INTELENCE 200 mg tablets

Local representative address updated in Ireland.

EMEA/H/C/000900/IB/0066/G-HIV transmission

EMA/H/C/900/IB/066G-HIV transmission

Update of Article 61(3)- common PIL for Northern ireland and Ireland

Update of Article 61(3)- common PIL for Northern ireland and Ireland

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.

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 6 2 years of age (see sections 4.4, 4.5 and 5.1).

4.2     Posology and method of administration

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

Posology

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

Adults

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

Paediatric population (6 2 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).

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”).

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).

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)

TMC125‑C234/IMPAACT P1090 is a Phase I/II½ trial evaluating the pharmacokinetics, safety, tolerability, and efficacy of INTELENCE in 20 antiretroviral treatment-experienced HIV‑1 infected pediatric patients 2 years to less than 6 years of age (Cohort I) and 6 antiretroviral treatment-experienced HIV‑1 infected pediatric patients 1 year to less than 2 years of age (Cohort II). 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 HIV‑1 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 TMC125‑C234/IMPAACT P1090 study.

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 AUC_12h and C_0h are summarised in the table below.

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 C_max, AUC_12h and C_min were observed during pregnancy compared to postpartum. During the 2^nd and 3^rd trimester of pregnancy mean values of these parameters were comparable.

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).

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).

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).

not enough space to add all ther changes. Please contact Janssen medicalInformation if detail is required.

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

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 C_max, AUC_12h and C_min were observed during pregnancy compared to postpartum. During the 2^nd and 3^rd trimester of pregnancy mean values of these parameters were comparable.

Each subject served as her own control, and with an intra-individual comparison, the total etravirine C_min, C_max and AUC_12h values were 1.2-, 1.4- and 1.4-fold higher, respectively, during the 2^nd trimester of pregnancy as compared to postpartum, and 1.1-, 1.4- and 1.2-fold higher, respectively, based during the 3^rd trimester of pregnancy as compared to postpartum.

Section 4.5

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

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.

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.