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Intelence (etravirine) – Summary of product characteristics - J05AG04

Updated on site: 08-Oct-2017

Medication nameIntelence
ATC CodeJ05AG04
Substanceetravirine
ManufacturerJanssen-Cilag International NV

1.NAME OF THE MEDICINAL PRODUCT

INTELENCE 25 mg tablets

INTELENCE 100 mg tablets

INTELENCE 200 mg tablets

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

INTELENCE 25 mg tablets

Each tablet contains 25 mg of etravirine.

Excipient with known effect: Each tablet contains 40 mg lactose.

INTELENCE 100 mg tablets

Each tablet contains 100 mg of etravirine.

Excipient with known effect: Each tablet contains 160 mg lactose.

INTELENCE 200 mg tablets

Each tablet contains 200 mg of etravirine.

For the full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM

INTELENCE 25 mg tablets

Tablet

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

The tablet can be divided into 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.

4.CLINICAL PARTICULARS

4.1Therapeutic indications

INTELENCE, in combination with a boosted protease inhibitor and other antiretroviral medicinal products, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-experienced adult patients and in antiretroviral treatment-experienced paediatric patients from 6 years of age (see sections 4.4, 4.5 and 5.1).

The indication in adults is based on week 48 analyses from 2 Phase III trials in highly pre-treated patients where INTELENCE was investigated in combination with an optimised background regimen (OBR) which included darunavir/ritonavir. The indication in paediatric patients is based on 48-week analyses of a single-arm, Phase II trial in antiretroviral treatment-experienced paediatric patients (see section 5.1).

4.2Posology 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.

Posology

Adults

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).

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

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).

Recommended dose of INTELENCE for paediatric patients 6 years to less than 18 years of age

Body 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

Missed dose

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.

Elderly

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.

Hepatic impairment

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).

Renal impairment

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

Paediatric population (less than 6 years of age)

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.

Pregnancy and postpartum

Based on limited data available, no dose adjustment is required during pregnancy and postpartum (see section 5.2).

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.

4.3Contraindications

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).

4.4Special 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 and hypersensitivity reactions

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

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).

Elderly

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).

Pregnancy

Given the increased etravirine exposure during pregnancy, caution should be applied for those pregnant patients that require concomitant medications or have comorbidities that may further increase etravirine exposure.

Patients with coexisting conditions

Hepatic impairment

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).

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 current limited data available. A potential increased risk of liver enzymes increase cannot be excluded.

Weight and metabolic parameters

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established 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, 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).

Osteonecrosis

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.

Interactions with medicinal products

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.

The combination of etravirine with simeprevir, daclatasvir, atazanavir/cobicistat or darunavir/cobicistat is not recommended (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. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

INTELENCE 100 mg tablets

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

4.5Interaction with other medicinal products and other forms of interaction

Medicinal products that affect etravirine exposure

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.

Medicinal products that are affected by the use 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. The table is not all-inclusive.

Interaction table

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”).

Table 1:

Interactions and dose recommendations with other medicinal products

Medicinal products by

Effects on drug levels

Recommendations

therapeutic areas

Least Squares Mean Ratio

concerning

 

 

(90% CI; 1.00 = No effect)

co-administration

ANTI-INFECTIVES

 

 

Antiretrovirals

 

 

NRTIs

 

 

 

Didanosine

 

didanosine

No significant effect on

400 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 didanosine

 

 

etravirine

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 on

245 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 tenofovir

 

 

etravirine

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

Etravirine can be used with

 

 

on the primary renal elimination route for other

these NRTIs without dose

 

 

NRTIs (e.g., abacavir, emtricitabine,

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 INTELENCE

co-administer INTELENCE

Rilpivirine

 

with efavirenz or nevirapine may cause a

with other NNRTIs.

 

 

significant decrease in the plasma concentration

 

 

 

of etravirine and loss of therapeutic effect of

 

 

 

INTELENCE.

 

 

 

Concomitant use of INTELENCE with

 

 

 

rilpivirine may cause a decrease in the plasma

 

 

 

concentration of rilpivirine and loss of

 

 

 

therapeutic effect of rilpivirine.

 

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

Indinavir

 

Concomitant use of INTELENCE with

It is not recommended to

 

 

indinavir may cause a significant decrease in

co-administer INTELENCE

 

 

the plasma concentration of indinavir and loss

with indinavir.

 

 

of therapeutic effect of indinavir.

 

Nelfinavir

 

Not studied. INTELENCE is expected to

It is not recommended to

 

 

increase nelfinavir plasma concentrations.

co-administer INTELENCE

 

 

 

with nelfinavir.

HIV PIs - Boosted with low-dose ritonavir

 

Atazanavir/ritonavir

atazanavir

INTELENCE and

300/100 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 and

600/100 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 also

 

etravirine

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 and

700/100 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 with

 

etravirine

INTELENCE. Using the oral

 

AUC ↔a

solution may be considered

 

Cmin a

for dose reduction.

 

Cmax a

 

Lopinavir/ritonavir

lopinavir

INTELENCE and

(tablet)

AUC ↔ 0.87 (0.83-0.92)

lopinavir/ritonavir can be

400/100 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 and

1,000/100 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 to

500/200 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 (see

 

etravirine

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 INTELENCE

Co-administration of

Darunavir/cobicistat

with atazanavir/cobicistat or

INTELENCE with

 

darunavir/cobicistat may decrease plasma

atazanavir/cobicistat or

 

concentrations of the PI and/or cobicistat,

darunavir/cobicistat is not

 

which may result in loss of therapeutic effect

recommended.

 

and development of resistance.

 

CCR5 Antagonists

 

 

Maraviroc

maraviroc

The recommended dose for

300 mg twice daily

AUC ↓ 0.47 (0.38-0.58)

maraviroc when combined

 

Cmin ↓ 0.61 (0.53-0.71)

with INTELENCE in the

 

Cmax ↓ 0.40 (0.28-0.57)

presence of potent CYP3A

 

etravirine

inhibitors (e.g. boosted PIs)

 

AUC ↔ 1.06 (0.99-1.14)

is 150 mg b.i.d. except for

 

Cmin ↔ 1.08 (0.98-1.19)

fosamprenavir/ritonavir

Maraviroc/darunavir/

Cmax ↔ 1.05 (0.95-1.17)

(maraviroc dose 300 mg

maraviroc*

b.i.d.). No dose adjustment

ritonavir

AUC ↑ 3.10 (2.57-3.74)

for INTELENCE is

150/600/100 mg twice

Cmin ↑ 5.27 (4.51-6.15)

necessary.

daily

Cmax ↑ 1.77 (1.20-2.60)

See also section 4.4.

 

* compared to maraviroc 150 mg b.i.d.

 

Fusion Inhibitors

Enfuvirtide

etravirine*

No interaction is expected for

90 mg twice daily

AUC ↔a

either INTELENCE or

 

C0h a

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 significantly

50 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 of

 

etravirine

etravirine on dolutegravir

 

AUC ↔a

plasma concentrations was

 

Cmin a

mitigated by

 

Cmax a

co-administration of

 

 

darunavir/ritonavir or

Dolutegravir +

dolutegravir

lopinavir/ritonavir, and is

darunavir/ritonavir

AUC↓ 0.75 (0.69-0.81)

expected to be mitigated by

50 mg once daily +

Cmin ↓ 0.63 (0.52-0.77)

atazanavir/ritonavir.

600/100 mg twice daily

Cmax ↓ 0.88 (0.78-1.00)

INTELENCE should only be

 

etravirine

 

AUC ↔a

used with dolutegravir when

 

Cmin a

co-administered with

 

Cmax a

atazanavir/ritonavir,

 

 

darunavir/ritonavir, or

Dolutegravir +

dolutegravir

lopinavir/ritonavir. This

Lopinavir/ritonavir

AUC↔ 1.11(1.02-1.20)

combination can be used

50 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

 

 

Cmax a

 

Raltegravir

raltegravir

INTELENCE and raltegravir

400 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 digoxin

0.5 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 digoxin

 

 

levels be monitored when

 

 

digoxin 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.

Quinidine

 

 

ANTIBIOTICS

Azithromycin

Not studied. Based on the biliary elimination

INTELENCE and

 

pathway of azithromycin, no drug interactions

azithromycin can be used

 

are expected between azithromycin and

without dose adjustments.

 

INTELENCE.

 

Clarithromycin

clarithromycin

Clarithromycin exposure was

500 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 against

 

etravirine

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; therefore

 

 

alternatives to clarithromycin

 

 

should be considered for the

 

 

treatment of MAC.

ANTICOAGULANTS

 

 

Warfarin

Not studied. INTELENCE is expected to

It is recommended that the

 

increase plasma concentrations of warfarin.

international normalised ratio

 

 

(INR) be monitored when

 

 

warfarin 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 and

200 mg once in the

AUC ↔ 0.94 (0.88-1.01)

fluconazole can be used

morning

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 of

 

 

itraconazole or ketoconazole and INTELENCE

 

 

may increase plasma concentrations of

 

 

etravirine. Simultaneously, plasma

 

 

concentrations of itraconazole or ketoconazole

 

 

may be decreased by INTELENCE.

 

Voriconazole

voriconazole

INTELENCE and

200 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 is

80/480 mg, 6 doses at 0,

Cmin ↓ 0.82 (0.67-1.01)

warranted when

8, 24, 36, 48, and

Cmax ↓ 0.72 (0.55-0.94)

co-administering

60 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 and

 

lumefantrine

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. No

 

etravirine

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 combination

 

 

with a boosted PI. Rifampicin is contraindicated

 

 

in combination with boosted PIs.

 

Rifabutin

With an associated boosted PI:

The combination of

300 mg once daily

No interaction study has been performed. Based

INTELENCE with a boosted

 

on historical data, a decrease in etravirine

PI and rifabutin should be

 

exposure may be expected whereas an increase

used with caution due to the

 

in rifabutin exposure and especially in

risk of decrease in etravirine

 

25-O-desacetyl-rifabutin may be expected.

exposure and the risk of

 

 

increase in rifabutin and

 

With no associated boosted PI (out of the

25-O-desacetyl-rifabutin

 

recommended 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 be

 

etravirine

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 diazepam

 

plasma 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 caution

 

 

or alternatives should be

 

 

considered, particularly for

 

 

chronic use.

OESTROGEN-BASED CONTRACEPTIVES

Ethinylestradiol

ethinylestradiol

The combination of

0.035 mg once daily

AUC ↑ 1.22 (1.13-1.31)

oestrogen- and/or

Norethindrone

Cmin ↔ 1.09 (1.01-1.18)

progesterone-based

1 mg once daily

Cmax ↑ 1.33 (1.21-1.46)

contraceptives and

 

norethindrone

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

 

 

Cmin a

 

 

Cmax a

 

HEPATITIS C VIRUS (HCV) DIRECT-ACTING ANTIVIRALS

 

Ribavirin

Not studied, but no interaction expected based

The combination of

 

on the renal elimination pathway of ribavirin.

INTELENCE and ribavirin

 

 

can be used without dose

 

 

adjustments.

Boceprevir

boceprevir

The clinical significance of

800 mg 3 times daily +

AUC ↑ 1.10 (0.94-1.28)

the reductions in etravirine

etravirine 200 mg every

Cmax ↑ 1.10 (0.94-1.29)

pharmacokinetic parameters

12 hours

Cmin ↓ 0.88 (0.66-1.17)

and boceprevir Cmin in the

 

etravirine

setting of the combination

 

AUC ↓ 0.77 (0.66-0.91)

therapy with HIV

 

Cmax ↓ 0.76 (0.68-0.85)

antiretroviral medicines

 

Cmin ↓ 0.71 (0.54-0.95)

which also affect the

 

 

pharmacokinetics of

 

 

etravirine and/or boceprevir

 

 

has not been directly

 

 

assessed. Increased clinical

 

 

and laboratory monitoring for

 

 

HIV and HCV suppression is

 

 

recommended.

Daclatasvir

Not studied. Co-administration of INTELENCE

Co-administration of

 

with daclatasvir may decrease daclatasvir

Intelence and daclatasvir is

 

concentrations.

not recommended.

Elbasvir/grazoprevir

Not studied. Co-administration of INTELENCE

Co-administration is

 

with elbasvir/grazoprevir may decrease elbasvir

contraindicated (see

 

and grazoprevir concentrations, leading to

section 4.3).

 

reduced therapeutic effect of

 

 

elbasvir/grazoprevir.

 

Simeprevir

Not studied. Concomitant use of INTELENCE

Co-administration of

 

with simeprevir may decrease plasma

Intelence and simeprevir is

 

concentrations of simeprevir.

not recommended.

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 of

40 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 dose

 

2-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 INTELENCE is expected.

HMG Co-A reductase

Pravastatin

Lovastatin, rosuvastatin and simvastatin are

inhibitors may be necessary.

Rosuvastatin

CYP3A4 substrates and co-administration with

 

Simvastatin

INTELENCE may result in lower plasma

 

 

concentrations of the HMG Co-A reductase

 

 

inhibitor. Fluvastatin, and rosuvastatin are

 

 

metabolised by CYP2C9 and co-administration

 

 

with INTELENCE may result in higher plasma

 

 

concentrations of the HMG Co-A reductase

 

 

inhibitor.

 

H2-RECEPTOR ANTAGONISTS

 

Ranitidine

etravirine

INTELENCE can be

150 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 should

 

 

be done with caution because

 

 

plasma concentrations of

 

 

cyclosporin, sirolimus and

 

 

tacrolimus may be affected

 

 

when co-administered with

 

 

INTELENCE.

NARCOTIC ANALGESICS

 

Methadone

R(-) methadone

No changes in methadone

individual dose ranging

AUC ↔ 1.06 (0.99-1.13)

dosage were required based

from 60 mg to 130 mg

Cmin ↔ 1.10 (1.02-1.19)

on clinical status during or

once 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

 

 

Cmin a

 

 

Cmax a

 

PHOSPHODIESTERASE, TYPE 5 (PDE-5) INHIBITORS

 

Sildenafil 50 mg single

sildenafil

Concomitant use of PDE-5

dose

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 is

 

properties on CYP2C19. It is therefore possible

recommended that

 

that etravirine may inhibit the metabolism of

concomitant use of etravirine

 

clopidogrel to its active metabolite by such

and clopidogrel should be

 

inhibition of CYP2C19 in vivo. The clinical

discouraged.

 

relevance of this interaction has not been

 

 

demonstrated.

 

PROTON PUMP INHIBITORS

 

Omeprazole

etravirine

INTELENCE can be

40 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 be

20 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)

 

aComparison based on historic control.

bStudy 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 similar exposures and, therefore, interactions relevant for one formulation are relevant for the other.

Paediatric population

Interaction studies have only been performed in adults.

4.6Fertility, pregnancy and lactation

Pregnancy

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.

Breast-feeding

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.

Fertility

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).

4.7Effects 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.

4.8Undesirable 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

Frequency

ADRs (INTELENCE + BR versus Placebo + BR)

(SOC)

Category

 

Blood and lymphatic

common

thrombocytopaenia (1.3% vs 1.5%), anaemia (4.0% vs

system disorders

 

3.8%)

Immune system

uncommon

immune reconstitution syndrome (0.2% vs 0.3%), drug

disorders

 

hypersensitivity (0.8% vs 1.2%)

Metabolism and

common

diabetes mellitus (1.3% vs 0.2%), hyperglycaemia

nutrition disorders

 

(1.5% vs 0.7%), hypercholesterolaemia (4.3% vs 3.6%),

 

 

hypertriglyceridaemia (6.3% vs 4.3%), hyperlipidaemia

 

 

(2.5% vs 1.3%)

 

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%)

 

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

common

peripheral neuropathy (3.8% vs 2.0%), headache (3.0%

disorders

 

vs 4.5%)

 

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

uncommon

vertigo (0.2% vs 0.5%)

disorders

 

 

Cardiac disorders

common

myocardial infarction (1.3% vs 0.3%)

 

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

uncommon

bronchospasm (0.2% vs 0%), exertional dyspnoea

and mediastinal

 

(0.5% vs 0.5%)

disorders

 

 

Gastrointestinal

common

gastrooesophageal reflux disease (1.8% vs 1.0%),

disorders

 

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%)

 

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

very common

rash (10.0% vs 3.5%)

tissue disorders

common

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

common

renal failure (2.7% vs 2.0%)

disorders

 

 

Reproductive system

uncommon

gynaecomastia (0.2% vs 0%)

and breast disorders

 

 

General disorders and

common

fatigue (3.5% vs 4.6%)

administration site

uncommon

sluggishness (0.2% vs 0%)

conditions

 

 

Additional ADRs of at least moderate intensity observed in other trials were 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

Metabolic parameters

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (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.

4.9Overdose

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. Since etravirine is highly protein bound, dialysis is unlikely to result in significant removal of the active substance.

5.PHARMACOLOGICAL PROPERTIES

5.1Pharmacodynamic properties

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

Mechanism of action

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.

Antiviral activity in vitro

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 0.3 to 1.7 nM and from 11.5 to 21.7 nM, respectively. Although etravirine demonstrates in vitro

activity 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 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.

Resistance

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.

Cross-resistance

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:

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 prior genotypic 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 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

 

INTELENCE + BR

Placebo + BR

Treatment

 

difference

 

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 viral

 

 

 

 

 

load (< 50 HIV-1 RNA

 

 

 

 

 

copies/ml)a

 

 

 

 

 

n (%)

 

 

 

 

20.9%

Overall

(60.6%)

(39.7%)

(15.3%; 26.4%)d

De novo ENF

(71.2%)

93 (58.5%)

12.8%

(2.3%; 23.2%)f

Not de novo ENF

(57.0%)

(33.0%)

23.9%

(17.6%; 30.3%)f

< 400 HIV-1 RNA copies/mla

(71.5%)

(47.4%)

24.1%

n (%)

(18.7%; 29.5%)d

HIV-1 RNA log10 mean change

-2.25

-1.49

-0.6

from baseline (log10 copies/ml)b

(-0.8; -0.5)c

CD4 cell count mean change

+98.2

+72.9

24.4

from baseline (x 106/l)b

(10.4; 38.5)c

Any AIDS defining illness

(5.8%)

(9.8%)

-3.9%

and/or death n (%)

(-6.9%; -0.9%)e

aImputations according to the TLOVR algorithm (TLOVR = Time to Loss of Virologic Response).

bNon-completer is failure (NC = F) imputation.

cTreatment 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.

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

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

fConfidence 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.

Table 4: DUET-1 and DUET-2 pooled data

 

Proportion of subjects with HIV-1 RNA < 50 copies/ml

Subgroups

at week 48

 

INTELENCE + 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, (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.

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

 

Etravirine arms

INTELENCE RAMs*

 

N = 549

 

Reused/not used ENF

 

De novo ENF

All ranges

63.3% (254/401)

 

78.4% (109/139)

74.1% (117/158)

 

91.3% (42/46)

61.3% (73/119)

 

80.4% (41/51)

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)

* INTELENCE 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 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 naïve 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-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 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.

Paediatric population

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.

Table 6: Virologic responses (ITT - TLOVR), change from baseline in log10 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

 

 

 

 

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 at

24 (58.5)

28 (46.7)

52 (51.5)

363 (60.6)

week 24, n (%)

 

 

 

 

Viral load < 400 copies/ml at

28 (68.3)

38 (63.3)

66 (65.3)

445 (74.3)

week 24, n (%)

 

 

 

 

≥ 1 log10 decrease from

26 (63.4)

38 (63.3)

64 (63.4)

475 (79.3)

baseline at week 24, n (%)

 

 

 

 

Change from baseline in log10

-1.62 (0.21)

-1.44 (0.17)

-1.51 (0.13)

-2.37 (0.05)

viral load (copies/ml) at

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 CD4

125 (33.0)

104 (17.5)

112 (16.9)

83.5 (3.64)

cell count (x 106 cells/l), mean

124 (-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 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).

Pregnancy and postpartum

INTELENCE (200 mg b.i.d.), evaluated in combination with other antiretroviral medicinal products in 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 with postpartum, and less so for unbound etravirine exposure (see section 5.2). There were no new clinically relevant safety findings in the mothers or in the newborns in this trial.

5.2Pharmacokinetic 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.

Table 7: Population pharmacokinetic estimates of etravirine 200 mg b.i.d. in HIV-1 infected adult subjects (integrated data from Phase III trials at week 48)*

Parameter

Etravirine 200 mg b.i.d.

 

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 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 darunavir/ritonavir.

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

Absorption

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.

Effect of food on absorption

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.

Distribution

Etravirine is approximately 99.9% bound to plasma proteins, primarily to albumin (99.6%) and α1-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.

Biotransformation

In vitro 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.

Elimination

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

Special populations

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

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.

Table 8: Population pharmacokinetic estimates for etravirine (all doses combined) in treatment-experienced HIV-1 infected paediatric patients 6 years to less than 18 years of age (PIANO 48 week analysis)

Parameter

Etravirine

 

N = 101

AUC12h (ng•h/ml)

 

Geometric Mean ± Standard Deviation

3,729 ± 4,305

Median (Range)

4,560 (62 - 28,865)

C0h (ng/ml)

 

Geometric Mean ± Standard Deviation

205 ± 342

Median (Range)

287 (2 – 2,276)

Paediatric population (less than 6 years of age)

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).

Elderly

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).

Gender

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

Race

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.

Hepatic impairment

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).

Hepatitis B and/or hepatitis C virus co-infection

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).

Renal impairment

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).

Pregnancy and postpartum

Study TMC114HIV3015 evaluated etravirine 200 mg b.i.d. in combination with other antiretroviral medicinal products in 15 pregnant women during the second and third trimesters of pregnancy and postpartum. The total etravirine exposure after intake of etravirine 200 mg b.i.d. as part of an antiretroviral regimen was generally higher during pregnancy compared with postpartum (see Table 9). The differences were less pronounced for unbound etravirine exposure.

In women receiving etravirine 200 mg b.i.d., higher mean values for Cmax, AUC12h and Cmin were observed during pregnancy compared to postpartum. During the 2nd and 3rd trimester of pregnancy mean values of these parameters were comparable.

Table 9: Pharmacokinetic results of total etravirine after administration of etravirine 200 mg b.i.d. as part of an antiretroviral regimen, during the 2nd trimester of pregnancy, the 3rd trimester of pregnancy, and postpartum.

Pharmacokinetics of

Etravirine 200 mg

Etravirine 200 mg

Etravirine 200 mg

etravirine

b.i.d. postpartum

b.i.d. 2nd trimester

b.i.d. 3rd trimester

Mean ± SD (median)

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 trimester of pregnancy as compared to postpartum, and 1.1-, 1.4- and 1.2-fold higher, respectively, based during

the 3rd trimester of pregnancy as compared to postpartum.

5.3Preclinical 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.

6.PHARMACEUTICAL PARTICULARS

6.1List of excipients

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

6.2Incompatibilities

Not applicable.

6.3Shelf life

INTELENCE 25 mg tablets 2 years if bottle is unopened.

8 weeks after opening the bottle.

INTELENCE 100 mg tablets 2 years.

INTELENCE 200 mg tablets 2 years if bottle is unopened.

6 weeks after opening the bottle.

6.4Special 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.

6.5Nature and contents of container

INTELENCE 25 mg tablets

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.

INTELENCE 100 mg tablets

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

Each carton contains one bottle.

6.6Special 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:

-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 the tablets in orange juice or milk without first adding water);

-drink it immediately;

-rinse the glass several times with water, orange juice, or milk and completely swallow the rinse each time to make sure the patient takes the entire dose.

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

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

7.MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

8.MARKETING AUTHORISATION NUMBER(S)

25 mg: EU/1/08/468/003

100 mg: EU/1/08/468/001

200 mg: EU/1/08/468/002

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 28 August 2008

Date of latest renewal: 28 August 2013

10.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/.

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