Intelence 200 mg tablets

  • Name:

    Intelence 200 mg tablets

  • Company:
    info
  • Active Ingredients:

    Etravirine

  • Legal Category:

    Product subject to medical prescription which may not be renewed (A)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 05/05/20

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Summary of Product Characteristics last updated on medicines.ie: 5/5/2020

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Janssen Sciences Ireland

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When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 5 May 2020 PIL

Reasons for updating

  • Change to section 1 - what the product is used for
  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 2 - use in children and adolescents
  • Change to section 2 - interactions with other medicines, food or drink
  • Change to section 3 - use in children/adolescents
  • Change to section 3 - how to take/use
  • Change to section 6 - date of revision

Free text change information supplied by the pharmaceutical company

1.       What INTELENCE is and what it is used for

INTELENCE is used in combination with other anti‑HIV medicines to treat adults and children 62 years of age and older who are infected by HIV and who have used other anti‑HIV medicines before.

 

2.       What you need to know before you take INTELENCE

 

Children and adolescents

 

Do not give this medicine to children less than 62 years of age and weighing less than 1610 kg because the potential benefits and risks have not yet been established.

Children and adolescents

 

Do not give this medicine to children less than 62 years of age and weighing less than 1610 kg because the potential benefits and risks have not yet been established.

 

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

  • tipranavir/ritonavir, efavirenz, nevirapine, rilpivirine, indinavir, nelfinavir, atazanavir/cobicistat, darunavir/cobicistat (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)
  • daclatasvir, simeprevir (a medicines to treat hepatitis C infection).
     
    The effects of INTELENCE or other medicines might be influenced if you take INTELENCE together with any of the following medicines. The dosages of some medicines might need to be changed since their therapeutic effect or side effects may be influenced when combined with INTELENCE. Tell your doctor if you take:
  • dolutegravir, maraviroc, amprevanir/ritonavir and fosamprenavir/ritonavir (anti-HIV medicine)
  • 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)
  • artemether/lumefantrine (a medicine to treat malaria)
  • 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)
  • boceprevir (a medicine to treat hepatitis C infection)
  • atorvastatin, fluvastatin, lovastatin, rosuvastatin, simvastatin (cholesterol‑lowering medicines)
  • cyclosporine, sirolimus, tacrolimus (immunosuppressants – medicines used to dampen down your immune system)
  • sildenafil, vardenafil, tadalafil (medicines to treat erectile dysfunction and/or pulmonary arterial hypertension)
  • clopidogrel (a medicine to prevent blood clots).
     
    3.       How to take INTELENCE
     
    Use in children and adolescents 62 years of age and older and weighing at least 1610 kg
    The doctor will work out the right dose based on the weight of the child.
    The doctor will inform you exactly how much INTELENCE the child should take.
    If you are unable to swallow the INTELENCE tablet(s) whole, you may do the following:
  • place the tablet(s) in 5 ml (1 teaspoon) of water, or at least enough liquid to cover the medicine,
  • stir well for about 1 minute until the water looks milky,
  • if desired, add up to 30 ml (2 tablespoons) more of water or alternatively orange juice or milk (do not place the tablets directly in orange juice or milk),
  • drink it immediately,
  •  
  • rinse the glass several times with water, orange juice, or milk and completely swallow the rinse each time to make sure you take the entire dose.
     
    If you mix INTELENCE tablet(s) with a liquid, take this first, before other liquid anti-HIV medicines that you need to take at the same time.
     
    Contact your doctor if you are not able to swallow the entire dose when mixed with a liquid.
     
    If your child needs to take INTELENCE tablet(s) mixed with a liquid, it is very important that he/she takes the entire dose so that the right amount of medicine enters into the body. If the full dose is not taken, the risk of the virus developing resistance is higher. Contact your doctor if your child is not able to swallow the entire dose when mixed with a liquid, as they may consider giving another medicine to treat your child.

Updated on 5 May 2020 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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 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 (years to less than 18 years of age)

The recommended dose of etravirine for paediatric patients (26 years to less than 18 years of age and weighing at least 106 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 years to less than 18 years of age

Body weight

Dose

Tablets

≥ 1016 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 26 years of age)

The safety and efficacy of etravirine in children less than 6 years of age and weighing less than 16 kg have not yet been established (see section 5.2). 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. No data are available.

 

Method of administration

 

Oral use.

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

 

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

 

4.4     Special warnings and precautions for use

 

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.

 

Interactions with medicinal products

 

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

 

The combination of etravirine with simeprevir, daclatasvir, atazanavir/cobicistat or darunavir/cobicistat is not recommended (see section 4.5).

 

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

 

4.5     Interaction with other medicinal products and other forms of interaction

 

 

Known and theoretical interactions with selected antiretrovirals and non‑antiretroviral medicinal products are listed in table 12. The table is not all-inclusive.

 

Interaction table

 

Interactions between etravirine and co‑administered medicinal products are listed in table 21 (increase is indicated as “↑”, decrease as “↓”, no change as “↔”, not done as “ND”, confidence interval as “CI”).

 

Table 12:       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.

Nelfinavir

Not studied. Etravirine is expected to increase nelfinavir plasma concentrations.

It is not recommended to co‑administer INTELENCE with nelfinavir.

HIV PIis – 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

Cmina

Cmaxa

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)

Cmin0.80 (0.46‑1.38)

Cmax ↔ 1.00 (0.70‑1.42)

etravirine

AUC ↓ 0.67 (0.56‑0.80)

Cmin0.71 (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 PIis – 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

C0ha

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

Cmina

Cmaxa

 

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

Cmina

Cmaxa

 

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

Cmina

Cmaxa

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

Cmina

Cmaxa

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.

Boceprevir

800 mg 3 times daily + etravirine 200 mg every 12 hours

boceprevir

AUC ↑ 1.10 (0.94‑1.28)

Cmax ↑ 1.10 (0.94‑1.29)

Cmin ↓ 0.88 (0.66‑1.17)

etravirine

AUC ↓ 0.77 (0.66‑0.91)

Cmax ↓ 0.76 (0.68‑0.85)

Cmin ↓ 0.71 (0.54‑0.95)

The clinical significance of the reductions in etravirine pharmacokinetic parameters and boceprevir Cmin in the setting of the combination therapy with HIV antiretroviral medicines which also affect the pharmacokinetics of etravirine and/or boceprevir has not been directly assessed. Increased clinical and laboratory monitoring for HIV and HCV suppression is recommended.

Daclatasvir

Not studied. Co‑administration of 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).

Simeprevir

Not studied. Concomitant use of etravirine with simeprevir may decrease plasma concentrations of simeprevir.

Co‑administration of Intelence and simeprevir is not recommended.

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

Cmina

Cmaxa

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.

 

4.8     Undesirable effects

 

Tabulated list of adverse reactions

 

Adverse reactions reported in patients treated with etravirine are summarised in Table 23. 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 23:    Adverse reactions observed with etravirine in clinical trials and post-marketing experience

 

Paediatric population (61 years 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 clinical trialsPIANO and TMC125-C234/IMPAACT P1090, the frequency, type and severity of adverse reactions in paediatric patients were comparable to those observed in adults. In PIANOa clinical trial in paediatric patients 6 years to less than 18 years of age, Rrash 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%).

 

5.1     Pharmacodynamic properties

 

Clinical efficacy and safety

Table 34:         DUET‑1 and DUET‑2 pooled 48‑week data

Table 45:         DUET‑1 and DUET‑2 pooled data

Table 56:         Proportion of subjects with < 50 HIV‑1 RNA copies/ml at week 48 by baseline number of etravirine RAMs in the non‑viral failure excluded population of pooled DUET‑1 and DUET‑2 trials

Table 67:              Virologic responses (ITT – TLOVR), change from baseline in log10 viral load (NC = F), and change from baseline in CD4 percentage and cell count (NC = F) at week 24 in the TMC125‑C213 and pooled DUET studies

 

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

 

TMC125C234/IMPAACT P1090 is a Phase I/II½ trial evaluating the pharmacokinetics, safety, tolerability, and efficacy of INTELENCE in 20 antiretroviral treatment-experienced HIV1 infected pediatric patients 2 years to less than 6 years of age (Cohort I) and 6 antiretroviral treatment-experienced HIV1 infected pediatric patients 1 year to less than 2 years of age (Cohort II). No patients have been enrolled in Cohort III (≥ 2 months to < 1 year). The study enrolled patients on a virologically failing antiretroviral treatment regimen for at least 8 weeks or on a treatment interruption of at least 4 weeks with a history of virologic failure while on an antiretroviral regimen, with a confirmed HIV1 RNA plasma viral load greater than 1,000 copies/mlL and with no evidence of phenotypic resistance to etravirine at screening.

 

Table 78 summarizes the virologic response results for the TMC125C234/IMPAACT P1090 study.

 

Table 78:       Virologic responses (ITT-FDA Snapshot*) at week 48 in the TMC125-C234/IMPAACT P1090 Study

 

Cohort I

 2 to < 6 years

(N = 20)

Cohort II

 1 to < 2 years

(N = 6)

Baseline

 

 

Plasma HIV1 RNA

4.4 log10 copies/ml

4.4 log10 copies/ml

Median CD4+ cell count

Median baseline CD4+ percentage

817.5 x 106 cells/l

(27.6%)

1,491.5 x 106 cells/l

(26.9%)

Week 48

 

 

Virologic Response (plasma viral load < 400 HIV1 RNA copies/ml)

16/20

(80.0%)

1/6

(16.7%)

Median change in plasma HIV1 RNA from baseline to Week 48

‑2.31 log10 copies/ml

‑0.665 log10 copies/ml

Median CD4+ change from baseline

298.5 x 106 cells/l

(5.15%)

x 106 cells/l

(-2.2%)

N = number of subjects per treatment group.

*    Intent-to-treat-FDA Snapshot approach.

 

Subgroup analyses showed that for subjects aged 2 to less than 6 years virologic response [HIV RNA < 400 copies/ml] was 100.0% [6/6] for subjects who swallowed the etravirine tablet whole, 100% [4/4] for subjects who took a combination of both etravirine dispersed in liquid and etravirine tablet whole and 60% [6/10] for subjects who took etravirine dispersed in liquid. Of the 4 subjects who did not show virologic response and took etravirine dispersed in liquid, 3 showed virologic failure and had adherence issues, and one discontinued prior to Week 48 for safety reasons.

 

5.2     Pharmacokinetic properties

Table 79:         Population pharmacokinetic estimates of etravirine 200 mg twice daily in HIV‑1 infected adult subjects (integrated data from Phase III trials at week 48)*

Special populations

 

Paediatric population (16 years to less than 18 years of age)

The pharmacokinetics of etravirine in 122101 treatment‑experienced HIV‑1 infected paediatric patients, 16 years to less than 18 years of age and weighing at least 16 kg, showed that the administered weight‑based dosages resulted in etravirine exposure comparable to that in adults receiving etravirine 200 mg twice daily (see sections 4.2 and 5.2) when administered at a dose corresponding to 5.2 mg/kg twice daily. The population pharmacokinetic estimates for etravirine AUC12h and C0h are summarised in the table below.

 

Table 10:    Pharmacokinetic parameters for etravirine in treatment-experienced HIV-1 infected paediatric patients 1 year to less than 18 years of age (TMC125-C234/IMPAACT P1090 [48 week analysis, intensive PK] and PIANO [48 Weeks analysis, population PK])

Age Range (years)

≥ 1 year to < 2 years

(Cohort II)

≥ 2 years to < 6 years

(Cohort I)

6 years to < 18 years

Parameter

Etravirine

N = 6

Etravirine

N = 15

Etravirine

N = 101

AUC12h (ng•h/ml)

 

 

 

Geometric Mean ± Standard Deviation

3,328 ± 3,138

3,824 ± 3,613

3,729 ± 4,305

Median (Range)

3,390 ± (1,148 ‑ 9,989)

3,709 (1,221 ‑ 12,999)

4,560 (62 ‑ 28,865)

C0h (ng/ml)

 

 

 

Geometric Mean ± Standard Deviation

193 ± 186

203 ± 280

205 ± 342

Median (Range)

147 (0a ‑ 503)

180 (54 ‑ 908)

287 (2 - 2,276)

a     One subject in Cohort II had etravirine predose concentrations below the detection limit at the intensive PK visit.

 

Paediatric population (less than 6 years of age)

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

Pregnancy and postpartum

Study TMC114HIV3015 evaluated etravirine 200 mg twice daily in combination with other antiretroviral medicinal products in 15 pregnant women during the second and third trimesters of pregnancy and postpartum. The total etravirine exposure after intake of etravirine 200 mg twice daily as part of an antiretroviral regimen was generally higher during pregnancy compared with postpartum (see Table 119). The differences were less pronounced for unbound etravirine exposure.

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

 

Table 911:  Pharmacokinetic results of total etravirine after administration of etravirine 200 mg twice daily as part of an antiretroviral regimen, during the 2nd trimester of pregnancy, the 3rd trimester of pregnancy, and postpartum.

Pharmacokinetics of etravirine

Mean ± SD (median)

Etravirine 200 mg twice daily postpartum

N = 10

Etravirine 200 mg twice daily 2nd trimester

N = 13

Etravirine 200 mg twice daily 3rd trimester

N = 10a

Cmin, ng/mlL

269 ± 182 (284)

383 ± 210 (346)

349 ± 103 (371)

Cmax, ng/mlL

AUC12h, h*ng /mlL

569 ± 261 (528)

5004 ± 2521 (5246)

774 ± 300 (828)

6617 ± 2766 (6836)

785 ± 238 (694)

6846 ± 1482 (6028)

a     n = 9 for AUC12h

 

6.6     Special precautions for disposal and other handling

 

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

 

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

 

Updated on 25 April 2019 PIL

Reasons for updating

  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 2 - excipient warnings
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Updated on 25 April 2019 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

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Updated on 30 October 2018 PIL

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  • Change to section 6 - date of revision
  • Change in co-marketing arrangement

Updated on 29 October 2018 SmPC

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  • Change to section 4.4 - Special warnings and precautions for use
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4.4     Special warnings and precautions for use

 

Immune reactivation syndrome

 

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).

4.8     Undesirable effects

 

Immune reconstitution inflammatory 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).

Updated on 29 October 2018 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 10 - Date of revision of the text

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4.4     Special warnings and precautions for use

 

Immune reactivation syndrome

 

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).

 

Updated on 28 August 2018 PIL

Reasons for updating

  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 2 - interactions with other medicines, food or drink
  • Change to section 3 - how to take/use
  • Change to section 3 - overdose, missed or forgotten doses
  • Change to section 4 - possible side effects
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Updated on 28 August 2018 SmPC

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  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.7 - Effects on ability to drive and use machines
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not enough space to add all ther changes. Please contact Janssen medicalInformation if detail is required.

Updated on 18 August 2017 SmPC

Reasons for updating

  • Change to section 1 - Name of medicinal product
  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 3 - Pharmaceutical form
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  • Change to section 4.4 - Special warnings and precautions for use
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  • Change to section 6.1 - List of excipients
  • Change to section 6.3 - Shelf life
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new combined SmPC forot Intelence 25mg 100gm and 200mg  (25mg not marketed in ireland)

Section 1, 2, 3, 6.1, 6.3, 6.5 and 8 information for all strengths added.

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

The combination of etravirine with simeprevir, daclatasvir, atazanavir/cobicistat or darunavir/cobicistat is not recommended (see section 4.5).

 

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

 

Lactose intolerance and lactase deficiency

INTELENCE 25 mg tablets

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

 

INTELENCE 100 mg tablets

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

4.5     Interaction with other medicinal products and other forms of interaction

HIV PIs – Boosted with cobicistat

Not studied. Co‑administration of INTELENCE 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.



Daclatasvir

Not studied. Co‑administration of INTELENCE with daclatasvir may decrease daclatasvir concentrations.

Co‑administration of Intelence and daclatasvir is not recommended.

Elbasvir/grazoprevir

Not studied. Co‑administration of INTELENCE 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).

Simeprevir

Not studied. Concomitant use of INTELENCE with simeprevir may decrease plasma concentrations of simeprevir.

Co‑administration of Intelence and simeprevir is not recommended.

 

 

 

 

 

Updated on 18 August 2017 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 16 August 2017 PIL

Reasons for updating

  • New PIL for new product

Updated on 16 August 2017 PIL

Reasons for updating

  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 2 - interactions with other medicines, food or drink
  • Change to section 6 - date of revision

Updated on 2 February 2016 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

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$0Updates to Section 4.4 Special warnings and precautions for use$0$0 $0$0Fatredistribution$0$0Combination antiretroviral therapy (CART) has beenassociated with redistribution of body fat (lipodystrophy) in HIV infectedpatients. The long‑term consequences of these events are currently unknown.Knowledge about the mechanism is incomplete. A connection between viscerallipomatosis and protease inhibitors (PIs), and lipoatrophy and nucleosidereverse transcriptase inhibitors (NRTIs), has been hypothesised. A higher riskof lipodystrophy has been associated with individual factors such as older age,and with treatment related factors such as longer duration of antiretroviraltreatment and associated metabolic disturbances. Clinical examination shouldinclude evaluation for physical signs of fat redistribution (seesection 4.8).$0$0 $0$0Weight and metabolic parameters$0$0An increase in weight and in levels of blood lipidsand glucose may occur during antiretroviral therapy. Such changes may in partbe linked to disease control and life style. For lipids, there is in some casesevidence for a treatment effect, while for weight gain there is no strongevidence relating this to any particular treatment. For monitoring of bloodlipids and glucose reference is made to established HIV treatment guidelines.Lipid disorders should be managed as clinically appropriate.$0$0 $0$0 $0$0 $0$04.8     Undesirable effects$0$0 $0$0$0$0$0$0$0Skin and subcutaneous tissue disorders$0$0$0$0very common$0$0$0$0rash (10.0% vs 3.5%)$0$0$0$0$0$0common$0$0$0$0lipohypertrophy (1.0% vs 0.3%), nightsweats (1.0% vs 1.0%)$0$0$0$0$0$0uncommon$0$0$0$0swelling face (0.3% vs 0%), hyperhidrosis (0.5% vs 0.2%),prurigo (0.7% vs 0.5%), dry skin (0.3% vs 0.2%)$0$0$0$0$0$0$0 $0$0Additional ADRs of at least moderate intensity observed inother trials were acquired lipodystrophy, angioneuroticoedema, erythema multiforme and haemorrhagic stroke, each reported in no morethan 0.5% of patients. Stevens‑Johnson Syndrome (rare; < 0.1%) andtoxic epidermal necrolysis (very rare; < 0.01%) have been reportedduring clinical development with INTELENCE.$0$0 $0$0Description of selectedadverse reactions$0$0Lipodystrophy$0$0Combination antiretroviral therapy has beenassociated with redistribution of body fat (lipodystrophy) in HIV infectedpatients, including loss of peripheral and facial subcutaneous fat, increasedintra‑abdominal and visceral fat, breast hypertrophy and dorsocervical fataccumulation (buffalo hump) (see section 4.4).$0$0 $0$0 $0$0Metabolic parameters$0$0Weight and levels of blood lipids and glucose mayincrease during antiretroviral therapy (see section 4.4).$0

Updated on 1 February 2016 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to side-effects

Updated on 27 October 2015 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

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4.2     Posology and method of administration

 

Pregnancy and postpartum

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

 

 

4.4     Special warnings and precautions for use

 

Pregnancy

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

 

 

4.9     Overdose

 

If indicated, elimination of unabsorbed active substance is to be achieved by emesis or gastric lavage.

 

5.1     Pharmacodynamic properties

 

Pregnancy and postpartum

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

 

5.2     Pharmacokinetic properties

 

Pregnancy and postpartum

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

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

 

 

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

Pharmacokinetics of etravirine (mean ± SD, median)

etravirine 200 mg b.i.d. postpartum

etravirine 200 mg b.i.d. 2nd trimester

etravirine 200 mg b.i.d. 3rd trimester

N

Cmin, ng/mL

10

269 ± 182

284

13

383 ± 210

346

10a

349 ± 103

371

Cmax, ng/mL

 

AUC12h, h*ng /mL

569 ± 261

528

5004 ± 2521

5246

774 ± 300

828

6617 ± 2766

6836

785 ± 238

694

6846 ± 1482

6028

a     n = 9 for AUC12h

 

Each subject served as her own control, and with an intra-individual comparison, the total etravirine Cmin, Cmax and AUC12h values were 1.2-, 1.4- and 1.4-fold higher, respectively, during the 2nd trimester of pregnancy as compared to postpartum, and 1.1-, 1.4- and 1.2-fold higher, respectively, based during the 3rd trimester of pregnancy as compared to postpartum.

 

 

Updated on 9 March 2015 PIL

Reasons for updating

  • Change to further information section
  • Change to date of revision
  • Addition of information on reporting a side effect.

Updated on 20 June 2014 SmPC

Reasons for updating

  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 10 - Date of revision of the text

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Section 4.5

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

Cmina

Cmaxa

 

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

Cmina

Cmaxa

 

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

Cmina

Cmaxa

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.

 

 

Section 4.8

 

Reporting of suspected adverse reactions

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

 

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

 

Ireland

IMB Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

Updated on 20 June 2014 PIL

Reasons for updating

  • Change to date of revision
  • Addition of information on reporting a side effect.

Updated on 28 March 2014 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to date of revision

Updated on 27 March 2014 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 10 - Date of revision of the text

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4.4          Special warnings and precautions for use

 

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.

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.

Updated on 17 January 2014 SmPC

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  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 - Date of revision of the text

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section 4.5 addition of

Boceprevir

Boceprevir 800 mg 3 times daily + etravirine 200 mg every 12 hours

boceprevir

AUC ↑ 1.10 (0.94‑1.28)

Cmax ↑ 1.10 (0.94‑1.29)

Cmin ↓ 0.88 (0.66‑1.17)

etravirine

AUC ↓ 0.77 (0.66‑0.91)

Cmax ↓ 0.76 (0.68‑0.85)

Cmin ↓ 0.71 (0.54‑0.95)

The clinical significance of the reductions in etravirine pharmacokinetic parameters and boceprevir Cmin in the setting of the combination therapy with HIV antiretroviral medicines which also affect the pharmacokinetics of etravirine and/or boceprevir has not been directly assessed. Increased clinical and laboratory monitoring for HIV and HCV suppression is recommended.


Updated on 17 January 2014 PIL

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  • Change to drug interactions
  • Change to date of revision

Updated on 3 December 2013 PIL

Reasons for updating

  • Change to further information section

Updated on 3 December 2013 SmPC

Reasons for updating

  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text

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Change to SPC removal of statement;

 

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 this medicinal product at least every year and this SPC will be updated as necessary.

Date of last renewal : 28 August 2013

Updated on 11 June 2013 PIL

Reasons for updating

  • Change to warnings or special precautions for use

Updated on 11 June 2013 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects

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Implement class labeling relating to Immune Reconstitution Syndrome (IRS).

Updated on 20 March 2013 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 3 - Pharmaceutical form
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 9 - Date of renewal of authorisation

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Paediatric indication
Interactions with telapervir, rilpivirine and antimalarials

Updated on 20 March 2013 PIL

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  • Change of trade or active ingredient name
  • Change to, or new use for medicine
  • Change to warnings or special precautions for use
  • Change to storage instructions
  • Change to side-effects
  • Change to date of revision

Updated on 7 August 2012 SmPC

Reasons for updating

  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text

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Renewal granted.

Updated on 2 July 2012 PIL

Reasons for updating

  • New PIL for new product

Updated on 30 March 2012 SmPC

Reasons for updating

  • Change to section 4.6 - Pregnancy and lactation

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Section 4.6 updated with additional information.

Updated on 5 December 2011 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.5 - Nature and contents of container
  • Change to section 6.6 - Special precautions for disposal and other handling

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SmPC wording amended for clarity.

Updated on 8 September 2011 SmPC

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  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 - Date of revision of the text

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Section 4.5 - Addition of interaction with Clopidogrel

Updated on 5 August 2011 SmPC

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  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text

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Section 9
Date of latest renewal: 28 August 2010

Section 10
July 2011

Updated on 21 May 2010 SmPC

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  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 - Date of revision of the text

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Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

Updated info regarding voriconazole and fluconazole DDI’s

Change to section 10 - Date of revision of the text

 Changed to April 2010

Updated on 23 December 2009 SmPC

Reasons for updating

  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 - Date of revision of the text

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Change to section 4.5 - Addition of further info regarding Lopinavir/ritonavir interaction.
Change to section 10 - Changed to Nov 2009.

Updated on 1 December 2009 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text

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Change to section 4.4 - Addition of information re. severe hypersensitivity reactions, DRESS.
Change to section 4.5 - Addition of further info regarding rifabutin interaction.
Change to section 4.8 - Addition of information re. severe hypersensitivity reactions, DRESS.
Change to section 9 - Addition of date of latest renewal.
Change to section 10 - Changed to November 2009.

Updated on 13 May 2009 SmPC

Reasons for updating

  • Change to section 10 - Date of revision of the text
  • Change to section 5.3 - Preclinical safety data
  • Change to section 4.8 - Undesirable effects

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4.8

Undesirable effects

Update with  pooled 48 week data from Phase III Clinical Trials

 

5.3

Preclinical Safety Data

Update with information form carcinogenicity studies

 

10.

DATE OF REVISION OF THE TEXT

 

Changed to April 2009

 

Updated on 30 October 2008 SmPC

Reasons for updating

  • New SPC for medicines.ie

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