INTELENCE

1. NAME OF THE MEDICINAL PRODUCT

INTELENCE 100 mg tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 100 mg of etravirine.

Excipient: Each tablet contains 160 mg lactose.

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

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

4. CLINICAL PARTICULARS

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 (see sections 4.4, 4.5 and 5.1).

This indication is based on week 48 analyses from 2 randomised, double-blind, placebo-controlled

Phase III trials in highly pre-treated patients with viral strains harbouring mutations of resistance to

non-nucleoside reverse transcriptase inhibitors and protease inhibitors, where INTELENCE was

investigated in combination with an optimised background regimen (OBR) which included

darunavir/ritonavir (see section 5.1).

4.2 Posology and method of administration

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

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

Adults

The recommended dose of INTELENCE is 200 mg (two 100 mg tablets) taken orally twice daily

(b.i.d.), following a meal (see section 5.2).

Patients who are unable to swallow INTELENCE tablets whole may disperse the tablets in a glass of

water. Once dispersed, patients should stir the dispersion well and drink it immediately. The glass

should be rinsed with water several times and each rinse completely swallowed to ensure the entire

dose is consumed.

Paediatric population

INTELENCE is not recommended for use in children and adolescents due to insufficient data on

safety and efficacy (see section 5.2).

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

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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).

If the patient misses a dose of INTELENCE within 6 hours of the time it is usually taken, the patient

should be told to take 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 be told not to take the missed dose and simply resume the usual dosing

schedule.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

4.4 Special warnings and precautions for use

Patients should be advised that current antiretroviral therapy does not cure HIV and has not been

proven to prevent the transmission of HIV to others through blood or sexual contact. Appropriate

precautions should continue to be employed.

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

Cutaneous reactions were most frequently mild to moderate, occurred in the second week of therapy,

and were infrequent after week 4. Cutaneous reactions were mostly self-limiting and generally

resolved within 1-2 weeks on continued therapy (see section 4.8).

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.

When prescribing INTELENCE to women, prescribers should be aware that the incidence of

cutaneous reactions was higher in women compared to men in the INTELENCE arm in the DUET

trials.

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,

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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,

eosinophilia). Time to onset is usually around 3-6 weeks and the outcome in most of 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 re-start therapy with

INTELENCE.

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 section 4.2 and 5.2).

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) 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 or HCV

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.

Fat redistribution

Combination antiretroviral therapy (CART) has been associated with redistribution of body fat

(lipodystrophy) in HIV infected patients. The long-term consequences of these events are currently

unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis

and protease inhibitors (PIs), and lipoatrophy and nucleoside reverse transcriptase inhibitors (NRTIs),

has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such

as older age, and with treatment related factors such as longer duration of antiretroviral treatment and

associated metabolic disturbances. Clinical examination should include evaluation for physical signs

of fat redistribution (see section 4.8).

Immune reconstitution syndrome

In HIV infected patients with severe immune deficiency at the time of institution 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 (see section

4.8).

Osteonecrosis

Although the etiology 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.

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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.

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

Lactose intolerance and lactase deficiency

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.

4.5 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 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.

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”, once daily as “q.d.”, once

daily in the morning as “q.a.m.”, twice daily as “b.i.d.”, confidence interval as “CI”).

Table 1: 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 q.d.

didanosine AUC ↔ 0.99 (0.79-1.25)

didanosine C min ND

didanosine C max ↔ 0.91 (0.58-1.42)

etravirine AUC ↔ 1.11 (0.99-1.25)

etravirine C min ↔ 1.05 (0.93-1.18)

etravirine C max ↔ 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.

5

Tenofovir

300 mg q.d.

tenofovir AUC ↔ 1.15 (1.09-1.21)

tenofovir C min ↑ 1.19 (1.13-1.26)

tenofovir C max ↑ 1.15 (1.04-1.27)

etravirine AUC ↓ 0.81 (0.75-0.88)

etravirine C min ↓ 0.82 (0.73-0.91)

etravirine C max ↓ 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).

Etravirine can be used with

these NRTIs without dose

adjustment.

NNRTIs

Efavirenz

Nevirapine

Combining two NNRTIs has not been shown to

be beneficial. Concomitant use of INTELENCE

with efavirenz or nevirapine may cause a

significant decrease in the plasma concentration

of etravirine and loss of therapeutic effect of

INTELENCE.

It is not recommended to

co-administer INTELENCE

with other NNRTIs.

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

Nelfinavir

Not studied. INTELENCE is expected to

increase nelfinavir plasma concentrations.

It is not recommended to

co-administer INTELENCE

with nelfinavir.

Indinavir

Concomitant use of INTELENCE 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.

PIs - Boosted (with low-dose ritonavir)

Tipranavir/ritonavir

500/200 mg b.i.d.

tipranavir AUC ↑ 1.18 (1.03-1.36)

tipranavir C min ↑ 1.24 (0.96-1.59)

tipranavir C max ↑ 1.14 (1.02-1.27)

etravirine AUC ↓ 0.24 (0.18-0.33)

etravirine C min ↓ 0.18 (0.13-0.25)

etravirine C max ↓ 0.29 (0.22-0.40)

It is not recommended to

co-administer

tipranavir/ritonavir and

INTELENCE (see section

4.4).

Fosamprenavir/ritonavir

700/100 mg b.i.d.

amprenavir AUC ↑ 1.69 (1.53-1.86)

amprenavir C min ↑ 1.77 (1.39-2.25)

amprenavir C max ↑ 1.62 (1.47-1.79)

etravirine AUC ↔ a

etravirine C min ↔ a

etravirine C max ↔ 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.

Atazanavir/ritonavir

300/100 mg q.d.

atazanavir AUC ↓ 0.86 (0.79-0.93)

atazanavir C min ↓ 0.62 (0.55-0.71)

atazanavir C max ↔ 0.97 (0.89-1.05)

etravirine AUC ↑ 1.30 (1.18-1.44)

etravirine C min ↑ 1.26 (1.12-1.42)

etravirine C max ↑ 1.30 (1.17-1.44)

INTELENCE and

atazanavir/ritonavir can be

used without dose adjustment.

Darunavir/ritonavir

600/100 mg b.i.d.

darunavir AUC ↔ 1.15 (1.05-1.26)

darunavir C min ↔ 1.02 (0.90-1.17)

darunavir C max ↔ 1.11 (1.01-1.22)

etravirine AUC ↓ 0.63 (0.54-0.73)

etravirine C min ↓ 0.51 (0.44-0.61)

etravirine C max ↓ 0.68 (0.57-0.82)

INTELENCE and

darunavir/ritonavir can be

used without dose

adjustments (see also section

5.1).

Lopinavir/ritonavir

(tablet)

400/100 mg b.i.d.

lopinavir AUC ↔ 0.87 (0.83-0.92)

lopinavir C min ↓ 0.80 (0.73-0.88)

lopinavir C max ↔ 0.89 (0.82-0.96)

etravirine AUC ↓ 0.65 (0.59-0.71)

etravirine C min ↓ 0.55 (0.49-0.62)

etravirine C max ↓ 0.70 (0.64-0.78)

INTELENCE and

lopinavir/ritonavir can be

used without dose

adjustments.

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Saquinavir/ritonavir

1,000/100 mg b.i.d.

saquinavir AUC ↔ 0.95 (0.64-1.42)

saquinavir C min ↓ 0.80 (0.46-1.38)

saquinavir C max ↔ 1.00 (0.70-1.42)

etravirine AUC ↓ 0.67 (0.56-0.80)

etravirine C min ↓ 0.71 (0.58-0.87)

etravirine C max ↓ 0.63 (0.53-0.75)

INTELENCE and

saquinavir/ritonavir can be

used without dose

adjustments.

CCR5 Antagonists

Maraviroc

300 mg b.i.d.

maraviroc AUC ↓ 0.47 (0.38-0.58)

maraviroc C min ↓ 0.61 (0.53-0.71)

maraviroc C max ↓ 0.40 (0.28-0.57)

etravirine AUC ↔ 1.06 (0.99-1.14)

etravirine C min ↔ 1.08 (0.98-1.19)

etravirine C max ↔ 1.05 (0.95-1.17)

maraviroc AUC ↑ 3.10* (2.57-3.74)

maraviroc C min ↑ 5.27* (4.51-6.15)

maraviroc C max ↑ 1.77* (1.20-2.60)

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

The recommended dose for

maraviroc when combined

with INTELENCE in the

presence of potent CYP3A

inhibitors (e.g. boosted PIs) is

150 mg b.i.d. except for

fosamprenavir/ritonavir

(maraviroc dose 300 mg

b.i.d.). No dose adjustment for

INTELENCE is necessary.

Category

ADRs (INTELENCE + BR versus Placebo + BR)

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%)

Blood and lymphatic

system disorders

common

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

3.8%)

Nervous system

disorders

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

disorders

uncommon vertigo (0.2% vs 0.5%)

Respiratory, thoracic and

mediastinal disorders

uncommon bronchospasm (0.2% vs 0%), exertional dyspnoea (0.5%

vs 0.5%)

Gastrointestinal

disorders

common gastrooesophageal reflux disease (1.8% vs 1.0%),

diarrhoea (7.0% vs 11.3%), vomiting (2.8% vs 2.8%),

nausea (5.2% vs 4.8%), abdominal pain (3.5% vs 3.1%),

flatulence (1.5% vs 1.0%), gastritis (1.5% vs 1.0%)

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%)

Renal and urinary

disorders

common

renal failure (2.7% vs 2.0%)

Skin and subcutaneous

tissue disorders

very common rash (10.0% vs 3.5%)

common lipohypertrophy (1.0% vs 0.3%), night sweats (1.0% vs

1.0%)

uncommon swelling face (0.3% vs 0%), hyperhidrosis (0.5% vs

0.2%), prurigo (0.7% vs 0.5%), dry skin (0.3% vs 0.2%)

Metabolism and

nutrition disorders

common diabetes mellitus (1.3% vs 0.2%), hyperglycaemia (1.5%

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

hypertriglyceridaemia (6.3% vs 4.3%), hyperlipidaemia

(2.5% vs 1.3%)

uncommon anorexia (0.8% vs 1.5%), dyslipidaemia (0.8% vs 0.3%)

Vascular disorders

common

hypertension (3.2% vs 2.5%)

General disorders and

administration site

conditions

common fatigue (3.5% vs 4.6%)

uncommon sluggishness (0.2% vs 0%)

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

hypersensitivity (0.8% vs 1.2%)

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%)

Reproductive system and

breast disorders

uncommon gynaecomastia (0.2% vs 0%)

Psychiatric disorders common

anxiety (1.7% vs 2.6%), insomnia (2.7% vs 2.8%)

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Immune system

disorders

uncommon confusional state (0.2% vs 0.2%), disorientation (0.2% vs

0.3%), nightmares (0.2% vs 0.2%), sleep disorders (0.5%

vs 0.5%), nervousness (0.2% vs 0.3%), abnormal dreams

(0.2% vs 0.2%)

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

angioneurotic oedema, erythema multiforme and haemorrhagic stroke, each reported in no more than

0.5% of patients. Stevens-Johnson Syndrome (rare; < 0.1%) and toxic epidermal necrolysis (very rare;

< 0.01%) have been reported during clinical development with INTELENCE.

Laboratory abnormalities

Treatment emergent clinical laboratory abnormalities (grade 3 or 4), considered ADRs, reported in

≥ 2% of patients in the INTELENCE arm versus the placebo arm, respectively, were increases in

amylase (8.9% vs 9.4%), creatinine (2.0% vs 1.7%), lipase (3.4% vs 2.6%), total cholesterol (8.1% vs

5.3%), low density lipoprotein (LDL) (7.2% vs 6.6%), triglycerides (9.2% vs 5.8%), glucose (3.5% vs

2.4%), alanine aminotransferase (ALT) (3.7% vs 2.0%), aspartate amino transferase (AST) (3.2% vs

2.0%) and decreases in neutrophils (5.0% vs 7.4%) and white blood cell count (2.0% vs 4.3%).

Lipodystrophy

Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy)

in HIV infected patients, including loss of peripheral and facial subcutaneous fat, increased

intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo

hump) (see section 4.4).

Immune reconstitution syndrome

In HIV infected patients with severe immune deficiency at the time of initiation of combination

antiretroviral therapy, an inflammatory reaction to asymptomatic or residual opportunistic infections

may arise (immune reconstitution syndrome) (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).

Additional information on 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 during post marketing experience with INTELENCE

Hypersensitivity reactions, including DRESS, have been reported with INTELENCE. These

hypersensitivity reactions are 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, eosinophilia) (see section 4.4).

4.9 Overdose

There is no specific antidote for overdose with INTELENCE. Treatment of overdose with

INTELENCE consists of general supportive measures including monitoring of vital signs and

observation of the clinical status of the patient. If indicated, elimination of unabsorbed active

substance is to be achieved by emesis or gastric lavage. Administration of activated charcoal may also

be used to aid in removal of unabsorbed active substance. Since etravirine is highly protein bound,

dialysis is unlikely to result in significant removal of the active substance.

5. PHARMACOLOGICAL PROPERTIES

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5.1 Pharmacodynamic properties

Pharmacotherapeutic group: NNRTI (non-nucleoside reverse transcriptase inhibitor), 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

EC 50 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 EC 50 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 EC 50 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 EC 50 ≤ 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 -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 experience

Treatment-experienced 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

14

 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

N=599

Placebo + BR

N=604

Treatment difference

(95% CI)

Baseline characteristics

Median plasma HIV-1 RNA

4.8 log 10 copies/ml 4.8 log 10 copies/ml

Median CD4 cell count

99 x 10 6 cells/l 109 x 10 6 cells/l

Outcomes

Confirmed undetectable viral load

(< 50 HIV-1 RNA copies/ml) a

n (%)

Overall

363 (60.6%)

240 (39.7%)

20.9%

(15.3%; 26.4%) d

12.8%

(2.3%; 23.2%) f

De novo ENF

109 (71.2%)

93 (58.5%)

23.9%

(17.6%; 30.3%) f

Not de novo ENF

254 (57.0%)

147 (33.0%)

< 400 HIV-1 RNA copies/ml a

n (%)

428 (71.5%)

286 (47.4%)

24.1%

(18.7%; 29.5%) d

HIV-1 RNA log 10 mean change

from baseline (log 10 copies/ml) b

-0.6

(-0.8; -0.5) c

-2.25

-1.49

CD4 cell count mean change from

baseline (x 10 6 /l) b

24.4

(10.4; 38.5) c

+98.2

+72.9

Any AIDS defining illness and/or

death n (%)

35 (5.8%)

59 (9.8%)

-3.9%

(-6.9%; -0.9%) e

a

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

b

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

c

Treatment differences are based on Least Square Means from an ANCOVA model including the stratification factors. P-value < 0.0001

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

d

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

stratification factors.

e

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

f

Confidence interval around observed difference of response rates; P-value from CMH test controlling for 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

Subgroups

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

week 48

15

INTELENCE + BR

N=599

Placebo + BR

N=604

Baseline HIV-1 RNA

< 30,000 copies/ml

≥ 30,000 and < 100,000 copies/ml

≥ 100,000 copies/ml

75.8%

61.2%

49.1%

55.7%

38.5%

28.1%

Baseline CD4 count (x 10 6 /l)

< 50

≥ 50 and < 200

≥ 200 and < 350

≥ 350

45.1%

65.4%

73.9%

72.4%

21.5%

47.6%

52.0%

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

INTELENCE RAMs*

Etravirine arms

N=549

Reused/not used ENF

De novo ENF

All ranges

63.3% (254/401)

78.4% (109/139)

0

74.1% (117/158)

91.3% (42/46)

1

61.3% (73/119)

80.4% (41/51)

2

64.1% (41/64)

66.7% (18/27)

≥ 3

38.3% (23/60)

53.3% (8/15)

Placebo arms

N=569

All ranges

37.1% (147/396)

64.1% (93/145)

* 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 EC 50 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)

16

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 log 10 copies/ml from baseline;

n=53) compared to the INTELENCE arm (-1.4 log 10 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.

This medicinal product has been authorised under a so-called “conditional approval” scheme.

This means that further evidence on this medicinal product is awaited.

The European Medicines Agency will review new information on the product every year and this SPC

will be updated as necessary.

5.2 Pharmacokinetic properties

The pharmacokinetic properties of etravirine have been evaluated in adult healthy subjects and in adult

treatment-experienced HIV-1 infected patients. Exposure to etravirine was lower (35-50%) in HIV-1

infected patients than in healthy subjects.

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.

Metabolism

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.

C-etravirine could be retrieved in faeces and urine, respectively. Unchanged etravirine accounted for

81.2% to 86.4% of the administered dose in faeces. Unchanged etravirine in faeces is likely to be

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

etravirine was approximately 30-40 hours.

Special populations

Paediatric population

17

Elimination

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

14

The pharmacokinetics of etravirine in paediatric patients are under investigation. There are insufficient

data at this time to recommend a dose (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 men and women. A limited

number of women 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 14 C-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).

5.3 Preclinical safety data

Animal toxicology studies have been conducted with etravirine in mice, rats, rabbits and dogs. In

mice, the key target organs identified were the liver and the coagulation system. Haemorrhagic

cardiomyopathy was only observed in male mice and was considered to be secondary to severe

coagulopathy mediated via the vitamin K pathway. In the rat, the key target organs identified were the

liver, the thyroid and the coagulation system. Exposure in mice was equivalent to human exposure

while in rats it was below the clinical exposure at the recommended dose. In the dog, changes were

observed in the liver and gall bladder at exposures approximately 8-fold higher than human exposure

observed at the recommended dose (200 mg b.i.d.).

In a study conducted in rats, there were no effects on mating or fertility at exposure levels equivalent

to those in humans at the clinically recommended dose. There was no teratogenicity with etravirine in

rats and rabbits at exposures equivalent to those observed in humans at the recommended clinical

18

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

6.1 List of excipients

Hypromellose

Microcrystalline cellulose

Colloidal anhydrous silica

Croscarmellose sodium

Magnesium stearate

Lactose monohydrate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

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

remove the desiccant pouches.

6.5 Nature and contents of container

High-density polyethylene (HDPE) plastic bottles containing 120 tablets and 3 desiccant pouches,

fitted with polypropylene (PP) child resistant closures.

Each carton contains one bottle.

6.6 Special precautions for disposal

No special requirements.

Any unused 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

19

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/08/468/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 28 August 2008

Date of latest renewal: 28 August 2009

10. DATE OF REVISION OF THE TEXT

{MM/YYYY}

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu/

20

ANNEX II

A. MANUFACTURING AUTHORISATION HOLDER

RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OF THE MARKETING AUTHORISATION

C. SPECIFIC OBLIGATIONS TO BE FULFILLED BY THE

MARKETING AUTHORISATION HOLDER

21

A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH

RELEASE

Name and address of the manufacturer responsible for batch release

Janssen-Cilag SpA

Via C. Janssen

04010 Borgo San Michele

Latina

Italy

B. CONDITIONS OF THE MARKETING AUTHORISATION

 CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON

THE MARKETING AUTHORISATION HOLDER

Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product

Characteristics, section 4.2).

 CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND

EFFECTIVE USE OF THE MEDICINAL PRODUCT

Not applicable.

 OTHER CONDITIONS

Pharmacovigilance system

The MAH must ensure that the system of pharmacovigilance, as described in version 5.1 (dated

1 March 2010) presented in Module 1.8.1. of the Marketing Authorisation, is in place and functioning

before and whilst the product is on the market.

Risk Management plan

The MAH commits to performing the studies and additional pharmacovigilance activities detailed in

the Pharmacovigilance Plan, as agreed in version 3.0 (dated 17 November 2009) of the Risk

Management Plan (RMP) presented in Module 1.8.2. of the Marketing Authorisation and any

subsequent updates of the RMP agreed by the CHMP.

As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the

updated RMP should be submitted at the same time as the next Periodic Safety Update Report

(PSUR).

In addition, an updated RMP should be submitted

 When new information is received that may impact on the current Safety Specification,

Pharmacovigilance Plan or risk minimisation activities.

 Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being

reached.

 At the request of the European Medicines Agency.

22

C. SPECIFIC OBLIGATIONS TO BE FULFILLED BY THE MARKETING

AUTHORISATION HOLDER

The Marketing Authorisation Holder shall complete the following programme of studies within the

specified time frame. The results of which shall be taken into account in the risk benefit balance

during the assessment of the application for a renewal.

Area Description

Due date

Clinical The MAH commits to conduct a confirmatory study with the

objective to provide reassurance on the extrapolation of the study

results from the two pivotal studies (DUET-1 and DUET-2) to the

combined use of etravirine with boosted PIs other than

darunavir/ritonavir. To meet this objective an adequately powered

clinical study should be designed to allow for a valid statistical

comparison between combination therapy including etravirine +

boosted PIs other than darunavir/ritonavir and standard triple

therapy. The design should employ NNRTI resistance as part of the

inclusion criteria, as well as individual stopping rules for non

response and failure to treatment. A DSMB should be set-up.

The MAH will provide regular updates on study progress within the

PSURs.

The final study report will be submitted for assessment whether the

objective of the study has been met. The SmPC and Package Leaflet

will be updated with the study results.

4Q 2014

(Final CSR*)

The MAH commits to conduct a feasibility study to provide further

information regarding the feasibility of conducting the currently

proposed confirmatory study. Should the outcome of such a

feasibility study be negative, the MAH will propose an alternative

study design to confirm results from the DUET-1 & -2 studies, in

line with current treatment guidelines for the target population.

31 August 2010

* Clinical Study Report

23

ANNEX III

LABELLING AND PACKAGE LEAFLET

24

A. LABELLING

25

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON

1. NAME OF THE MEDICINAL PRODUCT

INTELENCE 100 mg tablets

etravirine

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains 100 mg etravirine.

3. LIST OF EXCIPIENTS

Contains lactose monohydrate.

See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

120 tablets

5. METHOD AND ROUTE OF ADMINISTRATION

Oral use

Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE REACH AND SIGHT OF CHILDREN

Keep out of the reach and sight of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

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

remove the desiccant pouches.

26

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF

APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

12. MARKETING AUTHORISATION NUMBER

EU/1/08/468/001

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

intelence 100 mg

27

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

BOTTLE LABEL

1. NAME OF THE MEDICINAL PRODUCT

INTELENCE 100 mg tablets

etravirine

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains 100 mg etravirine.

3. LIST OF EXCIPIENTS

Contains lactose monohydrate.

4. PHARMACEUTICAL FORM AND CONTENTS

120 tablets

5. METHOD AND ROUTE OF ADMINISTRATION

Oral use

Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE REACH AND SIGHT OF CHILDREN

Keep out of the reach and sight of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in the original bottle. Keep the bottle tightly closed in order to protect from moisture.

28

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF

APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

12. MARKETING AUTHORISATION NUMBER

EU/1/08/468/001

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

29

B. PACKAGE LEAFLET

30

PACKAGE LEAFLET: INFORMATION FOR THE USER

INTELENCE 100 mg tablets

etravirine

Read all of this leaflet carefully before you start taking this medicine.

- Keep this leaflet. You may need to read it again.

- If you have any further questions, ask your doctor or pharmacist.

- This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even

if their symptoms are the same as yours.

- If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,

please tell your doctor or pharmacist.

In this leaflet :

1. What INTELENCE is and what it is used for

2. Before you take INTELENCE

3. How to take INTELENCE

4. Possible side effects

5. How to store INTELENCE

6. Further information

1. WHAT INTELENCE IS AND WHAT IT IS USED FOR

INTELENCE is a medicine used for the treatment of Human Immunodeficiency Virus (HIV)

infection. It belongs to a group of anti-HIV medicines called non-nucleoside reverse transcriptase

inhibitors (NNRTIs). INTELENCE works by reducing the amount of HIV in your body. This will

improve your immune system and reduces the risk of developing illnesses linked to HIV infection.

INTELENCE is used in combination with other anti-HIV medicines to treat adults who are infected by

HIV and who have used other anti-HIV medicines before.

Your doctor will discuss with you which combination of medicines is best for you.

2. BEFORE YOU TAKE INTELENCE

Do not take INTELENCE

- if you are allergic (hypersensitive) to etravirine or any of the other ingredients of INTELENCE.

These other ingredients are listed in section 6.

Take special care with INTELENCE

INTELENCE is not a cure for HIV infection. It is part of a treatment reducing the amount of virus in

the blood. INTELENCE does not reduce the risk of passing HIV to others through sexual contact or

contamination with blood. Therefore, you must continue to use appropriate precautions (a condom or

other barrier method) to lower the chance of sexual contact with any body fluids such as semen,

vaginal secretions or blood.

People taking INTELENCE may still develop infections or other illnesses associated with HIV

infection. You must keep in regular contact with your doctor.

INTELENCE is not for use in children or adolescents, because it has not been sufficiently studied in

patients under 18 years of age.

INTELENCE has only been used in a limited number of patients of 65 years or older. If you belong to

this age group, please discuss the use of INTELENCE with your doctor.

31

Tell your doctor about your situation

Make sure that you check the following points and tell your doctor if any of these apply to you.

- Tell your doctor if you develop a rash . If a rash occurs, it usually appears soon after anti-HIV

treatment with INTELENCE is started and often disappears within 1 to 2 weeks, even with

continued use of the medicine. Occasionally, during INTELENCE treatment, you can

experience hypersensitivity reaction (allergic reaction including rash and fever but also swelling

of the face, tongue or throat, difficulty in breathing or swallowing) which could be potentially

life-threatening. Please contact your doctor immediately if you get a hypersensitivity reaction.

Your doctor will advise you how to deal with your symptoms and whether INTELENCE must

be stopped. If you have stopped treatment due to a hypersensitivity reaction, you should not

re-start therapy with INTELENCE.

- Tell your doctor if you have or have had problems with your liver, including hepatitis B and/or

C. Your doctor may evaluate how severe your liver disease is before deciding if you can take

INTELENCE.

- Tell your doctor if you notice changes in body shape or fat . A gain, loss or redistribution of

body fat may occur if you take a combination of anti-HIV medicines.

- Tell your doctor immediately if you notice any symptoms of infections . In some patients with

advanced HIV infection and a history of opportunistic infection, signs and symptoms of

inflammation from previous infections may occur soon after anti-HIV treatment is started. It is

believed that these symptoms are due to an improvement in the body’s immune response,

enabling the body to fight infections that may have been present with no obvious symptoms.

Taking other medicines

INTELENCE might interact with other medicines. Please tell your doctor if you are taking or have

recently taken any other medicines, including medicines obtained without a prescription.

In most cases, INTELENCE can be combined with anti-HIV medicines belonging to another class.

However some combinations are not recommended. In other cases, increased monitoring and/or a

change in the dose of the medicine may be needed. Therefore always tell your doctor which other

anti-HIV medicines you take. Furthermore, it is important that you carefully read the package leaflets

that are provided with these medicines. Follow your doctor’s instruction carefully on which medicines

can be combined.

It is not recommended to combine INTELENCE with any of the following medicines :

- tipranavir/ritonavir (anti-HIV medicine)

- carbamazepine, phenobarbital, phenytoin (medicines to prevent seizures)

- rifampicin, because it is contraindicated with boosted protease inhibitors, and rifapentine

(medicines to treat some infections such as tuberculosis)

- products that contain St John’s wort ( Hypericum perforatum ) (a herbal product used for

depression).

If you are taking any of these, ask your doctor for advice.

The effects of INTELENCE or other medicines might be influenced if you take INTELENCE

together with any of the following medicines. Tell your doctor if you take:

- amiodarone, bepridil, digoxin, disopyramide, flecainide, lidocaine, mexiletine, propafenone and

quinidine (medicines to treat certain heart disorders, e.g., abnormal heart beat)

- warfarin (a medicine used to reduce clotting of the blood). Your doctor will have to check your

blood

- fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole (medicines to treat fungal

infections)

- clarithromycin, rifabutin (antibiotics)

- diazepam (medicines to treat trouble with sleeping and/or anxiety)

- dexamethasone (a corticosteroid used in a variety of conditions such as inflammation and

allergic reactions)

- atorvastatin, fluvastatin, lovastatin, rosuvastatin, simvastatin (cholesterol-lowering medicines)

- cyclosporine, sirolimus, tacrolimus (immunosuppressants)

32

- sildenafil, vardenafil, tadalafil (medicines to treat erectile dysfunction).

Taking INTELENCE with food and drink

It is important that you take INTELENCE following a meal. If you take it on an empty stomach, only

half the amount of INTELENCE is absorbed. For further information see section 3 ‘HOW TO TAKE

INTELENCE’.

Pregnancy and breast-feeding

Tell your doctor immediately if you are pregnant. Pregnant women should not take INTELENCE

unless specifically directed by the doctor.

HIV infected mothers must not breast-feed, as there is a possibility of infecting the baby with HIV.

Driving and using machines

No studies on the effects of INTELENCE on the ability to drive and use machines have been

performed. However, do not drive or operate machines if you feel sleepy or dizzy after taking your

medicines.

Important information about some of the ingredients of INTELENCE

INTELENCE tablets contain lactose. If you have been told by your doctor that you have an

intolerance to some sugars (lactose), contact your doctor before taking this medicine.

Bone problems

Some patients taking combination antiretroviral therapy may develop a bone disease called

osteonecrosis (death of bone tissue caused by loss of blood supply to the bone). The length of

combination antiretroviral therapy, corticosteroid use, alcohol consumption, severe

immunosuppression, higher body mass index, among others, may be some of the many risk factors for

developing this disease. Signs of osteonecrosis are joint stiffness, aches and pains (especially of the

hip, knee and shoulder) and difficulty in movement. If you notice any of these symptoms please

inform your doctor.

3. HOW TO TAKE INTELENCE

Always take INTELENCE exactly as your doctor has told you. You should check with your doctor if

you are not sure.

Instructions for proper use

The usual dose of INTELENCE is two tablets twice a day.

In the morning, take two 100 milligram INTELENCE tablets, following a meal.

In the evening, take two 100 milligram INTELENCE tablets, following a meal.

It is important that you take INTELENCE following a meal. If you take INTELENCE on an empty

stomach, only half the amount of INTELENCE is absorbed. Swallow the tablets whole with a glass of

water. Do not chew the tablets. If you are unable to swallow the INTELENCE tablets whole, you may

place the tablets in a glass of water. Stir well until the water looks milky, then drink it immediately.

Rinse the glass with water several times, and completely swallow the rinse each time to make sure you

take the entire dose.

Removing the child resistant cap

The plastic bottle comes with a child resistant cap and should be opened as

follows:

- Push the plastic screw cap down while turning it counter clockwise.

- Remove the unscrewed cap.

If you take more INTELENCE than you should

Contact your doctor or pharmacist immediately.

33

If you forget to take INTELENCE

If you notice within 6 hours of the time you usually take INTELENCE, you must take the tablets as

soon as possible. Always take the tablets following a meal. Then take the next dose as usual. If you

notice after 6 hours , then skip the intake and take the next doses as usual. Do not take a double dose

to make up for a forgotten dose.

Do not stop using INTELENCE without talking to your doctor first

HIV therapy may increase your sense of well-being. Even if you feel better, do not stop taking

INTELENCE or your other anti-HIV medicines. Doing so could increase the risk of the virus

developing resistance. Talk to your doctor first.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

4. POSSIBLE SIDE EFFECTS

Like any medicine, INTELENCE can cause side effects, although not everybody gets them.

The frequency of possible side effects listed below is defined using the following convention:

- very common: affects more than 1 user in 10

- common: affects 1 to 10 users in 100

- uncommon: affects 1 to 10 users in 1,000

- rare: affects 1 to 10 users in 10,000

- very rare: affects less than 1 user in 10,000

- not known: frequency cannot be estimated from the available data.

Very common side effects

- skin rash. The rash is usually mild to moderate. In rare instances, very serious rash has been

reported which can be potentially life-threatening. It is therefore important to contact your

doctor immediately if you develop a rash. Your doctor will advise you how to deal with your

symptoms and whether INTELENCE must be stopped.

Common side effects

- changes in some values of your blood cells or chemistry. These can be seen in the results from

blood tests. Your doctor will explain these to you. Examples are: low red blood cell count, low

blood platelet count, high or abnormal blood fat levels, high cholesterol levels, high sugar levels

- headache, tingling or pain in hands or feet, numbness, tiredness, sleeplessness, anxiety

- diarrhoea, nausea, vomiting, heartburn, abdominal pain, inflammation of the stomach, flatulence

- kidney failure, high blood pressure, heart attack, diabetes

- accumulation of fat, night sweats.

Uncommon side effects

- angina, irregular heart rhythm

- loss of skin sensibility, drowsiness, trembling, fainting, sleepiness, loss of memory, seizures,

stroke, disturbance in attention

- blurred vision, dizziness, sluggishness

- difficulty breathing

- dry mouth, mouth inflammation, retching, constipation, distension of the abdomen,

inflammation of the pancreas, vomiting blood, decrease of appetite

- excessive sweating, itching, dry skin, swelling of the face and/or throat

- allergic reactions (hypersensitivity), symptoms of infection (for example enlarged lymph nodes

and fever)

- liver problems such as hepatitis

- swelling of breasts in men

- sleep disorders, abnormal dreams, confusion, disorientation, nervousness

- body changes associated with fat redistribution.

34

Not known

- severe hypersensitivity reactions characterised by rash accompanied by fever and organ

inflammation such as hepatitis.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please

tell your doctor.

5. HOW TO STORE INTELENCE

Keep out of the reach and sight of children.

Do not use INTELENCE after the expiry date, which is stated on the carton and on the bottle after

EXP. The expiry date refers to the last day of that month.

INTELENCE tablets should be stored in the original bottle. Keep the bottle tightly closed in order to

protect from moisture. The bottle contains 3 little pouches (desiccants) to keep the tablets dry. These

pouches should stay in the bottle all the time and are not to be eaten.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to

dispose of medicines no longer required. These measures will help to protect the environment.

6. FURTHER INFORMATION

What INTELENCE contains

- The active substance is etravirine. Each tablet of INTELENCE contains 100 mg of etravirine.

- The other ingredients are hypromellose, microcrystalline cellulose, colloidal anhydrous silica,

croscarmellose sodium, magnesium stearate and lactose monohydrate.

What INTELENCE looks like and contents of the pack

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

A plastic bottle containing 120 tablets and 3 pouches to keep the tablets dry.

Marketing Authorisation Holder

Janssen-Cilag International NV, Turnhoutseweg 30, B-2340 Beerse, Belgium

Manufacturer

Janssen-Cilag SpA, Via C. Janssen, 04010 Borgo San Michele, Latina, Italy

For any information about this medicine, please contact the local representative of the Marketing

Authorisation Holder:

België/Belgique/Belgien

TIBOTEC, een divisie van, une division de, eine

Division der JANSSEN-CILAG NV/SA

Roderveldlaan 1

B-2600 Berchem

Tél/Tel: +32 3 280 54 11

Luxembourg/Luxemburg

TIBOTEC, une division de, eine Division der

JANSSEN-CILAG NV/SA

Roderveldlaan 1

B-2600 Berchem

Belgique/Belgien

Tél/Tel: +32 3 280 54 11

35

България

Представителство на TIBOTEC, дивизия на

Johnson & Johnson, d.o.o.

ж.к. Младост 4

Бизнес Парк София, сграда 4

София 1715

Тел.: +359 2 489 94 00

Magyarország

TIBOTEC, a JANSSEN-CILAG Kft. divíziója

H-2045 Törökbálint, Tó Park

Tel: +36 23 513 800

Česká republika

TIBOTEC, divize JANSSEN-CILAG s.r.o.

Karla Engliše 3201/06

CZ-150 00 Praha 5 - Smíchov

Tel: +420 227 012 222

Malta

AM MANGION LTD.

Mangion Building, Triq Ġdida fi Triq Valletta

MT-Ħal-Luqa LQA 6000

Tel: +356 2397 6000

Danmark

TIBOTEC, en division af JANSSEN-CILAG A/S

Hammerbakken 19

DK-3460 Birkerød

Tlf: +45 45 94 82 82

Nederland

TIBOTEC, een divisie van JANSSEN-CILAG

B.V.

Postbus 90240

NL-5000 LT Tilburg

Tel: +31 13 583 73 73

Deutschland

JANSSEN-CILAG GmbH

Johnson & Johnson Platz 1

D-41470 Neuss

Tel: +49 2137 955-955

Norge

TIBOTEC, en divisjon av JANSSEN-CILAG AS

Drammensveien 288

N-0283 Oslo

Tlf: +47 24 12 65 00

Eesti

TIBOTEC, JANSSEN-CILAG Polska Sp. z o.o.

Eesti filiaal

Lõõtsa 2

EE-11415 Tallinn

Tel: +372 617 7410

Österreich

TIBOTEC, eine Division von JANSSEN-CILAG

Pharma GmbH

Pfarrgasse 75

A-1232 Wien

Tel: +43 1 610 300

Ελλάδα

TIBOTEC, τμήμα της JANSSEN-CILAG

Φαρμακευτική Α.Ε.Β.Ε.

Λεωφόρος Ειρήνης 56

GR-151 21 Πεύκη, Αθήνα

Tηλ: +30 210 80 90 000

Polska

TIBOTEC, oddział JANSSEN-CILAG Polska Sp.

z o.o.

ul. Iłżecka 24

PL-02-135 Warszawa

Tel: +48 22 237 60 00

España

JANSSEN-CILAG, S.A. división TIBOTEC

Paseo de las Doce Estrellas, 5-7

Campo de las Naciones

E-28042 Madrid

Tel: +34 91 722 81 00

Portugal

TIBOTEC, uma divisão da JANSSEN-CILAG

FARMACÊUTICA, LDA.

Estrada Consiglieri Pedroso, 69 A

Queluz de Baixo

PT-2734-503 Barcarena

Tel: +351 21 43 68 835

France

TIBOTEC, une division de JANSSEN-CILAG

1, rue Camille Desmoulins, TSA 91003

F-92787 Issy Les Moulineaux, Cedex 9

Tél: 0 800 25 50 75 / +33 1 55 00 44 44

România

TIBOTEC, subsidiară a Janssen-Cilag, Johnson &

Johnson d.o.o.

Strada Tipografilor nr. 11-15, Clădirea S-Park,

corp A2, etaj 5

013714 Bucureşti

Tel: +40 21 2 071 800

36

Ireland

TIBOTEC, a division of JANSSEN-CILAG Ltd.

50-100 Holmers Farm Way

High Wycombe

Buckinghamshire HP12 4EG - UK

Tel: +44 1494 567 444

Slovenija

TIBOTEC za Janssen-Cilag, del

Johnson&Johnson d.o.o.

Šmartinska cesta 53

SI-1000 Ljubljana

Tel: +386 1 401 18 30

Ísland

TIBOTEC, deild hjá JANSSEN-CILAG

c/o Vistor hf.

Hörgatún 2

IS-210 Garðabær

Sími: +354 535 7000

Slovenská republika

TIBOTEC, divízia Johnson & Johnson s.r.o.

Plynárenská 7/B

SK-824 78 Bratislava

Tel: +421 233 552 600

Italia

TIBOTEC, una divisione di JANSSEN-CILAG

SpA

Via M.Buonarroti, 23

I-20093 Cologno Monzese MI

Tel: +39 02 2510 1

Suomi/Finland

TIBOTEC

JANSSEN-CILAG OY

Vaisalantie/Vaisalavägen 2

FI-02130 Espoo/Esbo

Puh/Tel: +358 207 531 300

Κύπρος

Βαρνάβας Χατζηπαναγής Λτδ,

7 Ανδροκλέους

CY-1060 Λευκωσία

Τηλ: +357 22 755 214

Sverige

TIBOTEC, en division inom JANSSEN-CILAG

AB

Box 7073

S-192 07 Sollentuna

Tel: +46 8 626 50 00

Latvija

TIBOTEC, JANSSEN-CILAG Polska Sp. z o.o.

filiāle Latvijā

Matrožu iela 15

LV-1048, Rīga

Tel: +371 678 93561

United Kingdom

TIBOTEC, a division of JANSSEN-CILAG Ltd.

50-100 Holmers Farm Way

High Wycombe

Buckinghamshire HP12 4EG - UK

Tel: +44 1494 567 444

Lietuva

UAB „Johnson & Johnson“

Geležinio Vilko g. 18A

LT-08104 Vilnius

Tel: +370 5 278 68 88

This leaflet was last approved in {MM/YYYY}.

This medicine has been given “conditional approval”.

This means that there is more evidence to come about this medicine.

The European Medicines Agency will review new information on the medicine every year and this

leaflet will be updated as necessary.

Detailed information on this medicine is available on the European Medicines Agency web site:

http://www.ema.europa.eu/ .

37

European Drugs Encyclopedia

European Drugs
Encyclopedia