are limited and an increased risk of cutaneous reactions in patients with a history of NNRTI-associated cutaneous reactions cannot be excluded. Caution should be observed in such patients, especially in case of history of a severe cutaneous drug reaction. Cases of severe hypersensitivity syndromes, including DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) and TEN (toxic epidermal necrolysis), sometimes fatal, have been reported with the use of INTELENCE (see section 4.8). The DRESS syndrome is characterised by rash, fever, eosinophilia and systemic involvement (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and eosinophilia). Time to onset is usually around 3-6 weeks and the outcome in most cases is favourable upon discontinuation and after initiation of corticosteroid therapy. Patients should be informed to seek medical advice if severe rash or hypersensitivity reactions occur. Patients who are diagnosed with a hypersensitivity reaction whilst on therapy must discontinue INTELENCE immediately. Delay in stopping INTELENCE treatment after the onset of severe rash may result in a life-threatening reaction. Patients who have stopped treatment due to hypersensitivity reactions should not restart therapy with INTELENCE.

Rash has been reported with INTELENCE. 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. When prescribing INTELENCE to females, prescribers should be aware that the incidence of rash was higher in females (see section 4.8).

Experience in geriatric patients is limited: in the Phase III trials, 6 patients aged 65 years or older and 53 patients aged 56-64 years received INTELENCE. The type and incidence of adverse reactions in patients > 55 years of age were similar to the ones in younger patients (see sections 4.2 and 5.2).

Etravirine is primarily metabolised and eliminated by the liver and highly bound to plasma proteins. Effects on unbound exposure could be expected (has not been studied) and therefore caution is advised in patients with moderate hepatic impairment. INTELENCE has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) and its use is therefore not recommended in this group of patients (see sections 4.2 and 5.2).

Caution should be exercised in patients co-infected with hepatitis B or C virus due to the current limited data available. A potential increased risk of liver enzymes increase cannot be excluded.

Combination antiretroviral therapy (CART) has been associated with redistribution of body fat (lipodystrophy) in HIV infected patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and protease inhibitors (PIs), and lipoatrophy and nucleoside reverse transcriptase inhibitors (NRTIs), has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with treatment related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution (see section 4.8).

In HIV infected patients with severe immune deficiency at the time of initiation of CART, an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and Pneumocystis jiroveci pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary. Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.8).

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV disease and/or long-term exposure to CART. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

It is not recommended to combine etravirine with tipranavir/ritonavir, due to a marked pharmacokinetic interaction (76% decrease of etravirine AUC) that could significantly impair the virologic response to etravirine. For further information on interactions with medicinal products see section 4.5.

Each tablet contains 40 mg of lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Interaction with other medicinal products and other forms of interaction

Etravirine is metabolised by CYP3A4, CYP2C9 and CYP2C19 followed by glucuronidation of the metabolites by uridine diphosphate glucuronosyl transferase (UDPGT). Medicinal products that induce CYP3A4, CYP2C9 or CYP2C19 may increase the clearance of etravirine, resulting in lowered plasma concentrations of etravirine. Co-administration of INTELENCE and medicinal products that inhibit CYP3A4, CYP2C9 or CYP2C19 may decrease the clearance of etravirine and may result in increased plasma concentrations of etravirine.

Etravirine is a weak inducer of CYP3A4. Co-administration of INTELENCE with medicinal products primarily metabolised by CYP3A4 may result in decreased plasma concentrations of such medicinal products, which could decrease or shorten their therapeutic effects. Etravirine is a weak inhibitor of CYP2C9 and CYP2C19. Etravirine is also a weak inhibitor of P-glycoprotein. Co-administration with medicinal products primarily metabolised by CYP2C9 or CYP2C19, or transported by P-glycoprotein, may result in increased plasma concentrations of such medicinal products, which could increase or prolong their therapeutic effect or alter their adverse events profile. Known and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal products are listed in table 1.

Interactions between etravirine and co-administered medicinal products are listed in table 1 (increase is indicated as "|", decrease as "|", no change as "-", not done as "ND", confidence interval as "CI").

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

Fertility, pregnancy and lactation

As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women, and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data as well as the clinical experience in pregnant women should be taken into account in order to characterise the safety for the foetus. Placental transfer has been seen in pregnant rats, but it is not known whether placental transfer of INTELENCE also occurs in pregnant women. Studies in animals do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Based on animal data the malformative risk is unlikely in humans. The clinical data do not raise safety concern but are very limited.

It is not known whether etravirine is excreted in human milk. As a general rule, it is recommended that mothers infected by HIV do not breast-feed their babies under any circumstances in order to avoid transmission of HIV.

No human data on the effect of etravirine on fertility are available. In rats, there was no effect on mating or fertility with etravirine treatment (see section 5.3).

Effects on ability to drive and use machines

INTELENCE has no or negligible influence on the ability to drive and use machines. Adverse drug reactions such as somnolence and vertigo have been reported in INTELENCE treated subjects at incidences similar to placebo (see section 4.8). There is no evidence that INTELENCE may alter the patient's ability to drive and operate machines, however, the adverse drug reaction profile should be taken into account.

Undesirable effects

Summary of the safety profile

The safety assessment is based on all data from 1,203 patients in the Phase III placebo-controlled trials DUET-1 and DUET-2 in antiretroviral treatment-experienced HIV-1 infected adult patients, 599 of whom received INTELENCE (200 mg b.i.d.) (see section 5.1). In these pooled trials, the median exposure for patients in the INTELENCE arm was 52.3 weeks. The most frequently reported adverse drug reactions (ADRs) (incidence >= 10% in the INTELENCE arm) of all intensities occurring in the Phase III studies were rash (19.2% in the INTELENCE arm versus 10.9% in the placebo arm), diarrhoea (18.0% in the INTELENCE arm versus 23.5% in the placebo arm), nausea (14.9% in the INTELENCE arm versus 12.7% in the placebo arm) and headache (10.9% in the INTELENCE arm versus 12.7% in the placebo arm). The rates of discontinuation due to any adverse reaction were 7.2% in patients receiving INTELENCE and 5.6% in patients receiving placebo. The most common ADR leading to discontinuation was rash (2.2% in the INTELENCE arm versus 0% in the placebo arm). Rash was most frequently mild to moderate, generally macular to maculopapular or erythematous, mostly occurred in the second week of therapy, and was infrequent after week 4. Rash was mostly self-limiting, and generally resolved within 1-2 weeks on continued therapy (see section 4.4). The incidence of rash was higher in women compared to men in the INTELENCE arm in the DUET trials (rash >= grade 2 was reported in 9/60 [15.0%] women versus 51/539 [9.5%] men; discontinuations due to rash were reported in 3/60 [5.0%] women versus 10/539 [1.9%] men) (see section 4.4). There was no gender difference in severity or treatment discontinuation due to rash. The clinical data are limited and an increased risk of cutaneous reactions in patients with a history of NNRTI-associated cutaneous reaction cannot be excluded (see section 4.4).

Tabulated list of adverse reactions

ADRs of moderate intensity or greater (>= grade 2) reported in patients treated with INTELENCE are summarised in table 2 (background regimen is indicated as "BR"). Laboratory abnormalities considered ADRs are included in a paragraph below table 2. The ADRs are listed by system organ class (SOC) and frequency. Within each frequency grouping, ADRs are presented in order of decreasing seriousness. Frequencies are defined as very common (>= 1/10), common (>= 1/100 to < 1/10) and uncommon (>= 1/1,000 to < 1/100). Rare and very rare ADRs cannot be detected based on the number of patients included in the DUET trials.

Table 2: DUET-1 and DUET-2 trials
System Organ Class (SOC)	Frequency Category	ADRs (INTELENCE + BR versus Placebo + BR)
Blood and lymphatic system disorders	common	thrombocytopaenia (1.3% vs 1.5%), anaemia (4.0% vs 3.8%)
Immune system disorders	uncommon	immune reconstitution syndrome (0.2% vs 0.3%), drug hypersensitivity (0.8% vs 1.2%)
Metabolism and nutrition disorders	common	diabetes mellitus (1.3% vs 0.2%), hyperglycaemia (1.5% vs 0.7%), hypercholesterolaemia (4.3% vs 3.6%), hypertriglyceridaemia (6.3% vs 4.3%), hyperlipidaemia (2.5% vs 1.3%)
Metabolism and nutrition disorders	uncommon	anorexia (0.8% vs 1.5%), dyslipidaemia (0.8% vs 0.3%)
Psychiatric disorders	common	anxiety (1.7% vs 2.6%), insomnia (2.7% vs 2.8%)
Psychiatric disorders	uncommon	confusional state (0.2% vs 0.2%), disorientation (0.2% vs 0.3%), nightmares (0.2% vs 0.2%), sleep disorders (0.5% vs 0.5%), nervousness (0.2% vs 0.3%), abnormal dreams (0.2% vs 0.2%)
Nervous system disorders	common	peripheral neuropathy (3.8% vs 2.0%), headache (3.0% vs 4.5%)
Nervous system disorders	uncommon	convulsion (0.5% vs 0.7%), syncope (0.3% vs 0.3%), amnesia (0.3% vs 0.5%), tremor (0.2% vs 0.3%), somnolence (0.7% vs 0.5%), paraesthesia (0.7% vs 0.7%), hypoaesthesia (0.5% vs 0.2%), hypersomnia (0.2% vs 0%), disturbance in attention (0.2% vs 0.2%)
Eye disorders	uncommon	blurred vision (0.7% vs 0%)
Ear and labyrinth disorders	uncommon	vertigo (0.2% vs 0.5%)
Cardiac disorders	common	myocardial infarction (1.3% vs 0.3%)
Cardiac disorders	uncommon	atrial fibrillation (0.2% vs 0.2%), angina pectoris (0.5% vs 0.3%)
Vascular disorders	common	hypertension (3.2% vs 2.5%)
Respiratory, thoracic and mediastinal disorders	uncommon	bronchospasm (0.2% vs 0%), exertional dyspnoea (0.5% vs 0.5%)
Gastrointestinal disorders	common	gastrooesophageal reflux disease (1.8% vs 1.0%), diarrhoea (7.0% vs 11.3%), vomiting (2.8% vs 2.8%), nausea (5.2% vs 4.8%), abdominal pain (3.5% vs 3.1%), flatulence (1.5% vs 1.0%), gastritis (1.5% vs 1.0%)
Gastrointestinal disorders	uncommon	pancreatitis (0.7% vs 0.3%), haematemesis (0.2% vs 0%), stomatitis (0.2% vs 0.2%), constipation (0.3% vs 0.5%), abdominal distension (0.7% vs 1.0%), dry mouth (0.3% vs 0%), retching (0.2% vs 0%)
Hepatobiliary disorders	uncommon	hepatitis (0.2% vs 0.3%), hepatic steatosis (0.3% vs 0%), cytolytic hepatitis (0.3% vs 0%), hepatomegaly (0.5% vs 0.2%)
Skin and subcutaneous tissue disorders	very common	rash (10.0% vs 3.5%)
	common	lipohypertrophy (1.0% vs 0.3%), night sweats (1.0% vs 1.0%)
	uncommon	swelling face (0.3% vs 0%), hyperhidrosis (0.5% vs 0.2%), prurigo (0.7% vs 0.5%), dry skin (0.3% vs 0.2%)
Renal and urinary disorders	common	renal failure (2.7% vs 2.0%)
Reproductive system and breast disorders	uncommon	gynaecomastia (0.2% vs 0%)
General disorders and administration site conditions	common	fatigue (3.5% vs 4.6%)
General disorders and administration site conditions	uncommon	sluggishness (0.2% vs 0%)

Additional ADRs of at least moderate intensity observed in other trials were acquired lipodystrophy, angioneurotic oedema, erythema multiforme and haemorrhagic stroke, each reported in no more than 0.5% of patients. Stevens-Johnson Syndrome (rare; < 0.1%) and toxic epidermal necrolysis (very rare; < 0.01%) have been reported during clinical development with INTELENCE.

Laboratory abnormalities

Treatment emergent clinical laboratory abnormalities (grade 3 or 4), considered ADRs, reported in >= 2% of patients in the INTELENCE arm versus the placebo arm, respectively, were increases in amylase (8.9% vs 9.4%), creatinine (2.0% vs 1.7%), lipase (3.4% vs 2.6%), total cholesterol (8.1% vs 5.3%), low density lipoprotein (LDL) (7.2% vs 6.6%), triglycerides (9.2% vs 5.8%), glucose (3.5% vs 2.4%), alanine aminotransferase (ALT) (3.7% vs 2.0%), aspartate amino transferase (AST) (3.2% vs 2.0%) and decreases in neutrophils (5.0% vs 7.4%) and white blood cell count (2.0% vs 4.3%).

Description of selected adverse reactions

Lipodystrophy

Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV infected patients, including loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump) (see section 4.4).

Immune reconstitution syndrome

In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4).

Osteonecrosis

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy. The frequency of this is unknown (see section 4.4).

Paediatric population (6 years to less than 18 years of age)

The safety assessment in children and adolescents is based on the week 48 analysis of the single-arm, Phase II PIANO trial in which 101 antiretroviral treatment-experienced HIV-1 infected paediatric patients, 6 years to less than 18 years of age and weighing at least 16 kg, received INTELENCE in combination with other antiretroviral agents (see section 5.1). The frequency, type and severity of adverse drug reactions in paediatric patients were comparable to those observed in adults. 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) (see section 4.4). Most often, rash was mild to moderate, of macular/papular type, and occurred in the second week of therapy. Rash was mostly self-limiting and generally resolved within 1 week on continued therapy.

Other special populations

Patients co-infected with hepatitis B and/or hepatitis C virus

In the pooled analysis for DUET-1 and DUET-2, the incidence of hepatic events tended to be higher in co-infected subjects treated with INTELENCE compared to co-infected subjects in the placebo group. INTELENCE should be used with caution in these patients (see also sections 4.4 and 5.2).

Adverse drug reactions identified through post marketing experience with INTELENCE

Hypersensitivity reactions, including DRESS, have been reported with INTELENCE. These hypersensitivity reactions were characterised by rash, fever and sometimes organ involvement (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and eosinophilia) (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via

the national reporting system

listed in Appendix V.

Overdose

There are no data with regard to symptomatic overdose with INTELENCE, but it is possible that the most frequent ADRs of INTELENCE, i.e. rash, diarrhoea, nausea, and headache would be the most common symptoms noted. 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. If indicated, elimination of unabsorbed active substance is to be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed active substance. Since etravirine is highly protein bound, dialysis is unlikely to result in significant removal of the active substance.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use, non-nucleoside reverse transcriptase inhibitors, ATC code: J05AG04.

Etravirine is an 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 exhibits activity against wild type HIV-1 in T-cell lines and primary cells with median EC50 values ranging from 0.9 to 5.5 nM. Etravirine demonstrates activity against HIV-1 group M (subtypes A, B, C, D, E, F, and G) and HIV-1 group O primary isolates with EC50 values ranging from

activity against wild type HIV-2 with median EC50 values ranging from 5.7 to 7.2 uM, treatment of HIV-2 infection with etravirine is not recommended in the absence of clinical data. Etravirine retains activity against HIV-1 viral strains resistant to nucleoside reverse transcriptase and/or protease inhibitors. In addition, etravirine demonstrates a fold change (FC) in EC50 <= 3 against 60% of 6,171 NNRTI-resistant clinical isolates.

Etravirine efficacy in relation to NNRTI resistance at baseline has mainly been analysed with etravirine given in combination with darunavir/ritonavir (DUET-1 and DUET-2). Boosted protease inhibitors, like darunavir/ritonavir, show a higher barrier to resistance compared to other classes of antiretrovirals. The breakpoints for reduced efficacy with etravirine (> 2 etravirine-associated mutations at baseline, see clinical results section) applies when etravirine is given in combination with a boosted protease inhibitor. This breakpoint might be lower in antiretroviral combination therapy not including a boosted protease inhibitor. In the Phase III trials DUET-1 and DUET-2, mutations that developed most commonly in patients with virologic failure to the INTELENCE containing regimen were V108I, V179F, V179I, Y181C and Y181I, which usually emerged in a background of multiple other NNRTI resistance-associated mutations (RAMs). In all the other trials conducted with INTELENCE in HIV-1 infected patients, the following mutations emerged most commonly: L100I, E138G, V179F, V179I, Y181C and H221Y.

Following virologic failure of an etravirine-containing regimen it is not recommended to treat patients with efavirenz and/or nevirapine.

Clinical efficacy and safety Treatment-experienced adult patients Pivotal studies The evidence of efficacy of INTELENCE is based on 48-week data from 2 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. Trial characteristics Design: randomised (1:1), double-blinded, placebo-controlled. Treatment: INTELENCE vs. placebo, in addition to a background regimen including darunavir/ritonavir (DRV/rtv), investigator-selected N(t)RTIs and optional enfuvirtide (ENF). Main inclusion criteria:

Stratification: Randomisation was stratified by the intended use of ENF in the BR, previous use of darunavir and screening viral load. Virologic response was defined as achieving a confirmed undetectable viral load (< 50 HIV-1 RNA copies/ml). Summary of efficacy results

Table 3: DUET-1 and DUET-2 pooled 48-week data

P-value < 0.0001 for mean decrease in HIV-1 RNA; P-value = 0.0006 for mean change in CD4 cell count.

Confidence interval around observed difference of response rates; P-value < 0.0001 from logistic regression model, including stratification factors.

Confidence interval around observed difference of response rates; P-value = 0.0408.

Confidence interval around observed difference of response rates; P-value from CMH test controlling for stratification factors = 0.0199 for de novo, and < 0.0001 for not de novo.

Since there was a significant interaction effect between treatment and ENF, the primary analysis was done for 2 ENF strata (patients reusing or not using ENF versus patients using ENF de novo). The week 48 results from the pooled analysis of DUET-1 and DUET-2 demonstrated that the INTELENCE arm was superior to the placebo arm irrespective of whether ENF was used de novo (p = 0.0199) or not (p < 0.0001). Results of this analysis (week 48 data) by ENF stratum are shown in table 3. Significantly fewer patients in the INTELENCE arm reached a clinical endpoint (AIDS-defining illness and/or death) as compared to the placebo arm (p = 0.0408). A subgroup analysis of the virologic response (defined as a viral load < 50 HIV-1 RNA copies/ml) at week 48 by baseline viral load and baseline CD4 count (pooled DUET data) is presented in table 4.

Note: Imputations according to the TLOVR algorithm (TLOVR = Time to Loss of Virologic Response)

In DUET-1 and DUET-2, the presence at baseline of 3 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 5). These individual mutations occurred in the presence of other NNRTI RAMs. V179F was never present without Y181C. Conclusions regarding the relevance of particular mutations or mutational patterns are subject to change with additional data, and it is recommended to always consult current interpretation systems for analysing resistance test results.

Note: all patients in the DUET trials received a background regimen consisting of darunavir/rtv, investigator-selected NRTIs and optional enfuvirtide.

The presence of K103N alone, 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. Furthermore, the presence of this mutation alone did not affect the response in the INTELENCE arm. Additional data is required to conclude on the influence of K103N when associated with other NNRTIs mutations. Data from the DUET studies suggest that baseline fold change (FC) in EC50 to etravirine was a predictive factor of virologic outcome, with gradually decreasing responses observed above FC 3 and FC 13. FC subgroups are based on the select patient populations in DUET-1 and DUET-2 and are not meant to represent definitive clinical susceptibility breakpoints for INTELENCE.

Exploratory head to head comparison with protease inhibitor in protease inhibitor naive patients (trial TMC125-C227)

TMC125-C227 was an exploratory, randomised, active-controlled open-label trial, which investigated the efficacy and safety of INTELENCE in a treatment regimen, which is not approved under the current indication. In the TMC125-C227 study, INTELENCE (N = 59) was administered with 2 investigator-selected NRTIs (i.e. without a ritonavir-boosted PI) and compared to an investigator-selected combination of a PI with 2 NRTIs (N = 57). The trial population included PI-naive, NNRTI-experienced patients with evidence of NNRTI resistance. At week 12, virologic response was greater in the control-PI arm (-2.2 log10 copies/ml from baseline; n = 53) compared to the INTELENCE arm (-1.4 log10 copies/ml from baseline; n = 40). This difference between treatment arms was statistically significant. Based on these trial results, INTELENCE is not recommended for use in combination with N(t)RTIs only in patients who have experienced virological failure on an NNRTI- and N(t)RTI-containing regimen.

Treatment-experienced paediatric patients (6 years to less than 18 years of age)

PIANO is a single-arm, Phase II trial evaluating the pharmacokinetics, safety, tolerability, and efficacy of INTELENCE in 101 antiretroviral treatment-experienced HIV-1 infected paediatric patients 6 years to less than 18 years of age and weighing at least 16 kg. The study enrolled patients 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 x 106 cells/l.

At week 48, 53.5% of all paediatric patients had a confirmed undetectable viral load < 50 HIV-1 RNA copies/ml according to the TLOVR algorithm. The proportion of paediatric 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 x 106 cells/l. The European Medicines Agency has deferred the obligation to submit the results of studies with INTELENCE in one or more subsets of the paediatric population in human immunodeficiency virus infection, as per Paediatric Investigation Plan (PIP) decision in the granted indication (see section 4.2 for information on paediatric use).

Pharmacokinetic properties

The pharmacokinetic properties of etravirine have been evaluated in adult healthy subjects and in adult and paediatric treatment-experienced HIV-1 infected patients. Exposure to etravirine was lower (35-50%) in HIV-1 infected patients than in healthy subjects.

All HIV-1 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 shown in the table account for

reductions in the pharmacokinetic parameters of etravirine due to co-administration of INTELENCE with

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

An intravenous formulation of etravirine is unavailable, thus, the absolute bioavailability of etravirine 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, medicinal products that are known to increase gastric pH.

The systemic exposure (AUC) to etravirine was decreased by about 50% when INTELENCE was administered under fasting conditions, as compared to administration following a meal. Therefore, INTELENCE should be taken following a meal.

Etravirine is approximately 99.9% bound to plasma proteins, primarily to albumin (99.6%) and a1-acid glycoprotein (97.66%-99.02%) in vitro. The distribution of etravirine into compartments other than plasma (e.g., cerebrospinal fluid, genital tract secretions) has not been evaluated in humans.

experiments with human liver microsomes (HLMs) indicate that etravirine primarily undergoes oxidative metabolism by the hepatic cytochrome CYP450 (CYP3A) system and, to a lesser extent, by the CYP2C family, followed by glucuronidation.

After administration of a radiolabeled 14C-etravirine dose, 93.7% and 1.2% of the administered dose of

C-etravirine could be retrieved in faeces and urine, respectively. Unchanged etravirine accounted for 81.2% to 86.4% of the administered dose in faeces. Unchanged etravirine in faeces is likely to be

unabsorbed drug. Unchanged etravirine was not detected in urine. The terminal elimination half-life of etravirine was approximately 30-40 hours.

The pharmacokinetics of etravirine in 101 treatment-experienced HIV-1 infected paediatric patients, 6 years to less than 18 years of age and weighing at least 16 kg, showed that the administered weight-based dosages resulted in etravirine exposure comparable to that in adults receiving INTELENCE 200 mg b.i.d. (see sections 4.2 and 5.2) when administered at a dose corresponding to 5.2 mg/kg b.i.d. The population pharmacokinetic estimates for etravirine AUC12h and C0h are summarised in the table below.

The pharmacokinetics of etravirine in paediatric patients less than 6 years of age are under investigation. There are insufficient data at this time to recommend a dose in paediatric patients less than 6 years of age or weighing less than 16 kg (see section 4.2).

Population pharmacokinetic analysis in HIV infected patients showed that etravirine pharmacokinetics are not considerably different in the age range (18 to 77 years) evaluated, with 6 subjects aged 65 years or older (see sections 4.2 and 4.4).

No significant pharmacokinetic differences have been observed between males and females. A limited number of females were included in the studies.

Population pharmacokinetic analysis of etravirine in HIV infected patients indicated no apparent difference in the exposure to etravirine between Caucasian, Hispanic and Black subjects. The pharmacokinetics in other races have not been sufficiently evaluated.

Etravirine is primarily metabolised and eliminated by the liver. In a study comparing 8 patients with mild (Child-Pugh Class A) hepatic impairment to 8 matched controls and 8 patients with moderate (Child-Pugh Class B) hepatic impairment to 8 matched controls, the multiple dose pharmacokinetic disposition of etravirine was not altered in patients with mild to moderate hepatic impairment. However, unbound concentrations have not been assessed. Increased unbound exposure could be expected. No dose adjustment is suggested but caution is adviced in patients with moderate hepatic impairment. INTELENCE has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) and is therefore not recommended (see sections 4.2 and 4.4).

Population pharmacokinetic analysis of the DUET-1 and DUET-2 trials showed reduced clearance (potentially leading to increased exposure and alteration of the safety profile) for INTELENCE in HIV-1 infected patients with hepatitis B and/or hepatitis C virus co-infection. In view of the limited data available in hepatitis B and/or C co-infected patients, particular caution should be paid when INTELENCE is used in these patients (see sections 4.4 and 4.8).

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 haemodialysis or peritoneal dialysis (see section 4.2).

Preclinical safety data

Animal toxicology studies have been conducted with etravirine in mice, rats, rabbits and dogs. 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. 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. In the dog, changes were observed in the liver and gall bladder at exposures approximately 8-fold higher than human exposure observed at the recommended dose (200 mg b.i.d. ). In a study conducted in rats, there were no effects on mating or fertility at exposure levels equivalent to those in humans at the clinically recommended dose. There was no teratogenicity with etravirine in rats and rabbits at exposures equivalent to those observed in humans at the recommended clinical dose. Etravirine had no effect on offspring development during lactation or post weaning at maternal exposures equivalent to those observed at the recommended clinical dose. Etravirine was not carcinogenic in rats and in male mice. An increase in the incidences of hepatocellular adenomas and carcinomas were observed in female mice. The observed hepatocellular findings in female mice are generally considered to be rodent specific, associated with liver enzyme induction, and of limited relevance to humans. At the highest tested doses, the systemic exposures (based on AUC) to etravirine were 0.6-fold (mice) and between 0.2- and 0.7-fold (rats), relative to those observed in humans at the recommended therapeutic dose (200 mg b.i.d. ).

In vitro and in vivo studies with etravirine revealed no evidence of a mutagenic potential.

PHARMACEUTICAL PARTICULARS

List of excipients

Hypromellose Microcrystalline cellulose Colloidal anhydrous silica Croscarmellose sodium Magnesium stearate Lactose monohydrate

Incompatibilities

Shelf life

Special precautions for storage

Store in the original bottle. Keep the bottle tightly closed in order to protect from moisture. Do not remove the desiccant pouches.

Nature and contents of container

The bottle is a high-density polyethylene (HDPE) plastic bottle containing 120 tablets and 2 desiccant pouches, fitted with a polypropylene (PP) child resistant closure. Each carton contains one bottle.

Special precautions for disposal and other handling

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

The use of warm (> 40degC) or carbonated beverages should be avoided. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

MARKETING AUTHORISATION HOLDER

MARKETING AUTHORISATION NUMBER(S)

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 28 August 2008 Date of latest renewal: 28 August 2013

DATE OF REVISION OF THE TEXT

Detailed information on this medicine is available on the website of the European Medicines Agency http://www.ema.europa.eu/.

Recommended dose of INTELENCE for paediatric patients 6 years to less than 18 years of age
Weight	Dose	Tablets
>= 16 to < 20 kg	100 mg b.i.d.	four 25 mg tablets twice daily or one 100 mg tablet twice daily
>= 20 to < 25 kg	125 mg b.i.d.	five 25 mg tablets twice daily or one 100 mg tablet and one 25 mg tablet twice daily
>= 25 to < 30 kg	150 mg b.i.d.	six 25 mg tablets twice daily or one 100 mg tablet and two 25 mg tablets twice daily
>= 30 kg	200 mg b.i.d.	eight 25 mg tablets twice daily or two 100 mg tablets twice daily or one 200 mg tablet twice daily

	INTELENCE + BR N = 599	Placebo + BR N = 604	Treatment difference (95% CI)
Baseline characteristics
Median plasma HIV-1 RNA	4.8 log 10 copies/ml	4.8 log 10 copies/ml
Median CD4 cell count	99 x 10 6 cells/l	109 x 10 6 cells/l
Outcomes
Confirmed undetectable viral	363 (60.6%)	240 (39.7%)	20.9% (15.3%; 26.4%) d
load (< 50 HIV-1 RNA
copies/ml) a
n (%)
Overall
De novo ENF	109 (71.2%)	93 (58.5%)	12.8% (2.3%; 23.2%) f
Not de novo ENF	254 (57.0%)	147 (33.0%)	23.9% (17.6%; 30.3%) f
< 400 HIV-1 RNA copies/ml a n (%)	428 (71.5%)	286 (47.4%)	24.1% (18.7%; 29.5%) d
HIV-1 RNA log 10 mean change from baseline (log 10 copies/ml) b	-2.25	-1.49	-0.6 (-0.8; -0.5) c
CD4 cell count mean change from baseline (x 10 6 /l) b	+98.2	+72.9	24.4 (10.4; 38.5) c
Any AIDS defining illness and/or death n (%)	35 (5.8%)	59 (9.8%)	-3.9% (-6.9%; -0.9%) e

Table 4: DUET-1 and DUET-2 pooled data
Subgroups	Proportion of subjects with HIV-1 RNA < 50 copies/ml at week 48
Subgroups	INTELENCE + BR N = 599	Placebo + BR N = 604
Baseline HIV-1 RNA	75.8%	55.7%
< 30,000 copies/ml	75.8%	55.7%
>= 30,000 and < 100,000 copies/ml	61.2%	38.5%
>= 100,000 copies/ml	49.1%	28.1%
Baseline CD4 count (x 10 6 /l)	45.1%	21.5%
< 50	45.1%	21.5%
>= 50 and < 200	65.4%	47.6%
>= 200 and < 350	73.9%	52.0%
>= 350	72.4%	50.8%

Table 5: Proportion of subjects with < 50 HIV-1 RNA copies/ml at week 48 by baseline number of INTELENCE RAMs in the non-viral failure excluded population of pooled DUET-1 and DUET-2 trials
Baseline number of INTELENCE RAMs *	Etravirine arms N = 549
	Reused/not used ENF	De novo ENF
All ranges	63.3% (254/401)	78.4% (109/139)
0	74.1% (117/158)	91.3% (42/46)
1	61.3% (73/119)	80.4% (41/51)
2	64.1% (41/64)	66.7% (18/27)
>= 3	38.3% (23/60)	53.3% (8/15)
	Placebo arms N = 569
All ranges	37.1% (147/396)	64.1% (93/145)

Table 6: Virologic responses (ITT - TLOVR), change from baseline in log 10 viral load (NC = F), and change from baseline in CD4 percentage and cell count (NC = F) at week 24 in the TMC125-C213 and pooled DUET studies
Study Age at screening Treatment group	TMC125-C213 6 to < 12 years ETR N = 41	TMC125-C213 12 to < 18 years ETR N = 60	TMC125-C213 6 to < 18 years ETR N = 101	Pooled DUET Studies >= 18 years ETR N = 599
Virologic parameters
Viral load < 50 copies/ml at week 24, n (%)	24 (58.5)	28 (46.7)	52 (51.5)	363 (60.6)
Viral load < 400 copies/ml at week 24, n (%)	28 (68.3)	38 (63.3)	66 (65.3)	445 (74.3)
>= 1 log 10 decrease from baseline at week 24, n (%)	26 (63.4)	38 (63.3)	64 (63.4)	475 (79.3)
Change from baseline in log 10 viral load (copies/ml) at week 24, mean (SE) and median (range)	-1.62 (0.21) -1.68 (-4.3; 0.9)	-1.44 (0.17) -1.68 (-4.0; 0.7)	-1.51 (0.13) -1.68 (-4.3; 0.9)	-2.37 (0.05) -2.78 (-4.6; 1.4)
Immunologic parameters
Change from baseline in CD4 cell count (x 106 cells/l), mean (SE) and median (range)	125 (33.0) 124 (-410; 718)	104 (17.5) 81 (-243; 472)	112 (16.9) 108 (-410; 718)	83.5 (3.64) 77.5 (-331; 517)
Change from baseline in CD4 percentage, median (range)	4% (-9; 20)	3% (-4; 14)	4% (-9; 20)	3% (-7; 23)
N = number of subjects with data; n = number of observations.

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

NAME OF THE MEDICINAL PRODUCT

QUALITATIVE AND QUANTITATIVE COMPOSITION

PHARMACEUTICAL FORM