INTELENCE 100mg tablets medication leaflet

INTELENCE 25 mg tablets

INTELENCE 100 mg tablets

INTELENCE 200 mg tablets

INTELENCE 25 mg tablets

Each tablet contains 25 mg of etravirine.

Each tablet contains 40 mg lactose (as monohydrate).

Each tablet contains less than 1 mmol sodium (23 mg), and is essentially sodium-free.

INTELENCE 100 mg tablets

Each tablet contains 100 mg of etravirine.

Each tablet contains 160 mg lactose (as monohydrate).

Each tablet contains less than 1 mmol sodium (23 mg), and is essentially sodium-free.

INTELENCE 200 mg tablets

Each tablet contains 200 mg of etravirine.

Each tablet contains less than 1 mmol sodium (23 mg), and is essentially sodium-free.

For the full list of excipients, see section 6.1.

INTELENCE 25 mg tablets

Tablet

White to off-white, oval, scored tablet, debossed with “TMC” on one side.

The tablet can be divided into two equal doses.

INTELENCE 100 mg tablets

Tablet

White to off-white, oval tablet debossed with “T125” on one side and “100” on the other side.

INTELENCE 200 mg tablets

Tablet

White to off-white, biconvex, oblong tablet debossed with “T200” on one side.

INTELENCE, in combination with a boosted protease inhibitor and other antiretroviral medicinalproducts, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection inantiretroviral treatment-experienced adult patients and in antiretroviral treatment-experiencedpaediatric patients from 2 years of age (see sections 4.4, 4.5 and 5.1).

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 etravirine for adults is 200 mg (one 200 mg tablet or two 100 mg tablets)taken orally twice daily following a meal (see section 5.2).

Paediatric population (2 years to less than 18 years of age)

The recommended dose of etravirine for paediatric patients (2 years to less than 18 years of age andweighing at least 10 kg) is based on body weight (see table below). INTELENCE tablet(s) should betaken orally, following a meal (see section 5.2).

Table 1: Recommended dose of etravirine for paediatric patients 2 years to less than18 years of age

Body weight Dose Tablets≥ 10 to < 20 kg 100 mg twice four 25 mg tablets twice daily ordaily one 100 mg tablet twice daily≥ 20 to < 25 kg 125 mg twice five 25 mg tablets twice daily ordaily one 100 mg tablet and one 25 mg tablet twice daily≥ 25 to < 30 kg 150 mg twice six 25 mg tablets twice daily ordaily one 100 mg tablet and two 25 mg tablets twice daily≥ 30 kg 200 mg twice eight 25 mg tablets twice daily ordaily two 100 mg tablets twice dailyor one 200 mg tablet twice daily

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

If a patient vomits within 4 hours of taking the medicine, another dose of INTELENCE should betaken following a meal as soon as possible. If a patient vomits more than 4 hours after taking themedicine, the patient does not need to take another dose until the next regularly scheduled time.

There is limited information regarding the use of INTELENCE in patients > 65 years of age (seesection 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 hepaticimpairment. The pharmacokinetics of etravirine have not been studied in patients with severe hepaticimpairment (Child-Pugh Class C). Therefore, INTELENCE is not recommended in patients withsevere hepatic impairment (see sections 4.4 and 5.2).

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

Paediatric population (less than 2 years of age)

INTELENCE should not be used in children less than 2 years of age. Currently available data forchildren between 1 and 2 years old are described in sections 4.8, 5.1 and 5.2 and suggest that thebenefits do not outweigh the risks in this age group. No data are available for children less than 1 yearof age.

Oral use.

Patients should be instructed to swallow the tablet(s) whole with a liquid such as water. Patients whoare unable to swallow the tablet(s) whole may disperse the tablet(s) in a glass of water (seesection 4.4).

For instructions on dispersion of the medicinal product before administration, see section 6.6.

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

Co-administration with elbasvir/grazoprevir (see section 4.5).

INTELENCE should optimally be combined with other antiretrovirals that exhibit activity against thepatient’s virus (see section 5.1).

A decreased virologic response to etravirine was observed in patients with viral strains harbouring 3 ormore 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 tochange with additional data, and it is recommended to always consult current interpretation systemsfor analysing resistance test results.

No data other than drug-drug interaction data (see section 4.5) are available when etravirine iscombined with raltegravir or maraviroc.

Severe cutaneous and hypersensitivity reactions

Severe cutaneous adverse reactions have been reported with etravirine. In clinical trials,

Stevens-Johnson Syndrome and erythema multiforme have been rarely (< 0.1%) reported. Treatmentwith 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 suchpatients, 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 withthe use of etravirine (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 accompaniedby fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitisand eosinophilia). Time to onset is usually around 3-6 weeks and the outcome in most cases isfavourable 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-threateningreaction.

Patients who have stopped treatment due to hypersensitivity reactions should not restart therapy with

INTELENCE.

Rash has been reported with etravirine. Most frequently, rash was mild to moderate, occurred in thesecond week of therapy, and was infrequent after week 4. Rash was mostly self-limiting and generallyresolved 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).

For children who cannot swallow the tablet(s) whole, the tablet(s) may be dispersed in liquid. Thisshould only be considered if the child is likely to take the entire dose of the tablet(s) in liquid (seesections 4.2 and 6.6). The importance of consuming the entire dose needs to be highlighted to the childand his/her caregiver to avoid too low exposure and lack of virologic response. In case of any doubtthat a child will take the entire dose of the tablet(s) dispersed in liquid, treatment with anotherantiretroviral product needs to be considered.

Experience in geriatric patients is limited: in the Phase III trials, 6 patients aged 65 years or older and53 patients aged 56-64 years received etravirine. The type and incidence of adverse reactions inpatients > 55 years of age were similar to the ones in younger patients (see sections 4.2 and 5.2).

Given the increased etravirine exposure during pregnancy, caution should be applied for thosepregnant patients that require concomitant medicinal products or have comorbidities that may furtherincrease etravirine exposure.

Patients with coexisting conditions

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 advisedin patients with moderate hepatic impairment. Etravirine has not been studied in patients with severehepatic impairment (Child-Pugh Class C) and its use is therefore not recommended in this group ofpatients (see sections 4.2 and 5.2).

Co-infection with HBV (hepatitis B virus) or HCV (hepatitis C virus)

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

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviraltherapy. Such changes may in part be linked to disease control and life style. For lipids, there is insome cases evidence for a treatment effect, while for weight gain there is no strong evidence relatingthis to any particular treatment. For monitoring of blood lipids and glucose reference is made toestablished HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Immune reconstitution syndrome

In HIV infected patients with severe immune deficiency at the time of initiation of CART, aninflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and causeserious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observedwithin the first weeks or months of initiation of CART. Relevant examples are cytomegalovirusretinitis, generalised and/or focal mycobacterial infections and Pneumocystis jiroveci pneumonia. Anyinflammatory symptoms should be evaluated and treatment instituted when necessary.

Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported tooccur in the setting of immune reactivation; however, the reported time to onset is more variable andthese events can occur many months after initiation of treatment (see section 4.8).

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcoholconsumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have beenreported 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, jointstiffness or difficulty in movement.

It is not recommended to combine etravirine with tipranavir/ritonavir, due to a markedpharmacokinetic interaction (76% decrease of etravirine AUC) that could significantly impair thevirologic response to etravirine.

The combination of etravirine with daclatasvir, atazanavir/cobicistat or darunavir/cobicistat is notrecommended (see section 4.5).

For further information on interactions with medicinal products see section 4.5.

Lactose intolerance and lactase deficiency

INTELENCE 25 mg tablets

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

INTELENCE 100 mg tablets

Each tablet contains 160 mg of lactose monohydrate. Patients with rare hereditary problems ofgalactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not takethis medicine.

Medicinal products that affect etravirine exposure

Etravirine is metabolised by CYP3A4, CYP2C9 and CYP2C19 followed by glucuronidation of themetabolites by uridine diphosphate glucuronosyl transferase (UDPGT). Medicinal products thatinduce CYP3A4, CYP2C9 or CYP2C19 may increase the clearance of etravirine, resulting in loweredplasma concentrations of etravirine.

Co-administration of etravirine and medicinal products that inhibit CYP3A4, CYP2C9 or CYP2C19may decrease the clearance of etravirine and may result in increased plasma concentrations ofetravirine.

Medicinal products that are affected by the use of etravirine

Etravirine is a weak inducer of CYP3A4. Co-administration of etravirine with medicinal productsprimarily metabolised by CYP3A4 may result in decreased plasma concentrations of such medicinalproducts, 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 suchmedicinal products, which could increase or prolong their therapeutic effect or alter their adverseevents profile.

Known and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinalproducts are listed in table 2. The table is not all-inclusive.

Interactions between etravirine and co-administered medicinal products are listed in table 2 (increaseis indicated as “↑”, decrease as “↓”, no change as “↔”, not done as “ND”, confidence interval as“CI”).

Table 2: Interactions and dose recommendations with other medicinal products

Medicinal products by Effects on drug levels Recommendationstherapeutic areas Least Squares Mean Ratio concerning(90% CI; 1.00 = No effect) co-administration

ANTI-INFECTIVES

Antiretrovirals

NRTIs

Didanosine didanosine No significant effect on400 mg once daily AUC ↔ 0.99 (0.79-1.25) didanosine and etravirine PK

Cmin ND parameters is seen.

Cmax ↔ 0.91 (0.58-1.42) INTELENCE and didanosineetravirine can be used without dose

AUC ↔ 1.11 (0.99-1.25) adjustments.

Cmin ↔ 1.05 (0.93-1.18)

Cmax ↔ 1.16 (1.02-1.32)

Tenofovir disoproxil tenofovir No significant effect on245 mg once dailyb AUC ↔ 1.15 (1.09-1.21) tenofovir and etravirine PK

Cmin ↑ 1.19 (1.13-1.26) parameters is seen.

Cmax ↑ 1.15 (1.04-1.27) INTELENCE and tenofoviretravirine can be used without dose

AUC ↓ 0.81 (0.75-0.88) adjustments.

Cmin ↓ 0.82 (0.73-0.91)

Cmax ↓ 0.81 (0.75-0.88)

Other NRTIs Not studied, but no interaction expected based INTELENCE can be usedon the primary renal elimination route for other with these NRTIs without

NRTIs (e.g., abacavir, emtricitabine, dose adjustment.lamivudine, stavudine and zidovudine).

NNRTIs

Efavirenz Combining two NNRTIs has not been shown to It is not recommended to

Nevirapine be beneficial. Concomitant use of etravirine co-administer INTELENCE

Rilpivirine with efavirenz or nevirapine may cause a with other NNRTIs.

significant decrease in the plasma concentrationof etravirine and loss of therapeutic effect ofetravirine.

Concomitant use of etravirine with rilpivirinemay cause a decrease in the plasmaconcentration of rilpivirine and loss oftherapeutic effect of rilpivirine.

HIV Protease Inhibitors (PIs) - Unboosted (i.e. without co-administration of low-dose ritonavir)

Indinavir Concomitant use of etravirine with indinavir It is not recommended tomay cause a significant decrease in the plasma co-administer INTELENCEconcentration of indinavir and loss of with indinavir.therapeutic effect of indinavir.

HIV PIs - Boosted with low-dose ritonavir

Atazanavir/ritonavir atazanavir INTELENCE and300/100 mg once daily AUC ↓ 0.86 (0.79-0.93) atazanavir/ritonavir can be

Cmin ↓ 0.62 (0.55-0.71) used without dose

Cmax ↔ 0.97 (0.89-1.05) adjustment.etravirine

AUC ↑ 1.30 (1.18-1.44)

Cmin ↑ 1.26 (1.12-1.42)

Cmax ↑ 1.30 (1.17-1.44)

Darunavir/ritonavir darunavir INTELENCE and600/100 mg twice daily AUC ↔ 1.15 (1.05-1.26) darunavir/ritonavir can be

Cmin ↔ 1.02 (0.90-1.17) used without dose

Cmax ↔ 1.11 (1.01-1.22) adjustments (see alsoetravirine section 5.1).

AUC ↓ 0.63 (0.54-0.73)

Cmin ↓ 0.51 (0.44-0.61)

Cmax ↓ 0.68 (0.57-0.82)

Fosamprenavir/ritonavir amprenavir Amprenavir/ritonavir and700/100 mg twice daily AUC ↑ 1.69 (1.53-1.86) fosamprenavir/ritonavir may

Cmin ↑ 1.77 (1.39-2.25) require dose reduction when

Cmax ↑ 1.62 (1.47-1.79) co-administered withetravirine INTELENCE. Using the oral

AUC ↔a solution may be considered

C amin ↔ for dose reduction.

C amax ↔

Lopinavir/ritonavir lopinavir INTELENCE and(tablet) AUC ↔ 0.87 (0.83-0.92) lopinavir/ritonavir can be400/100 mg twice daily Cmin ↓ 0.80 (0.73-0.88) used without dose

Cmax ↔ 0.89 (0.82-0.96) adjustments.etravirine

AUC ↓ 0.65 (0.59-0.71)

Cmin ↓ 0.55 (0.49-0.62)

Cmax ↓ 0.70 (0.64-0.78)

Saquinavir/ritonavir saquinavir INTELENCE and1,000/100 mg twice daily AUC ↔ 0.95 (0.64-1.42) saquinavir/ritonavir can be

Cmin ↓ 0.80 (0.46-1.38) used without dose

Cmax ↔ 1.00 (0.70-1.42) adjustments.etravirine

AUC ↓ 0.67 (0.56-0.80)

Cmin ↓ 0.71 (0.58-0.87)

Cmax ↓ 0.63 (0.53-0.75)

Tipranavir/ritonavir tipranavir It is not recommended to500/200 mg twice daily AUC ↑ 1.18 (1.03-1.36) co-administer

Cmin ↑ 1.24 (0.96-1.59) tipranavir/ritonavir and

Cmax ↑ 1.14 (1.02-1.27) INTELENCE (seeetravirine section 4.4).

AUC ↓ 0.24 (0.18-0.33)

Cmin ↓ 0.18 (0.13-0.25)

Cmax ↓ 0.29 (0.22-0.40)

HIV PIs - Boosted with cobicistat

Atazanavir/cobicistat Not studied. Co-administration of etravirine Co-administration of

Darunavir/cobicistat with atazanavir/cobicistat or INTELENCE withdarunavir/cobicistat may decrease plasma atazanavir/cobicistat orconcentrations of the PI and/or cobicistat, darunavir/cobicistat is notwhich may result in loss of therapeutic effect recommended.and development of resistance.

CCR5 Antagonists

Maraviroc maraviroc The recommended dose for300 mg twice daily AUC ↓ 0.47 (0.38-0.58) maraviroc when combined

Cmin ↓ 0.61 (0.53-0.71) with INTELENCE and a PI

Cmax ↓ 0.40 (0.28-0.57) is 150 mg twice daily, exceptetravirine for fosamprenavir/ritonavir

AUC ↔ 1.06 (0.99-1.14) which is not recommended

Cmin ↔ 1.08 (0.98-1.19) with maraviroc. No dose

Cmax ↔ 1.05 (0.95-1.17) adjustment for INTELENCE

Maraviroc/darunavir/ maraviroc* is necessary.ritonavir AUC ↑ 3.10 (2.57-3.74) See also section 4.4.150/600/100 mg twice Cmin ↑ 5.27 (4.51-6.15)daily Cmax ↑ 1.77 (1.20-2.60)

* compared to maraviroc 150 mg twice daily

Fusion Inhibitors

Enfuvirtide etravirine* No interaction is expected for90 mg twice daily AUC ↔a either INTELENCE or

C a0h ↔ enfuvirtide when

Enfuvirtide concentrations not studied and no co-administered.effect is expected.

* based on population pharmacokinetic analyses

Integrase Strand Transfer Inhibitors

Dolutegravir dolutegravir Etravirine significantly50 mg once daily AUC ↓ 0.29 (0.26-0.34) reduced plasma

Cmin ↓ 0.12 (0.09-0.16) concentrations of

Cmax ↓ 0.48 (0.43-0.54) dolutegravir. The effect ofetravirine etravirine on dolutegravir

AUC ↔a plasma concentrations was

C amin ↔ mitigated by

Cmax ↔a co-administration ofdarunavir/ritonavir or

Dolutegravir + dolutegravir lopinavir/ritonavir, and isdarunavir/ritonavir AUC↓ 0.75 (0.69-0.81) expected to be mitigated by50 mg once daily + Cmin ↓ 0.63 (0.52-0.77) atazanavir/ritonavir.600/100 mg twice daily Cmax ↓ 0.88 (0.78-1.00)etravirine INTELENCE should only be

AUC ↔a used with dolutegravir when

C amin ↔ co-administered with

C amax ↔ atazanavir/ritonavir,darunavir/ritonavir, or

Dolutegravir + dolutegravir lopinavir/ritonavir. This

Lopinavir/ritonavir AUC↔ 1.11(1.02-1.20) combination can be used50 mg once daily + Cmin ↑ 1.28 (1.13-1.45) without dose adjustment.400/100 mg twice daily Cmax ↔ 1.07 (1.02-1.13)etravirine

AUC ↔a

Cmin ↔a

C amax ↔

Raltegravir raltegravir INTELENCE and raltegravir400 mg twice daily AUC ↓ 0.90 (0.68-1.18) can be used without dose

Cmin ↓ 0.66 (0.34-1.26) adjustments.

Cmax ↓ 0.89 (0.68-1.15)etravirine

AUC ↔ 1.10 (1.03-1.16)

Cmin ↔ 1.17 (1.10-1.26)

Cmax ↔ 1.04 (0.97-1.12)

ANTIARRHYTHMICS

Digoxin digoxin INTELENCE and digoxin0.5 mg single dose AUC ↑ 1.18 (0.90-1.56) can be used without dose

Cmin ND adjustments. It is

Cmax ↑ 1.19 (0.96-1.49) recommended that digoxinlevels be monitored whendigoxin is combined with

INTELENCE.

Amiodarone Not studied. INTELENCE is expected to Caution is warranted and

Bepridil decrease plasma concentrations of these therapeutic concentration

Disopyramide antiarrhythmics. monitoring, if available, is

Flecainide recommended for

Lidocaine (systemic) antiarrhythmics when

Mexiletine co-administered with

Propafenone INTELENCE.

ANTIBIOTICS

Azithromycin Not studied. Based on the biliary elimination INTELENCE andpathway of azithromycin, no drug interactions azithromycin can be usedare expected between azithromycin and without dose adjustments.

INTELENCE.

Clarithromycin clarithromycin Clarithromycin exposure was500 mg twice daily AUC ↓ 0.61 (0.53-0.69) decreased by etravirine;

Cmin ↓ 0.47 (0.38-0.57) however, concentrations of

Cmax ↓ 0.66 (0.57-0.77) the active metabolite,14-OH-clarithromycin 14-OH-clarithromycin, were

AUC ↑ 1.21 (1.05-1.39) increased. Because

Cmin ↔ 1.05 (0.90-1.22) 14-OH-clarithromycin has

Cmax ↑ 1.33 (1.13-1.56) reduced activity againstetravirine Mycobacterium avium

AUC ↑ 1.42 (1.34-1.50) complex (MAC), overall

Cmin ↑ 1.46 (1.36-1.58) activity against this pathogen

Cmax ↑ 1.46 (1.38-1.56) may be altered; thereforealternatives to clarithromycinshould be considered for thetreatment of MAC.

ANTICOAGULANTS

Warfarin Not studied. Etravirine is expected to increase It is recommended that theplasma concentrations of warfarin. international normalised ratio(INR) be monitored whenwarfarin is combined with

INTELENCE.

ANTICONVULSANTS

Carbamazepine Not studied. Carbazamepine, phenobarbital and Combination not

Phenobarbital phenytoin are expected to decrease plasma recommended.

Phenytoin concentrations of etravirine.

ANTIFUNGALS

Fluconazole fluconazole INTELENCE and200 mg once in the AUC ↔ 0.94 (0.88-1.01) fluconazole can be usedmorning Cmin ↔ 0.91 (0.84-0.98) without dose adjustments.

Cmax ↔ 0.92 (0.85-1.00)etravirine

AUC ↑ 1.86 (1.73-2.00)

Cmin ↑ 2.09 (1.90-2.31)

Cmax ↑ 1.75 (1.60-1.91)

Itraconazole Not studied. Posaconazole, a potent inhibitor of INTELENCE and these

Ketoconazole CYP3A4, may increase plasma concentrations antifungals can be used

Posaconazole of etravirine. Itraconazole and ketoconazole are without dose adjustments.

potent inhibitors as well as substrates of

CYP3A4. Concomitant systemic use ofitraconazole or ketoconazole and etravirine mayincrease plasma concentrations of etravirine.

Simultaneously, plasma concentrations ofitraconazole or ketoconazole may be decreasedby etravirine.

Voriconazole voriconazole INTELENCE and200 mg twice daily AUC ↑ 1.14 (0.88-1.47) voriconazole can be used

Cmin ↑ 1.23 (0.87-1.75) without dose adjustments.

Cmax ↓ 0.95 (0.75-1.21)etravirine

AUC ↑ 1.36 (1.25-1.47)

Cmin ↑ 1.52 (1.41-1.64)

Cmax ↑ 1.26 (1.16-1.38)

ANTIMALARIALS

Artemether/ artemether Close monitoring of

Lumefantrine AUC ↓ 0.62 (0.48-0.80) antimalarial response is80/480 mg, 6 doses at 0, Cmin ↓ 0.82 (0.67-1.01) warranted when8, 24, 36, 48, and Cmax ↓ 0.72 (0.55-0.94) co-administering60 hours dihydroartemisinin INTELENCE and

AUC ↓ 0.85 (0.75-0.97) artemether/lumefantrine as a

Cmin ↓ 0.83 (0.71-0.97) significant decrease in

Cmax ↓ 0.84 (0.71-0.99) exposure of artemether andlumefantrine its active metabolite,

AUC ↓ 0.87 (0.77-0.98) dihydroartemisinin, may

Cmin ↔ 0.97 (0.83-1.15) result in decreased

Cmax ↔ 1.07 (0.94-1.23) antimalarial efficacy. Noetravirine dose adjustment is needed for

AUC ↔ 1.10 (1.06-1.15) INTELENCE.

Cmin ↔ 1.08 (1.04-1.14)

Cmax ↔ 1.11 (1.06-1.17)

ANTIMYCOBACTERIALS

Rifampicin Not studied. Rifampicin and rifapentine are Combination not

Rifapentine expected to decrease plasma concentrations of recommended.

etravirine.

INTELENCE should be used in combinationwith a boosted PI. Rifampicin is contraindicatedin combination with boosted Pis.

Rifabutin With an associated boosted PI: The combination of300 mg once daily No interaction study has been performed. Based INTELENCE with a boostedon historical data, a decrease in etravirine PI and rifabutin should beexposure may be expected whereas an increase used with caution due to thein rifabutin exposure and especially in risk of decrease in etravirine25-O-desacetyl-rifabutin may be expected. exposure and the risk ofincrease in rifabutin and

With no associated boosted PI (out of the 25-O-desacetyl-rifabutinrecommended indication for etravirine): exposures.rifabutin Close monitoring for

AUC ↓ 0.83 (0.75-0.94) virologic response and for

Cmin ↓ 0.76 (0.66-0.87) rifabutin related adverse

Cmax ↓ 0.90 (0.78-1.03) reactions is recommended.25-O-desacetyl-rifabutin Please refer to the product

AUC ↓ 0.83 (0.74-0.92) information of the associated

Cmin ↓ 0.78 (0.70-0.87) boosted PI for the dose

Cmax ↓ 0.85 (0.72-1.00) adjustment of rifabutin to beetravirine used.

AUC ↓ 0.63 (0.54-0.74)

Cmin ↓ 0.65 (0.56-0.74)

Cmax ↓ 0.63 (0.53-0.74)

BENZODIAZEPINES

Diazepam Not studied. Etravirine is expected to increase Alternatives to diazepamplasma concentrations of diazepam. should be considered.

CORTICOSTEROIDS

Dexamethasone Not studied. Dexamethasone is expected to Systemic dexamethasone(systemic) decrease plasma concentrations of etravirine should be used with cautionor alternatives should beconsidered, particularly forchronic use.

OESTROGEN-BASED CONTRACEPTIVES

Ethinylestradiol ethinylestradiol The combination of0.035 mg once daily AUC ↑ 1.22 (1.13-1.31) oestrogen- and/or

Norethindrone Cmin ↔ 1.09 (1.01-1.18) progesterone-based1 mg once daily Cmax ↑ 1.33 (1.21-1.46) contraceptives andnorethindrone INTELENCE can be used

AUC ↔ 0.95 (0.90-0.99) without dose adjustment.

Cmin ↓ 0.78 (0.68-0.90)

Cmax ↔ 1.05 (0.98-1.12)etravirine

AUC ↔a

C amin ↔

C ↔amax

HEPATITIS C VIRUS (HCV) DIRECT-ACTING ANTIVIRALS

Ribavirin Not studied, but no interaction expected based The combination ofon the renal elimination pathway of ribavirin. INTELENCE and ribavirincan be used without doseadjustments.

Daclatasvir Not studied. Co-administration of etravirine Co-administration ofwith daclatasvir may decrease daclatasvir INTELENCE and daclatasvirconcentrations. is not recommended.

Elbasvir/grazoprevir Not studied. Co-administration of etravirine Co-administration iswith elbasvir/grazoprevir may decrease elbasvir contraindicated (seeand grazoprevir concentrations, leading to section 4.3).reduced therapeutic effect ofelbasvir/grazoprevir.

HERBAL PRODUCTS

St John’s wort Not studied. St John’s wort is expected to Combination not(Hypericum perforatum) decrease the plasma concentrations of recommended.

etravirine.

HMG CO-A REDUCTASE INHIBITORS

Atorvastatin atorvastatin The combination of40 mg once daily AUC ↓ 0.63 (0.58-0.68) INTELENCE and

Cmin ND atorvastatin can be given

Cmax ↑ 1.04 (0.84-1.30) without any dose2-OH-atorvastatin adjustments, however, the

AUC ↑ 1.27 (1.19-1.36) dose of atorvastatin may

Cmin ND need to be altered based on

Cmax ↑ 1.76 (1.60-1.94) clinical response.etravirine

AUC ↔ 1.02 (0.97-1.07)

Cmin ↔ 1.10 (1.02-1.19)

Cmax ↔ 0.97 (0.93-1.02)

Fluvastatin Not studied. No interaction between pravastatin Dose adjustments for these

Lovastatin and etravirine is expected. HMG Co-A reductase

Pravastatin Lovastatin, rosuvastatin and simvastatin are inhibitors may be necessary.

Rosuvastatin CYP3A4 substrates and co-administration with

Simvastatin etravirine may result in lower plasmaconcentrations of the HMG Co-A reductaseinhibitor. Fluvastatin, and rosuvastatin aremetabolised by CYP2C9 and co-administrationwith etravirine may result in higher plasmaconcentrations of the HMG Co-A reductaseinhibitor.

H2-RECEPTOR ANTAGONISTS

Ranitidine etravirine INTELENCE can be150 mg twice daily AUC ↓ 0.86 (0.76-0.97) co-administered with

Cmin ND H2-receptor antagonists

Cmax ↓ 0.94 (0.75-1.17) without dose adjustments.

IMMUNOSUPPRESSANTS

Cyclosporin Not studied. Etravirine is expected to decrease Co-administration with

Sirolimus plasma concentrations of cyclosporine, systemic

Tacrolimus sirolimus and tacrolimus. immunosuppressants shouldbe done with caution becauseplasma concentrations ofcyclosporin, sirolimus andtacrolimus may be affectedwhen co-administered with

INTELENCE.

NARCOTIC ANALGESICS

Methadone R(-) methadone No changes in methadoneindividual dose ranging AUC ↔ 1.06 (0.99-1.13) dosage were required basedfrom 60 mg to 130 mg Cmin ↔ 1.10 (1.02-1.19) on clinical status during oronce daily Cmax ↔ 1.02 (0.96-1.09) after the period of

S(+) methadone INTELENCE

AUC ↔ 0.89 (0.82-0.96) co-administration.

Cmin ↔ 0.89 (0.81-0.98)

Cmax ↔ 0.89 (0.83-0.97)etravirine

AUC ↔a

C amin ↔

Cmax ↔a

PHOSPHODIESTERASE, TYPE 5 (PDE-5) INHIBITORS

Sildenafil 50 mg single sildenafil Concomitant use of PDE-5dose AUC ↓ 0.43 (0.36-0.51) inhibitors with INTELENCE

Tadalafil Cmin ND may require dose adjustment

Vardenafil Cmax ↓ 0.55 (0.40-0.75) of the PDE-5 inhibitor to

N-desmethyl-sildenafil attain the desired clinical

AUC ↓ 0.59 (0.52-0.68) effect.

Cmin ND

Cmax ↓ 0.75 (0.59-0.96)

PLATELET AGGREGGATION INHIBITORS

Clopidogrel In vitro data show that etravirine has inhibitory As a precaution it isproperties on CYP2C19. It is therefore possible recommended thatthat etravirine may inhibit the metabolism of concomitant use of etravirineclopidogrel to its active metabolite by such and clopidogrel should beinhibition of CYP2C19 in vivo. The clinical discouraged.relevance of this interaction has not beendemonstrated.

PROTON PUMP INHIBITORS

Omeprazole etravirine INTELENCE can be40 mg once daily AUC ↑ 1.41 (1.22-1.62) co-administered with proton

Cmin ND pump inhibitors without dose

Cmax ↑ 1.17 (0.96-1.43) adjustments.

SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIS)

Paroxetine paroxetine INTELENCE can be20 mg once daily AUC ↔ 1.03 (0.90-1.18) co-administered with

Cmin ↓ 0.87 (0.75-1.02) paroxetine without dose

Cmax ↔ 1.06 (0.95-1.20) adjustments.etravirine

AUC ↔ 1.01 (0.93-1.10)

Cmin ↔ 1.07 (0.98-1.17)

Cmax ↔ 1.05 (0.96-1.15)a Comparison based on historic control.b Study was conducted with tenofovir disoproxil fumarate 300 mg once daily

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

Interaction studies have only been performed in adults.

As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection inpregnant 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 inorder to characterise the safety for the foetus.

Placental transfer has been seen in pregnant rats, but it is not known whether placental transfer ofetravirine also occurs in pregnant women. Studies in animals do not indicate direct or indirect harmfuleffects 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 datado not raise safety concern but are very limited.

Etravirine is excreted in human milk.

Because of the potential for adverse events in nursing infants, women should be instructed not tobreastfeed if they are receiving INTELENCE. It is recommended that women living with HIV do notbreastfeed 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 onmating or fertility with etravirine treatment (see section 5.3).

INTELENCE has minor influence on the ability to drive and use machines. No studies on the effectsof INTELENCE on the ability to drive or operate machines have been performed. Adverse reactionssuch as somnolence and vertigo have been reported in etravirine-treated patients and should beconsidered when assessing a patient’s ability to drive or operate machinery (see section 4.8).

The most frequent (incidence ≥ 10%) adverse reactions of all intensities reported for etravirine wererash, diarrhoea, nausea and headache. In the Phase III studies, the rates of discontinuation due to anyadverse reaction were 7.2% in patients receiving etravirine. The most common adverse reactionleading to discontinuation was rash.

Adverse reactions reported in patients treated with etravirine are summarised in Table 3. The adversereactions are listed by system organ class (SOC) and frequency. Within each frequency grouping,adverse reactions are presented in order of decreasing seriousness. Frequencies are defined as verycommon (≥ 1/10), common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1,000 to < 1/100), rare(≥ 1/10,000 to < 1/1,000) and very rare (< 1/10,000).

Table 3: Adverse reactions observed with etravirine in clinical trials and post-marketingexperience

System Organ Class Frequency Adverse Reaction(SOC) category

Blood and lymphatic common thrombocytopaenia, anaemia, decreased neutrophilssystem disorders uncommon decreased white blood cell count

Immune system common drug hypersensitivitydisorders uncommon immune reconstitution syndrome

Metabolism and common diabetes mellitus, hyperglycaemia,nutrition disorders hypercholesterolaemia, increased low densitylipoprotein (LDL), hypertriglyceridaemia,hyperlipidaemia, dyslipidaemia, anorexia

Psychiatric disorders common anxiety, insomnia, sleep disordersuncommon confusional state, disorientation, nightmares,nervousness, abnormal dreams

Nervous system very common headachedisorders common peripheral neuropathy, paraesthesia, hypoaesthesia,amnesia, somnolenceuncommon convulsion, syncope, tremor, hypersomnia, disturbancein attention

Eye disorders common blurred vision

Ear and labyrinth uncommon vertigodisorders

Cardiac disorders common myocardial infarctionuncommon atrial fibrillation, angina pectoris

Vascular disorders common hypertensionrare haemorrhagic strokea

Respiratory, thoracic common exertional dyspnoeaand mediastinal uncommon bronchospasmdisorders

Gastrointestinal very common diarrhoea, nauseadisorders common gastrooesophageal reflux disease, vomiting, abdominalpain, abdominal distension, flatulence, gastritis,constipation, dry mouth, stomatitis, lipase increased,blood amylase increaseduncommon pancreatitis, haematemesis, retching

Hepatobiliary disorders common increased alanine aminotransferase (ALT), increasedaspartate aminotransferase (AST)uncommon hepatitis, hepatic steatosis, cytolytic hepatitis,hepatomegaly

Skin and subcutaneous very common rashtissue disorders common night sweats, dry skin, prurigouncommon angioneurotic oedemaa, swelling face, hyperhidrosisrare Stevens-Johnson Syndromea, erythema multiformeavery rare toxic epidermal necrolysisa, DRESSb

Renal and urinary common renal failure, blood creatinine increaseddisorders

Reproductive system uncommon gynaecomastiaand breast disorders

General disorders and common fatigueadministration site uncommon sluggishnessconditionsa These adverse reactions were observed in other clinical trials than DUET-1 and DUET-2.b These adverse reactions have been identified through postmarketing experience with etravirine.

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 mostlyself-limiting, and generally resolved within 1-2 weeks on continued therapy (see section 4.4). Theincidence of rash was higher in women compared to men in the etravirine arm in the DUET trials(rash ≥ grade 2 was reported in 9/60 [15.0%] women versus 51/539 [9.5%] men; discontinuations dueto rash were reported in 3/60 [5.0%] women versus 10/539 [1.9%] men) (see section 4.4). There wasno gender difference in severity or treatment discontinuation due to rash. The clinical data are limitedand an increased risk of cutaneous reactions in patients with a history of NNRTI-associated cutaneousreaction cannot be excluded (see section 4.4).

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (seesection 4.4)

Immune reconstitution syndrome

In HIV infected patients with severe immune deficiency at the time of initiation of combinationantiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunisticinfections may arise. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) havealso been reported; however, the reported time to onset is more variable and these events can occurmany months after initiation of treatment (see section 4.4).

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

Paediatric population (1 year to less than 18 years of age)

The safety assessment in children and adolescents is based on two single-arm trials. PIANO(TMC125-C213) is a Phase II trial in which 101 antiretroviral treatment-experienced HIV-1 infectedpaediatric patients 6 years to less than 18 years of age received INTELENCE in combination withother antiretroviral agents. TMC125-C234/IMPAACT P1090 is a Phase I/II trial in which26 antiretroviral treatment-experienced HIV-1 infected paediatric patients aged 1 years to less than6 years received INTELENCE in combination with other antiretroviral agents (see section 5.1).

In PIANO and TMC125-C234/IMPAACT P1090, the frequency, type and severity of adversereactions in paediatric patients were comparable to those observed in adults. In PIANO, rash wasreported more frequently in female subjects than in male subjects (rash ≥ grade 2 was reported in13/64 [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, ofmacular/papular type, and occurred in the second week of therapy. Rash was mostly self-limiting andgenerally resolved within 1 week on continued therapy.

In a postmarketing retrospective cohort study aiming at substantiating the long-term safety profile ofetravirine in HIV-1-infected children and adolescents receiving etravirine with other HIV-1antiretrovirals (N = 182), Stevens-Johnson Syndrome was reported at a higher incidence (1%) than hasbeen reported in adult clinical trials (< 0.1%).

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 inco-infected subjects treated with etravirine 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).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There are no data with regard to symptomatic overdose with etravirine, but it is possible that the mostfrequent adverse reactions of etravirine, i.e. rash, diarrhoea, nausea, and headache would be the mostcommon symptoms noted. There is no specific antidote for overdose with etravirine. Treatment ofoverdose with INTELENCE consists of general supportive measures including monitoring of vitalsigns and observation of the clinical status of the patient. Since etravirine is highly protein bound,dialysis is unlikely to result in significant removal of the active substance.

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

Etravirine is an NNRTI of human immunodeficiency virus type 1 (HIV-1). Etravirine binds directly toreverse transcriptase (RT) and blocks the RNA-dependent and DNA-dependent DNA polymeraseactivities 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 from0.3 to 1.7 nM and from 11.5 to 21.7 nM, respectively. Although etravirine demonstrates in vitroactivity against wild type HIV-2 with median EC50 values ranging from 5.7 to 7.2 µM, treatment of

HIV-2 infection with etravirine is not recommended in the absence of clinical data. Etravirine retainsactivity against HIV-1 viral strains resistant to nucleoside reverse transcriptase and/or proteaseinhibitors. In addition, etravirine demonstrates a fold change (FC) in EC50 ≤ 3 against 60% of6,171 NNRTI-resistant clinical isolates.

Etravirine efficacy in relation to NNRTI resistance at baseline has mainly been analysed withetravirine given in combination with darunavir/ritonavir (DUET-1 and DUET-2). Boosted proteaseinhibitors, like darunavir/ritonavir, show a higher barrier to resistance compared to other classes ofantiretrovirals. The breakpoints for reduced efficacy with etravirine (> 2 etravirine-associatedmutations at baseline, see clinical results section) applies when etravirine is given in combination witha boosted protease inhibitor. This breakpoint might be lower in antiretroviral combination therapy notincluding a boosted protease inhibitor.

In the Phase III trials DUET-1 and DUET-2, mutations that developed most commonly in patientswith virologic failure to the etravirine containing regimen were V108I, V179F, V179I, Y181C and

Y181I, which usually emerged in a background of multiple other NNRTI resistance-associatedmutations (RAMs). In all the other trials conducted with etravirine in HIV-1 infected patients, thefollowing 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 patientswith efavirenz and/or nevirapine.

Treatment-experienced adult patients

Pivotal studies

The evidence of efficacy of etravirine 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 etravirine 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: Etravirine vs. placebo, in addition to a background regimen (BR) includingdarunavir/ritonavir (DRV/rtv), investigator-selected N(t)RTIs and optional enfuvirtide (ENF).

- Main inclusion criteria:

- HIV-1 plasma viral load > 5,000 HIV-1 RNA copies/ml at screening

- 1 or more NNRTI resistance-associated mutations (RAMs) at screening or from priorgenotypic analysis (i.e., archived resistance)

- 3 or more primary PI mutations at screening

- on a stable antiretroviral regimen for at least 8 weeks.

- Stratification: Randomisation was stratified by the intended use of ENF in the BR, previous useof 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 4: DUET-1 and DUET-2 pooled 48-week data

Etravirine + BR Placebo + BRdifference

N = 599 N = 604(95% CI)

Baseline characteristics

Median plasma HIV-1 RNA 4.8 log10 copies/ml 4.8 log10 copies/ml

Median CD4 cell count 99 x 106 cells/l 109 x 106 cells/l

Outcomes

Confirmed undetectable viralload (< 50 HIV-1 RNAcopies/ml)an (%)20.9%

Overall 363 (60.6%) 240 (39.7%)(15.3%; 26.4%)d12.8%de novo ENF 109 (71.2%) 93 (58.5%)(2.3%; 23.2%)f23.9%

Not de novo ENF 254 (57.0%) 147 (33.0%)(17.6%; 30.3%)f< 400 HIV-1 RNA copies/mla 24.1%428 (71.5%) 286 (47.4%)n (%) (18.7%; 29.5%)d

HIV-1 RNA log10 mean change -0.6

- 2.25 -1.49from baseline (log10 copies/ml)b (-0.8; -0.5)c

CD4 cell count mean change 24.46 b +98.2 +72.9from baseline (x 10 /l) (10.4; 38.5)c

Any AIDS defining illness -3.9%35 (5.8%) 59 (9.8%)and/or death n (%) (-6.9%; -0.9%)ea Imputations according to the TLOVR algorithm (TLOVR = Time to Loss of Virologic Response).b Non-completer is failure (NC = F) imputation.c Treatment differences are based on Least Square Means from an ANCOVA model including the stratification factors.

P-value < 0.0001 for mean decrease in HIV-1 RNA; P-value = 0.0006 for mean change in CD4 cell count.d Confidence interval around observed difference of response rates; P-value < 0.0001 from logistic regression model,including stratification factors.e Confidence interval around observed difference of response rates; P-value = 0.0408.f Confidence interval around observed difference of response rates; P-value from CMH test controlling for stratificationfactors = 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 wasdone for 2 ENF strata (patients reusing or not using ENF versus patients using ENF de novo). Theweek 48 results from the pooled analysis of DUET-1 and DUET-2 demonstrated that the etravirinearm was superior to the placebo arm irrespective of whether ENF was used de novo (p = 0.0199) ornot (p < 0.0001). Results of this analysis (week 48 data) by ENF stratum are shown in table 4.

Significantly fewer patients in the etravirine arm reached a clinical endpoint (AIDS-defining illnessand/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) atweek 48 by baseline viral load and baseline CD4 count (pooled DUET data) is presented in table 5.

Table 5: DUET-1 and DUET-2 pooled data

Proportion of subjects with HIV-1 RNA < 50 copies/mlat week 48

Subgroups

Etravirine + BR Placebo + BR

N = 599 N = 604

Baseline HIV-1 RNA< 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 106/l)< 50 45.1% 21.5%≥ 50 and < 200 65.4% 47.6%≥ 200 and < 350 73.9% 52.0%≥ 350 72.4% 50.8%

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

Baseline genotype or phenotype and virologic outcome analyses

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,(etravirine RAMs) was associated with a decreased virologic response to etravirine (see table 6).

These individual mutations occurred in the presence of other NNRTI RAMs. V179F was never presentwithout Y181C.

Conclusions regarding the relevance of particular mutations or mutational patterns are subject tochange with additional data, and it is recommended to always consult current interpretation systemsfor analysing resistance test results.

Table 6: Proportion of subjects with < 50 HIV-1 RNA copies/ml at week 48 by baselinenumber of etravirine RAMs in the non-viral failure excluded population of pooled

DUET-1 and DUET-2 trials

Baseline number of Etravirine arms

Etravirine RAMs* 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)

* Etravirine RAMs = V90I, A98G, L100I, K101E/P, V106I, V179D/F, Y181C/I/V, G190A/S

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 etravirine.

Furthermore, the presence of this mutation alone did not affect the response in the etravirine 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 apredictive 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 meantto represent definitive clinical susceptibility breakpoints for etravirine.

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

TMC125-C227 was an exploratory, randomised, active-controlled open-label trial, which investigatedthe efficacy and safety of etravirine in a treatment regimen, which is not approved under the currentindication. In the TMC125-C227 study, etravirine (N = 59) was administered with2 investigator-selected NRTIs (i.e. without a ritonavir-boosted PI) and compared to aninvestigator-selected combination of a PI with 2 NRTIs (N = 57). The trial population included

PI-naïve, 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 etravirine arm (-1.4 log10 copies/ml from baseline; n = 40). This differencebetween treatment arms was statistically significant.

Based on these trial results, etravirine is not recommended for use in combination with N(t)RTIs onlyin 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 efficacyof etravirine in 101 antiretroviral treatment-experienced HIV-1 infected paediatric patients 6 years toless than 18 years of age and weighing at least 16 kg. The study enrolled patients on a stable butvirologically failing antiretroviral treatment regimen, with a confirmed HIV-1 RNA plasma viral load≥ 500 copies/ml. Sensitivity of the virus to etravirine at screening was required.

The median baseline plasma HIV-1 RNA was 3.9 log10 copies/ml, and the median baseline CD4 cellcount was 385 x 106 cells/l.

Table 7: Virologic responses (ITT - TLOVR), change from baseline in log10 viral load (NC = F), andchange from baseline in CD4 percentage and cell count (NC = F) at week 24 in the

TMC125-C213 and pooled DUET studies

Pooled DUET

Study TMC125-C213 TMC125-C213 TMC125-C213 Studies

Age at screening 6 to < 12 years 12 to < 18 years 6 to < 18 years ≥ 18 years

Treatment group ETR ETR ETR ETR

N = 41 N = 60 N = 101 N = 599

Virologic parameters

Viral load < 50 copies/ml at24 (58.5) 28 (46.7) 52 (51.5) 363 (60.6)week 24, n (%)

Viral load < 400 copies/ml at28 (68.3) 38 (63.3) 66 (65.3) 445 (74.3)week 24, n (%)≥ 1 log10 decrease from26 (63.4) 38 (63.3) 64 (63.4) 475 (79.3)baseline at week 24, n (%)

Change from baseline in log10viral load (copies/ml) at -1.62 (0.21) -1.44 (0.17) -1.51 (0.13) -2.37 (0.05)week 24, mean (SE) and -1.68 (-4.3; 0.9) -1.68 (-4.0; 0.7) -1.68 (-4.3; 0.9) -2.78 (-4.6; 1.4)median (range)

Immunologic parameters

Change from baseline in CD4125 (33.0) 104 (17.5) 112 (16.9) 83.5 (3.64)cell count (x 106 cells/l), mean124 (-410; 718) 81 (-243; 472) 108 (-410; 718) 77.5 (-331; 517)(SE) and median (range)

Change from baseline in CD4 4% 3% 4% 3%percentage, median (range) (-9; 20) (-4; 14) (-9; 20) (-7; 23)

N = number of subjects with data; n = number of observations.

At week 48, 53.5% of all paediatric patients had a confirmed undetectable viral load < 50 HIV-1 RNAcopies/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 toweek 48 was -1.53 log10 copies/ml, and the mean CD4 cell count increase from baseline was156 x 106 cells/l.

Treatment-experienced paediatric patients (1 year to less than 6 years of age)

TMC125-C234/IMPAACT P1090 is a Phase I/II trial evaluating the pharmacokinetics, safety,tolerability, and efficacy of INTELENCE in 20 antiretroviral treatment-experienced HIV-1 infectedpediatric patients 2 years to less than 6 years of age (Cohort I) and 6 antiretroviral treatment-experienced HIV-1 infected pediatric patients 1 year to less than 2 years of age (Cohort II). Nopatients have been enrolled in Cohort III (≥ 2 months to < 1 year). The study enrolled patients on avirologically failing antiretroviral treatment regimen for at least 8 weeks or on a treatment interruptionof at least 4 weeks with a history of virologic failure while on an antiretroviral regimen, with aconfirmed HIV-1 RNA plasma viral load greater than 1,000 copies/ml and with no evidence ofphenotypic resistance to etravirine at screening.

Table 8 summarizes the virologic response results for the TMC125-C234/IMPAACT P1090 study.

Table 8: Virologic responses (ITT-FDA Snapshot*) at week 48 in the TMC125-C234/IMPAACT

P1090 Study

Cohort I Cohort II≥ 2 to < 6 years ≥ 1 to < 2 years(N = 20) (N = 6)

Baseline

Plasma HIV-1 RNA 4.4 log10 copies/ml 4.4 log10 copies/ml

Median CD4+ cell count817.5 x 106 cells/l 1,491.5 x 106 cells/l

Median baseline CD4+(27.6%) (26.9%)percentage

Week 48

Virologic Response (plasma16/20 1/6viral load < 400 HIV-1 RNA(80.0%) (16.7%)copies/ml)

Median change in plasma

HIV-1 RNA from baseline to -2.31 log10 copies/ml -0.665 log10 copies/ml

Week 48

Median CD4+ change from 298.5 x 106 cells/l 0 x 106 cells/lbaseline (5.15%) (-2.2%)

N = number of subjects per treatment group.

* Intent-to-treat-FDA Snapshot approach.

Subgroup analyses showed that for subjects aged 2 to less than 6 years virologic response [HIV RNA< 400 copies/ml] was 100.0% [6/6] for subjects who swallowed the etravirine tablet whole, 100%[4/4] for subjects who took a combination of both etravirine dispersed in liquid and etravirine tabletwhole and 60% [6/10] for subjects who took etravirine dispersed in liquid. Of the 4 subjects who didnot show virologic response and took etravirine dispersed in liquid, 3 showed virologic failure and hadadherence issues, and one discontinued prior to Week 48 for safety reasons.

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 virusinfection, as per Paediatric Investigation Plan (PIP) decision in the granted indication (see section 4.2for information on paediatric use).

Etravirine (200 mg twice daily), evaluated in combination with other antiretroviral medicinal productsin a study of 15 pregnant women during the second and third trimesters of pregnancy and postpartum,demonstrated that exposure to total etravirine was generally higher during pregnancy compared withpostpartum, and less so for unbound etravirine exposure (see section 5.2). There were no newclinically relevant safety findings in the mothers or in the newborns in this trial.

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

Table 9: Population pharmacokinetic estimates of etravirine 200 mg twice daily in HIV-1infected adult subjects (integrated data from Phase III trials at week 48)*

Parameter Etravirine 200 mg twice daily

N = 575

AUC12h (ng*h/ml)

Geometric Mean ± Standard Deviation 4,522 ± 4,710

Median (Range) 4,380 (458 - 59,084)

C0h (ng/ml)

Geometric Mean ± Standard Deviation 297 ± 391

Median (Range) 298 (2 - 4,852)

* All HIV-1 infected subjects enrolled in Phase III clinical trials received darunavir/ritonavir 600/100 mg twice daily aspart of their background regimen. Therefore, the pharmacokinetic parameter estimates shown in the table account forreductions in the pharmacokinetic parameters of etravirine due to co-administration of etravirine withdarunavir/ritonavir.

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 etravirineis unknown. After oral administration with food, the maximum plasma concentration of etravirine isgenerally achieved within 4 hours.

In healthy subjects, the absorption of etravirine is not affected by co-administration of oral ranitidineor omeprazole, medicinal products that are known to increase gastric pH.

Effect of food on absorption

The systemic exposure (AUC) to etravirine was decreased by about 50% when etravirine wasadministered 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 α1-acidglycoprotein (97.66%-99.02%) in vitro. The distribution of etravirine into compartments other thanplasma (e.g., cerebrospinal fluid, genital tract secretions) has not been evaluated in humans.

In vitro experiments with human liver microsomes (HLMs) indicate that etravirine primarilyundergoes oxidative metabolism by the hepatic cytochrome CYP450 (CYP3A) system and, to a lesserextent, by the CYP2C family, followed by glucuronidation.

After administration of a radiolabeled 14C-etravirine dose, 93.7% and 1.2% of the administered dose of14C-etravirine could be retrieved in faeces and urine, respectively. Unchanged etravirine accounted for81.2% to 86.4% of the administered dose in faeces. Unchanged etravirine in faeces is likely to beunabsorbed drug. Unchanged etravirine was not detected in urine. The terminal elimination half-life ofetravirine was approximately 30-40 hours.

Paediatric population (1 year to less than 18 years of age)

The pharmacokinetics of etravirine in 122 treatment-experienced HIV-1 infected paediatric patients,1 year to less than 18 years of age, showed that the administered weight-based dosages resulted inetravirine exposure comparable to that in adults receiving etravirine 200 mg twice daily (seesections 4.2 and 5.2). The population pharmacokinetic estimates for etravirine AUC12h and C0h aresummarised in the table below.

Table 10: Pharmacokinetic parameters for etravirine in treatment-experienced HIV-1infected paediatric patients 1 year to less than 18 years of age (TMC125-

C234/IMPAACT P1090 [48 week analysis, intensive PK] and PIANO [48 Weeksanalysis, population PK])

Age Range (years) ≥ 1 year to < 2 years ≥ 2 years to < 6 years 6 years to < 18 years(Cohort II) (Cohort I)

Parameter Etravirine Etravirine Etravirine

N = 6 N = 15 N = 101

AUC12h (ng*h/ml)

Geometric 3,328 ± 3,138 3,824 ± 3,613 3,729 ± 4,305

Mean ± Standard

Deviation

Median (Range) 3,390 (1,148 - 9,989) 3,709 (1,221 - 12,999) 4,560 (62 - 28,865)

C0h (ng/ml)

Geometric 193 ± 186 203 ± 280 205 ± 342

Mean ± Standard

Deviation

Median (Range) 147 (0a - 503) 180 (54 - 908) 287 (2 - 2,276)a One subject in Cohort II had etravirine predose concentrations below the detection limit at the intensive PK visit.

Population pharmacokinetic analysis in HIV infected patients showed that etravirine pharmacokineticsare not considerably different in the age range (18 to 77 years) evaluated, with 6 subjects aged65 years or older (see sections 4.2 and 4.4).

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

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

Etravirine is primarily metabolised and eliminated by the liver. In a study comparing 8 patients withmild (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 pharmacokineticdisposition of etravirine was not altered in patients with mild to moderate hepatic impairment.

However, unbound concentrations have not been assessed. Increased unbound exposure could beexpected. No dose adjustment is suggested but caution is advised in patients with moderate hepaticimpairment. 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 etravirine in HIV-1infected patients with hepatitis B and/or hepatitis C virus co-infection. In view of the limited dataavailable 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. Resultsfrom a mass balance study with radioactive 14C-etravirine showed that < 1.2% of the administereddose of etravirine is excreted in the urine. No unchanged drug was detected in urine so the impact ofrenal impairment on etravirine elimination is expected to be minimal. As etravirine is highly bound toplasma proteins, it is unlikely that it will be significantly removed by haemodialysis or peritonealdialysis (see section 4.2).

Study TMC114HIV3015 evaluated etravirine 200 mg twice daily in combination with otherantiretroviral medicinal products in 15 pregnant women during the second and third trimesters ofpregnancy and postpartum. The total etravirine exposure after intake of etravirine 200 mg twice dailyas 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 etravirine 200 mg twice daily, higher mean values for Cmax, AUC12h and Cmin wereobserved during pregnancy compared to postpartum. During the 2nd and 3rd trimester of pregnancymean values of these parameters were comparable.

Table 11: Pharmacokinetic results of total etravirine after administration of etravirine200 mg twice daily as part of an antiretroviral regimen, during the 2nd trimester ofpregnancy, the 3rd trimester of pregnancy, and postpartum.

Pharmacokinetics of Etravirine 200 mg Etravirine 200 mg Etravirine 200 mgetravirine twice daily twice daily 2nd twice daily 3rd

Mean ± SD (median) postpartum trimester trimester

N = 10 N = 13 N = 10a

Cmin, ng/ml 269 ± 182 (284) 383 ± 210 (346) 349 ± 103 (371)

Cmax, ng/ml 569 ± 261 (528) 774 ± 300 (828) 785 ± 238 (694)

AUC12h, h*ng /ml 5004 ± 2521 (5246) 6617 ± 2766 (6836) 6846 ± 1482 (6028)a n = 9 for AUC12h

Each subject served as her own control, and with an intra-individual comparison, the total etravirine

Cmin, Cmax and AUC12h values were 1.2-, 1.4- and 1.4-fold higher, respectively, during the 2nd trimesterof pregnancy as compared to postpartum, and 1.1-, 1.4- and 1.2-fold higher, respectively, based duringthe 3rd trimester of pregnancy as compared to postpartum.

Animal toxicology studies have been conducted with etravirine in mice, rats, rabbits and dogs. Inmice, the key target organs identified were the liver and the coagulation system. Haemorrhagiccardiomyopathy was only observed in male mice and was considered to be secondary to severecoagulopathy mediated via the vitamin K pathway. In the rat, the key target organs identified were theliver, the thyroid and the coagulation system. Exposure in mice was equivalent to human exposurewhile in rats it was below the clinical exposure at the recommended dose. In the dog, changes wereobserved in the liver and gall bladder at exposures approximately 8-fold higher than human exposureobserved at the recommended dose (200 mg twice daily).

In a study conducted in rats, there were no effects on mating or fertility at exposure levels equivalentto those in humans at the clinically recommended dose. There was no teratogenicity with etravirine inrats and rabbits at exposures equivalent to those observed in humans at the recommended clinicaldose. Etravirine had no effect on offspring development during lactation or post weaning at maternalexposures equivalent to those observed at the recommended clinical dose.

Etravirine was not carcinogenic in rats and in male mice. An increase in the incidences ofhepatocellular adenomas and carcinomas were observed in female mice. The observed hepatocellularfindings in female mice are generally considered to be rodent specific, associated with liver enzymeinduction, 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 tothose observed in humans at the recommended therapeutic dose (200 mg twice daily).

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

INTELENCE 25 mg tablets

Hypromellose

Microcrystalline cellulose

Colloidal anhydrous silica

Croscarmellose sodium

Magnesium stearate

Lactose monohydrate

INTELENCE 100 mg tablets

Hypromellose

Microcrystalline cellulose

Colloidal anhydrous silica

Croscarmellose sodium

Magnesium stearate

Lactose monohydrate

INTELENCE 200 mg tablets

Hypromellose

Silicified microcrystalline cellulose

Microcrystalline cellulose

Colloidal anhydrous silica

Croscarmellose sodium

Magnesium stearate

Not applicable.

INTELENCE 25 mg tablets2 years.8 weeks after opening the bottle.

INTELENCE 100 mg tablets2 years.

INTELENCE 200 mg tablets2 years.6 weeks after opening the bottle.

Store in the original bottle and keep the bottle tightly closed in order to protect from moisture. Do notremove the desiccant pouches.

INTELENCE 25 mg tablets

The bottle is a high-density polyethylene (HDPE) plastic bottle containing 120 tablets and 2 desiccantpouches, fitted with a polypropylene (PP) child resistant closure.

Each carton contains one bottle.

INTELENCE 100 mg tablets

The bottle is a high-density polyethylene (HDPE) plastic bottle containing 120 tablets and 3 desiccantpouches, fitted with a polypropylene (PP) child resistant closure.

Each carton contains one bottle.

INTELENCE 200 mg tablets

The bottle is a high-density polyethylene (HDPE) plastic bottle containing 60 tablets and 3 desiccantpouches, fitted with a polypropylene (PP) child resistant closure.

Each carton contains one bottle.

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:

- place the tablet(s) in 5 ml (1 teaspoon) of water, or at least enough liquid to cover the medicine,

- stir well until the water looks milky,

- if desired, add more water or alternatively orange juice or milk (patients should not place thetablets 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 rinseeach time to make sure the patient takes the entire dose.

INTELENCE tablet(s) dispersed in liquid should be taken before other antiretroviral liquids that mayneed to be taken concomitantly.

The patient and his/her caregiver should be instructed to contact the prescribing physician if unable toswallow the entire dose when dispersed in liquid (see section 4.4).

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

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

25 mg: EU/1/08/468/003100 mg: EU/1/08/468/001200 mg: EU/1/08/468/002

Date of first authorisation: 28 August 2008

Date of latest renewal: 23 August 2018

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