4.1. Therapeutic 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 2 years of age (see sections 4.4, 4.5 and 5.1).

4.2. Posology and method of administration

Therapy should be initiated by a physician experienced in the management of HIV infection.

Posology

INTELENCE must always be given in combination with other antiretroviral medicinal products.

Adults

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 and weighing at least 10 kg) is based on body weight (see table below). INTELENCE tablet(s) should be taken orally, following a meal (see section 5.2).

Table 1: Recommended dose of etravirine for paediatric patients 2 years to less than 18 years of age

Body weight

Dose

Tablets

≥ 10 to < 20 kg

100 mg twice daily

four 25 mg tablets twice daily or

one 100 mg tablet twice daily

≥ 20 to < 25 kg

125 mg twice daily

five 25 mg tablets twice daily or

one 100 mg tablet and one 25 mg tablet twice daily

≥ 25 to < 30 kg

150 mg twice daily

six 25 mg tablets twice daily or

one 100 mg tablet and two 25 mg tablets twice daily

≥ 30 kg

200 mg twice daily

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.

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

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 2 years of age)

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

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 (see section 4.4).

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

4.3. Contraindications

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).

4.4. Special warnings and precautions for use

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 reactions have been reported with etravirine. In clinical trials, 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 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 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 etravirine. 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).

Paediatric population

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

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 etravirine. 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 medicinal products 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. Etravirine 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 and autoimmune hepatitis) 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 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 monohydrate. 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 monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5. Interaction 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 etravirine 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 etravirine 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 2. The table is not all-inclusive.

Interaction table

Interactions between etravirine and co-administered medicinal products are listed in table 2 (increase is 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 therapeutic areas

Effects on drug levels

Least Squares Mean Ratio

(90% CI; 1.00 = No effect)

Recommendations concerning co-administration

ANTI-INFECTIVES

Antiretrovirals

NRTIs

Didanosine

400 mg once daily

didanosine

AUC ↔ 0.99 (0.79-1.25)

Cmin ND

Cmax ↔ 0.91 (0.58-1.42)

etravirine

AUC ↔ 1.11 (0.99-1.25)

Cmin ↔ 1.05 (0.93-1.18)

Cmax ↔ 1.16 (1.02-1.32)

No significant effect on didanosine and etravirine PK parameters is seen. INTELENCE and didanosine can be used without dose adjustments.

Tenofovir disoproxil

245 mg once dailyb

tenofovir

AUC ↔ 1.15 (1.09-1.21)

Cmin ↑ 1.19 (1.13-1.26)

Cmax ↑ 1.15 (1.04-1.27)

etravirine

AUC ↓ 0.81 (0.75-0.88)

Cmin ↓ 0.82 (0.73-0.91)

Cmax ↓ 0.81 (0.75-0.88)

No significant effect on tenofovir and etravirine PK parameters is seen. INTELENCE and tenofovir can be used without dose adjustments.

Other NRTIs

Not studied, but no interaction expected based on the primary renal elimination route for other NRTIs (e.g., abacavir, emtricitabine, lamivudine, stavudine and zidovudine).

INTELENCE can be used with these NRTIs without dose adjustment.

NNRTIs

Efavirenz

Nevirapine

Rilpivirine

Combining two NNRTIs has not been shown to be beneficial. Concomitant use of etravirine with efavirenz or nevirapine may cause a significant decrease in the plasma concentration of etravirine and loss of therapeutic effect of etravirine.

Concomitant use of etravirine with rilpivirine may cause a decrease in the plasma concentration of rilpivirine and loss of therapeutic effect of rilpivirine.

It is not recommended to co-administer INTELENCE with other NNRTIs.

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

Indinavir

Concomitant use of etravirine with indinavir may cause a significant decrease in the plasma concentration of indinavir and loss of therapeutic effect of indinavir.

It is not recommended to co-administer INTELENCE with indinavir.

HIV PIs – Boosted with low-dose ritonavir

Atazanavir/ritonavir

300/100 mg once daily

atazanavir

AUC ↓ 0.86 (0.79-0.93)

Cmin ↓ 0.62 (0.55-0.71)

Cmax ↔ 0.97 (0.89-1.05)

etravirine

AUC ↑ 1.30 (1.18-1.44)

Cmin ↑ 1.26 (1.12-1.42)

Cmax ↑ 1.30 (1.17-1.44)

INTELENCE and atazanavir/ritonavir can be used without dose adjustment.

Darunavir/ritonavir

600/100 mg twice daily

darunavir

AUC ↔ 1.15 (1.05-1.26)

Cmin ↔ 1.02 (0.90-1.17)

Cmax ↔ 1.11 (1.01-1.22)

etravirine

AUC ↓ 0.63 (0.54-0.73)

Cmin ↓ 0.51 (0.44-0.61)

Cmax ↓ 0.68 (0.57-0.82)

INTELENCE and darunavir/ritonavir can be used without dose adjustments (see also section 5.1).

Fosamprenavir/ ritonavir

700/100 mg twice daily

amprenavir

AUC ↑ 1.69 (1.53-1.86)

Cmin ↑ 1.77 (1.39-2.25)

Cmax ↑ 1.62 (1.47-1.79)

etravirine

AUC ↔a

Cmin ↔a

Cmax ↔a

Amprenavir/ritonavir and fosamprenavir/ritonavir may require dose reduction when co-administered with INTELENCE. Using the oral solution may be considered for dose reduction.

Lopinavir/ritonavir

(tablet)

400/100 mg twice daily

lopinavir

AUC ↔ 0.87 (0.83-0.92)

Cmin ↓ 0.80 (0.73-0.88)

Cmax ↔ 0.89 (0.82-0.96)

etravirine

AUC ↓ 0.65 (0.59-0.71)

Cmin ↓ 0.55 (0.49-0.62)

Cmax ↓ 0.70 (0.64-0.78)

INTELENCE and lopinavir/ritonavir can be used without dose adjustments.

Saquinavir/ritonavir

1,000/100 mg twice daily

saquinavir

AUC ↔ 0.95 (0.64-1.42)

Cmin ↓ 0.80 (0.46-1.38)

Cmax ↔ 1.00 (0.70-1.42)

etravirine

AUC ↓ 0.67 (0.56-0.80)

Cmin ↓ 0.71 (0.58-0.87)

Cmax ↓ 0.63 (0.53-0.75)

INTELENCE and saquinavir/ritonavir can be used without dose adjustments.

Tipranavir/ritonavir

500/200 mg twice daily

tipranavir

AUC ↑ 1.18 (1.03-1.36)

Cmin ↑ 1.24 (0.96-1.59)

Cmax ↑ 1.14 (1.02-1.27)

etravirine

AUC ↓ 0.24 (0.18-0.33)

Cmin ↓ 0.18 (0.13-0.25)

Cmax ↓ 0.29 (0.22-0.40)

It is not recommended to co-administer tipranavir/ritonavir and INTELENCE (see section 4.4).

HIV PIs – Boosted with cobicistat

Atazanavir/cobicistat

Darunavir/cobicistat

Not studied. Co-administration of etravirine with atazanavir/cobicistat or darunavir/cobicistat may decrease plasma concentrations of the PI and/or cobicistat, which may result in loss of therapeutic effect and development of resistance.

Co-administration of INTELENCE with atazanavir/cobicistat or darunavir/cobicistat is not recommended.

CCR5 Antagonists

Maraviroc

300 mg twice daily

Maraviroc/darunavir/

ritonavir

150/600/100 mg twice daily

maraviroc

AUC ↓ 0.47 (0.38-0.58)

Cmin ↓ 0.61 (0.53-0.71)

Cmax ↓ 0.40 (0.28-0.57)

etravirine

AUC ↔ 1.06 (0.99-1.14)

Cmin ↔ 1.08 (0.98-1.19)

Cmax ↔ 1.05 (0.95-1.17)

maraviroc*

AUC ↑ 3.10 (2.57-3.74)

Cmin ↑ 5.27 (4.51-6.15)

Cmax ↑ 1.77 (1.20-2.60)

* compared to maraviroc 150 mg twice daily

The recommended dose for maraviroc when combined with INTELENCE and a PI is 150 mg twice daily, except for fosamprenavir/ritonavir which is not recommended with maraviroc. No dose adjustment for INTELENCE is necessary.

See also section 4.4.

Fusion Inhibitors

Enfuvirtide

90 mg twice daily

etravirine*

AUC ↔a

C0h ↔a

Enfuvirtide concentrations not studied and no effect is expected.

* based on population pharmacokinetic analyses

No interaction is expected for either INTELENCE or enfuvirtide when co-administered.

Integrase Strand Transfer Inhibitors

Dolutegravir

50 mg once daily

Dolutegravir + darunavir/ritonavir

50 mg once daily + 600/100 mg twice daily

Dolutegravir + Lopinavir/ritonavir

50 mg once daily + 400/100 mg twice daily

dolutegravir

AUC ↓ 0.29 (0.26-0.34)

Cmin ↓ 0.12 (0.09-0.16)

Cmax ↓ 0.48 (0.43-0.54)

etravirine

AUC ↔a

Cmin ↔a

Cmax ↔a

dolutegravir

AUC↓ 0.75 (0.69-0.81)

Cmin ↓ 0.63 (0.52-0.77)

Cmax ↓ 0.88 (0.78-1.00)

etravirine

AUC ↔a

Cmin ↔a

Cmax ↔a

dolutegravir

AUC↔ 1.11(1.02-1.20)

Cmin ↑ 1.28 (1.13-1.45)

Cmax ↔ 1.07 (1.02-1.13)

etravirine

AUC ↔a

Cmin ↔a

Cmax ↔a

Etravirine significantly reduced plasma concentrations of dolutegravir. The effect of etravirine on dolutegravir plasma concentrations was mitigated by co-administration of darunavir/ritonavir or lopinavir/ritonavir, and is expected to be mitigated by atazanavir/ritonavir.

INTELENCE should only be used with dolutegravir when co-administered with atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. This combination can be used without dose adjustment.

Raltegravir

400 mg twice daily

raltegravir

AUC ↓ 0.90 (0.68-1.18)

Cmin ↓ 0.66 (0.34-1.26)

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)

INTELENCE and raltegravir can be used without dose adjustments.

ANTIARRHYTHMICS

Digoxin

0.5 mg single dose

digoxin

AUC ↑ 1.18 (0.90-1.56)

Cmin ND

Cmax ↑ 1.19 (0.96-1.49)

INTELENCE and digoxin can be used without dose adjustments. It is recommended that digoxin levels be monitored when digoxin is combined with INTELENCE.

Amiodarone

Bepridil

Disopyramide

Flecainide

Lidocaine (systemic)

Mexiletine

Propafenone

Quinidine

Not studied. INTELENCE is expected to decrease plasma concentrations of these antiarrhythmics.

Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when co-administered with INTELENCE.

ANTIBIOTICS

Azithromycin

Not studied. Based on the biliary elimination pathway of azithromycin, no drug interactions are expected between azithromycin and INTELENCE.

INTELENCE and azithromycin can be used without dose adjustments.

Clarithromycin

500 mg twice daily

clarithromycin

AUC ↓ 0.61 (0.53-0.69)

Cmin ↓ 0.47 (0.38-0.57)

Cmax ↓ 0.66 (0.57-0.77)

14-OH-clarithromycin

AUC ↑ 1.21 (1.05-1.39)

Cmin ↔ 1.05 (0.90-1.22)

Cmax ↑ 1.33 (1.13-1.56)

etravirine

AUC ↑ 1.42 (1.34-1.50)

Cmin ↑ 1.46 (1.36-1.58)

Cmax ↑ 1.46 (1.38-1.56)

Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.

ANTICOAGULANTS

Warfarin

Not studied. Etravirine is expected to increase plasma concentrations of warfarin.

It is recommended that the international normalised ratio (INR) be monitored when warfarin is combined with INTELENCE.

ANTICONVULSANTS

Carbamazepine

Phenobarbital

Phenytoin

Not studied. Carbazamepine, phenobarbital and phenytoin are expected to decrease plasma concentrations of etravirine.

Combination not recommended.

ANTIFUNGALS

Fluconazole

200 mg once in the morning

fluconazole

AUC ↔ 0.94 (0.88-1.01)

Cmin ↔ 0.91 (0.84-0.98)

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)

INTELENCE and fluconazole can be used without dose adjustments.

Itraconazole

Ketoconazole

Posaconazole

Not studied. Posaconazole, a potent inhibitor of CYP3A4, may increase plasma concentrations of etravirine. Itraconazole and ketoconazole are potent inhibitors as well as substrates of CYP3A4. Concomitant systemic use of itraconazole or ketoconazole and etravirine may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of itraconazole or ketoconazole may be decreased by etravirine.

INTELENCE and these antifungals can be used without dose adjustments.

Voriconazole

200 mg twice daily

voriconazole

AUC ↑ 1.14 (0.88-1.47)

Cmin ↑ 1.23 (0.87-1.75)

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)

INTELENCE and voriconazole can be used without dose adjustments.

ANTIMALARIALS

Artemether/

Lumefantrine

80/480 mg, 6 doses at 0, 8, 24, 36, 48, and 60 hours

artemether

AUC ↓ 0.62 (0.48-0.80)

Cmin ↓ 0.82 (0.67-1.01)

Cmax ↓ 0.72 (0.55-0.94)

dihydroartemisinin

AUC ↓ 0.85 (0.75-0.97)

Cmin ↓ 0.83 (0.71-0.97)

Cmax ↓ 0.84 (0.71-0.99)

lumefantrine

AUC ↓ 0.87 (0.77-0.98)

Cmin ↔ 0.97 (0.83-1.15)

Cmax ↔ 1.07 (0.94-1.23)

etravirine

AUC ↔ 1.10 (1.06-1.15)

Cmin ↔ 1.08 (1.04-1.14)

Cmax ↔ 1.11 (1.06-1.17)

Close monitoring of antimalarial response is warranted when co-administering INTELENCE and artemether/lumefantrine as a significant decrease in exposure of artemether and its active metabolite, dihydroartemisinin, may result in decreased antimalarial efficacy. No dose adjustment is needed for INTELENCE.

ANTIMYCOBACTERIALS

Rifampicin

Rifapentine

Not studied. Rifampicin and rifapentine are expected to decrease plasma concentrations of etravirine.

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

Combination not recommended.

Rifabutin

300 mg once daily

With an associated boosted PI:

No interaction study has been performed. Based on historical data, a decrease in etravirine exposure may be expected whereas an increase in rifabutin exposure and especially in 25-O-desacetyl-rifabutin may be expected.

With no associated boosted PI (out of the recommended indication for etravirine):

rifabutin

AUC ↓ 0.83 (0.75-0.94)

Cmin ↓ 0.76 (0.66-0.87)

Cmax ↓ 0.90 (0.78-1.03)

25-O-desacetyl-rifabutin

AUC ↓ 0.83 (0.74-0.92)

Cmin ↓ 0.78 (0.70-0.87)

Cmax ↓ 0.85 (0.72-1.00)

etravirine

AUC ↓ 0.63 (0.54-0.74)

Cmin ↓ 0.65 (0.56-0.74)

Cmax ↓ 0.63 (0.53-0.74)

The combination of INTELENCE with a boosted PI and rifabutin should be used with caution due to the risk of decrease in etravirine exposure and the risk of increase in rifabutin and 25-O-desacetyl-rifabutin exposures.

Close monitoring for virologic response and for rifabutin related adverse reactions is recommended.

Please refer to the product information of the associated boosted PI for the dose adjustment of rifabutin to be used.

BENZODIAZEPINES

Diazepam

Not studied. Etravirine is expected to increase plasma concentrations of diazepam.

Alternatives to diazepam should be considered.

CORTICOSTEROIDS

Dexamethasone (systemic)

Not studied. Dexamethasone is expected to decrease plasma concentrations of etravirine

Systemic dexamethasone should be used with caution or alternatives should be considered, particularly for chronic use.

OESTROGEN-BASED CONTRACEPTIVES

Ethinylestradiol

0.035 mg once daily

Norethindrone

1 mg once daily

ethinylestradiol

AUC ↑ 1.22 (1.13-1.31)

Cmin ↔ 1.09 (1.01-1.18)

Cmax ↑ 1.33 (1.21-1.46)

norethindrone

AUC ↔ 0.95 (0.90-0.99)

Cmin ↓ 0.78 (0.68-0.90)

Cmax ↔ 1.05 (0.98-1.12)

etravirine

AUC ↔a

Cmin ↔a

Cmax ↔a

The combination of oestrogen- and/or progesterone-based contraceptives and INTELENCE can be used without dose adjustment.

HEPATITIS C VIRUS (HCV) DIRECT-ACTING ANTIVIRALS

Ribavirin

Not studied, but no interaction expected based on the renal elimination pathway of ribavirin.

The combination of INTELENCE and ribavirin can be used without dose adjustments.

Daclatasvir

Not studied. Co-administration of etravirine with daclatasvir may decrease daclatasvir concentrations.

Co-administration of Intelence and daclatasvir is not recommended.

Elbasvir/grazoprevir

Not studied. Co-administration of etravirine with elbasvir/grazoprevir may decrease elbasvir and grazoprevir concentrations, leading to reduced therapeutic effect of elbasvir/grazoprevir.

Co-administration is contraindicated (see section 4.3).

HERBAL PRODUCTS

St John's wort (Hypericum perforatum)

Not studied. St John's wort is expected to decrease the plasma concentrations of etravirine.

Combination not recommended.

HMG CO-A REDUCTASE INHIBITORS

Atorvastatin

40 mg once daily

atorvastatin

AUC ↓ 0.63 (0.58-0.68)

Cmin ND

Cmax ↑ 1.04 (0.84-1.30)

2-OH-atorvastatin

AUC ↑ 1.27 (1.19-1.36)

Cmin ND

Cmax ↑ 1.76 (1.60-1.94)

etravirine

AUC ↔ 1.02 (0.97-1.07)

Cmin ↔ 1.10 (1.02-1.19)

Cmax ↔ 0.97 (0.93-1.02)

The combination of INTELENCE and atorvastatin can be given without any dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response.

Fluvastatin

Lovastatin

Pravastatin

Rosuvastatin

Simvastatin

Not studied. No interaction between pravastatin and etravirine is expected.

Lovastatin, rosuvastatin and simvastatin are CYP3A4 substrates and co-administration with etravirine may result in lower plasma concentrations of the HMG Co-A reductase inhibitor. Fluvastatin, and rosuvastatin are metabolised by CYP2C9 and co-administration with etravirine may result in higher plasma concentrations of the HMG Co-A reductase inhibitor.

Dose adjustments for these HMG Co-A reductase inhibitors may be necessary.

H2-RECEPTOR ANTAGONISTS

Ranitidine

150 mg twice daily

etravirine

AUC ↓ 0.86 (0.76-0.97)

Cmin ND

Cmax ↓ 0.94 (0.75-1.17)

INTELENCE can be co-administered with H2-receptor antagonists without dose adjustments.

IMMUNOSUPPRESSANTS

Cyclosporin

Sirolimus

Tacrolimus

Not studied. Etravirine is expected to decrease plasma concentrations of cyclosporine, sirolimus and tacrolimus.

Co-administration with systemic 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

individual dose ranging from 60 mg to 130 mg once daily

R(-) methadone

AUC ↔ 1.06 (0.99-1.13)

Cmin ↔ 1.10 (1.02-1.19)

Cmax ↔ 1.02 (0.96-1.09)

S(+) methadone

AUC ↔ 0.89 (0.82-0.96)

Cmin ↔ 0.89 (0.81-0.98)

Cmax ↔ 0.89 (0.83-0.97)

etravirine

AUC ↔a

Cmin ↔a

Cmax ↔a

No changes in methadone dosage were required based on clinical status during or after the period of INTELENCE co-administration.

PHOSPHODIESTERASE, TYPE 5 (PDE-5) INHIBITORS

Sildenafil 50 mg single dose

Tadalafil

Vardenafil

sildenafil

AUC ↓ 0.43 (0.36-0.51)

Cmin ND

Cmax ↓ 0.55 (0.40-0.75)

N-desmethyl-sildenafil

AUC ↓ 0.59 (0.52-0.68)

Cmin ND

Cmax ↓ 0.75 (0.59-0.96)

Concomitant use of PDE-5 inhibitors with INTELENCE may require dose adjustment of the PDE-5 inhibitor to attain the desired clinical effect.

PLATELET AGGREGGATION INHIBITORS

Clopidogrel

In vitro data show that etravirine has inhibitory properties on CYP2C19. It is therefore possible that etravirine may inhibit the metabolism of clopidogrel to its active metabolite by such inhibition of CYP2C19 in vivo. The clinical relevance of this interaction has not been demonstrated.

As a precaution it is recommended that concomitant use of etravirine and clopidogrel should be discouraged.

PROTON PUMP INHIBITORS

Omeprazole

40 mg once daily

etravirine

AUC ↑ 1.41 (1.22-1.62)

Cmin ND

Cmax ↑ 1.17 (0.96-1.43)

INTELENCE can be co-administered with proton pump inhibitors without dose adjustments.

SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIS)

Paroxetine

20 mg once daily

paroxetine

AUC ↔ 1.03 (0.90-1.18)

Cmin ↓ 0.87 (0.75-1.02)

Cmax ↔ 1.06 (0.95-1.20)

etravirine

AUC ↔ 1.01 (0.93-1.10)

Cmin ↔ 1.07 (0.98-1.17)

Cmax ↔ 1.05 (0.96-1.15)

INTELENCE can be co-administered with paroxetine without dose adjustments.

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

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, 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 etravirine 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

Etravirine is excreted in human milk.

Because of the potential for adverse events in nursing infants, women should be instructed not to breastfeed if they are receiving INTELENCE.

It is recommended that women living with HIV do not breastfeed 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).

4.7. Effects on ability to drive and use machines

INTELENCE has minor influence on the ability to drive and use machines. No studies on the effects of INTELENCE on the ability to drive or operate machines have been performed. Adverse reactions such as somnolence and vertigo have been reported in etravirine-treated patients and should be considered when assessing a patient's ability to drive or operate machinery (see section 4.8).

4.8. Undesirable effects

Summary of the safety profile

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

Tabulated list of adverse reactions

Adverse reactions reported in patients treated with etravirine are summarised in Table 3. The adverse reactions 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 very common (≥ 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-marketing experience

System Organ Class (SOC)

Frequency category

Adverse Reaction

Blood and lymphatic system disorders

common

thrombocytopaenia, anaemia, decreased neutrophils

uncommon

decreased white blood cell count

Immune system disorders

common

drug hypersensitivity

uncommon

immune reconstitution syndrome

Metabolism and nutrition disorders

common

diabetes mellitus, hyperglycaemia, hypercholesterolaemia, increased low density lipoprotein (LDL), hypertriglyceridaemia, hyperlipidaemia, dyslipidaemia, anorexia

Psychiatric disorders

common

anxiety, insomnia, sleep disorders

uncommon

confusional state, disorientation, nightmares, nervousness, abnormal dreams

Nervous system disorders

very common

headache

common

peripheral neuropathy, paraesthesia, hypoaesthesia, amnesia, somnolence

uncommon

convulsion, syncope, tremor, hypersomnia, disturbance in attention

Eye disorders

common

blurred vision

Ear and labyrinth disorders

uncommon

vertigo

Cardiac disorders

common

myocardial infarction

uncommon

atrial fibrillation, angina pectoris

Vascular disorders

common

hypertension

rare

haemorrhagic strokea

Respiratory, thoracic and mediastinal disorders

common

exertional dyspnoea

uncommon

bronchospasm

Gastrointestinal disorders

very common

diarrhoea, nausea

common

gastrooesophageal reflux disease, vomiting, abdominal pain, abdominal distension, flatulence, gastritis, constipation, dry mouth, stomatitis, lipase increased, blood amylase increased

uncommon

pancreatitis, haematemesis, retching

Hepatobiliary disorders

common

increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST)

uncommon

hepatitis, hepatic steatosis, cytolytic hepatitis, hepatomegaly

Skin and subcutaneous tissue disorders

very common

rash

common

night sweats, dry skin, prurigo

uncommon

angioneurotic oedemaa, swelling face, hyperhidrosis

rare

Stevens-Johnson Syndromea, erythema multiformea

very rare

toxic epidermal necrolysisa, DRESSb

Renal and urinary disorders

common

renal failure, blood creatinine increased

Reproductive system and breast disorders

uncommon

gynaecomastia

General disorders and administration site conditions

common

fatigue

uncommon

sluggishness

a 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.

Description of selected adverse reactions

Rash

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 etravirine 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).

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 and autoimmune hepatitis) 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 (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 infected paediatric patients 6 years to less than 18 years of age received INTELENCE in combination with other antiretroviral agents. TMC125-C234/IMPAACT P1090 is a Phase I/II trial in which 26 antiretroviral treatment-experienced HIV-1 infected paediatric patients aged 1 years to less than 6 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 adverse reactions in paediatric patients were comparable to those observed in adults. In PIANO, 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.

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

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 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 of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medical 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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There are no data with regard to symptomatic overdose with etravirine, but it is possible that the most frequent adverse reactions of etravirine, i.e. rash, diarrhoea, nausea, and headache would be the most common symptoms noted. There is no specific antidote for overdose with etravirine. 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.