Edurant 25mg film-coated tablets

Section 1-what edurant and what it is used for- /.../EDURANT is used in combination with other HIV medicines to treat adults, adolescents and children weighing at least 25 kg who are infected with HIV /../. 

Section 2-what you need to know before you take Edurant- /.../ Children

EDURANT is not for use in children less than 2 years of age or weighing less than 14 kg, because it has not been evaluated in these patients./.../ Tell your doctor if you take any of the medicines listed above.../.../

Section 3-How to take Edurant- /.../ Instructions for proper use in adults, adolescents and children (weighing at least 25 kg) EDURANT is also available as dispersible tablets for paediatric patients 2 to less than 18 years of age weighing at least 14 kg and less than 25 kg (see the separate instructions for use). Film-coated tablets and dispersible tablets are not the same. Do not replace the 25 mg film-coated tablet with ten 2.5 mg dispersible tablets./../

Section 4-Possible side effects- ./.../Very common (may affect more than 1 in 10 people):/../

Renamed to feeling dizzy./../

Common (may affect up to 1 in 10 people):

Renamed to feeling very tired

Renamed to feeling sleepy

Renamed to feeling depressed

/../

Uncommon (may affect up to 1 in 100 people):/../

Section 5-How to store Edurant /../ Store in the original bottle in order to protect from light. This medicinal product does not require any special temperature storage conditions./../

Section 6-Content of pack and other information /../ -            croscarmellose sodium (E468), povidone K30 (E1201), polysorbate 20, silicified microcrystalline cellulose (E460) and magnesium stearate (E470b). The film‑coating contains lactose monohydrate, hypromellose 2910 6 mPa.s (E464), titanium dioxide (E171), macrogol 3000 and triacetin (E1518)./.../

Section 6 (Other Local info and last revision date of text)- contact details like telephone number and email address of local affiliate updated.

Approval Type IB-EMEA/H/C/002264/IB/0041 -Update HIV Transmission and Breast-feeding 

Approval Type IB-EMEA/H/C/002264/IB/0041 - Update HIV Transmission and Breast-feeding 

4.9     Overdose

There is no specific antidote for overdose with EDURANT. Human experience of overdose with rilpivirine is limited. Symptoms of overdose may include headache, nausea, dizziness and/or abnormal dreams. Treatment of overdose with rilpivirine consists of general supportive measures including monitoring of vital signs and ECG (QT interval) as well as observation of the clinical status of the patient. Administration of activated charcoal may be used to aid in removal of unabsorbed active substance.Further management should be as clinically indicated or as recommended by the national poisons centre, where available. Since rilpivirine is highly bound to plasma protein, dialysis is unlikely to result in significant removal of the active substance.

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).

4.2       Posology and method of administration

Pregnancy

Lower exposures of rilpivirine were observed during pregnancy, therefore viral load should be monitored closely. Alternatively, switching to another ART regimen could be considered (see sections 4.4, 4.6, 5.1 and 5.2).

4.4       Special warnings and precautions for use

Pregnancy

Edurant should be used during pregnancy only if the potential benefit justifies the potential risk. Lower exposures of rilpivirine were observed when rilpivirine 25 mg once daily was taken during pregnancy. In the phase 3 studies, lower rilpivirine exposure, similar to that seen during pregnancy, has been associated with an increased risk of virological failure, therefore viral load should be monitored closely (see sections 4.6, 5.1 and 5.2). Alternatively, switching to another ART regimen could be considered.

4.6       Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of rilpivirine in pregnant women (see sections 4.4, 5.1 and 5.2). Lower exposures of rilpivirine were observed during pregnancy, therefore viral load should be monitored closely.

5.1          Pharmacodynamic properties

Pregnancy

Rilpivirine in combination with a background regimen was evaluated in a clinical trial of 19 pregnant women during the second and third trimesters, and postpartum. The pharmacokinetic data demonstrate that total exposure (AUC) to rilpivirine as a part of an antiretroviral regimen was approximately 30% lower during pregnancy compared with postpartum (6-12 weeks). The virologic response was generally preserved throughout the study: of the 12 subjects that completed the study, 10 subjects were suppressed at the end of the study; in the other 2 subjects an increase in viral load was observed only postpartum, for at least 1 subject due to suspected suboptimal adherence. No mother to child transmission occurred in all 10 infants born to the mothers who completed the trial and for whom the HIV status was available. Rilpivirine was well tolerated during pregnancy and postpartum. There were no new safety findings compared with the known safety profile of rilpivirine in HIV-1 infected adults (see sections 4.2, 4.4 and 5.2).

5.2          Pharmacokinetic properties

Pregnancy and Postpartum

The exposure to total rilpivirine after intake of rilpivirine 25 mg once daily as part of an antiretroviral regimen was lower during pregnancy (similar for the 2nd and 3rd trimester) compared with postpartum (see table 6). The decrease in unbound (ie, active) rilpivirine pharmacokinetic parameters during pregnancy compared to postpartum was less pronounced than for total rilpivirine.

In women receiving rilpivirine 25 mg once daily during the 2nd trimester of pregnancy, mean intra-individual values for total rilpivirine C_max, AUC_24h and C_min values were, respectively, 21%, 29% and 35% lower as compared to postpartum; during the 3rd trimester of pregnancy, C_max, AUC_24h and C_min values were, respectively, 20%, 31% and 42% lower as compared to postpartum.

4.5     Interaction with other medicinal products and other forms of interaction

4.1     Therapeutic indications

EDURANT, in combination with other antiretroviral medicinal products, is indicated for the treatment of human immunodeficiency virus type 1 (HIV‑1) infection in antiretroviral treatment‑naïve adult patients 12 years of age and older with a viral load ≤ 100,000 HIV‑1 RNA copies/ml.

4.2     Posology and method of administration

Adults and adolescents (12 to less than 18 years of age)

The recommended dose of EDURANT is one 25 mg tablet taken once daily. EDURANT must be taken with a meal (see section 5.2).

Paediatric population

The safety and efficacy of EDURANT in children aged < 1812 years have not yet been established.

No data are available.

4.4     Special warnings and precautions for use

Virologic failure and development of resistance

Findings in adolescents (12 to less than 18 years of age) in trial C213 were generally in line with these data (for details see section 5.1).

Only adolescents deemed likely to have good adherence to antiretroviral therapy should be treated with rilpivirine, as suboptimal adherence can lead to development of resistance and the loss of future treatment options.

4.5     Interaction with other medicinal products and other forms of interaction

Interaction table

Interaction studies have only been performed in adults.

4.8     Undesirable effects

Paediatric population (12 to less than 18 years of age)

The safety assessment is based on the week 48 analysis of the single‑arm, open-label, Phase 2 trial, TMC278‑C213, in which 36 antiretroviral treatment‑naïve HIV‑1 infected adolescent patients weighing at least 32 kg received EDURANT (25 mg once daily) in combination with other antiretroviral agents (see section 5.1). The median duration of exposure for patients was 63.5 weeks. There were no patients who discontinued treatment due to ADRs. No new ADRs were identified compared to those seen in adults.

Most ADRs were Grade 1 or 2. The most common ADRs (all grades, greater than or equal to 10%) were headache (19.4%), depression (19.4%), somnolence (13.9%), and nausea (11.1%). No grade 3‑4 laboratory abnormalities for AST/ALT or grade 3‑4 ADRs of transaminase increased were reported.

The safety and efficacy of EDURANT in children aged < 1812 years have not yet been established. No data are available.

5.1     Pharmacodynamic properties

Paediatric population

The pharmacokinetics, safety, tolerability and efficacy of EDURANT 25 mg once daily, in combination with an investigator-selected BR containing two NRTIs, was evaluated in trial TMC278‑C213, a single‑arm, open‑label Phase 2 trial in antiretroviral treatment‑naïve HIV‑1 infected adolescent subjects weighing at least 32 kg. This analysis included 36 patients who had completed at least 48 weeks of treatment or discontinued earlier.

The 36 subjects had a median age of 14.5 years (range: 12 to 17 years), and were 55.6% female, 88.9% Black and 11.1% Asian. The median baseline plasma HIV‑1 RNA was 4.8 log₁₀ copies per mL, and the median baseline CD4+ cell count was 414 x 10⁶ cells/l (range: 25 to 983 x 10⁶ cells/l).

The proportion of subjects with HIV‑1 RNA < 50 copies/mL at week 48 (TLOVR) was 72.2% (26/36). The proportion of responders was higher in subjects with a baseline viral load ≤ 100,000 copies/mL (78.6%, 22/28) as compared to those with a baseline viral load > 100,000 copies/mL (50.0%, 4/8). The proportion of virological failures was 22.2% (8/36). The proportion of virologic failures was lower in subjects with a baseline viral load ≤ 100,000 copies/mL (17.9%, 5/28) as compared to those with a baseline viral load > 100,000 copies/mL (37.5%, 3/8). Rilpivirine resistance mutations were observed in 62.5% (5/8) of subjects with virological failure. In 4 of those 5 subjects, NRTI resistance was observed as well. One subject discontinued due to an adverse event and 1 subject discontinued due to reasons other than an adverse event or virological failure. At week 48, the mean increase in CD4+ cell count from baseline was 201.2 x 10⁶ cells/l.

5.2     Pharmacokinetic properties

Additional information on special populations

Paediatric population (less than 18 years of age)

The pharmacokinetics of rilpivirine in antiretroviral treatment‑naïve HIV‑1 infected adolescent subjects receiving EDURANT 25 mg once daily were comparable to those in treatment‑naïve HIV‑1 infected adults receiving EDURANT 25 mg once daily. There was no impact of body weight on rilpivirine pharmacokinetics in paediatric subjects in trial C213 (33 to 93 kg), similar to what was observed in adults.

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.

Rilpivirine inhibits the active renal tubular secretion of creatinine. Via the same mechanism exposure to metformin may be increased. Patients should be carefully monitored when initiating or stopping the concomitant administration of rilpivirine and metformin.Rilpivirine is an in vitro inhibitor of the transporter MATE‑2K with an IC₅₀ of < 2.7 nM. The clinical implications of this finding are currently unknown.

section 4.2 Add:

Dose adjustment

For patients concomitantly receiving rifabutin, the EDURANT dose should be increased to 50 mg (two tablets of 25 mg each) taken once daily. When rifabutin co‑administration is stopped, the EDURANT dose should be decreased to 25 mg once daily (see section 4.5).

Section 4.3

Contraindications

; the antimycobacterials rifabutin  rifampicin, rifapentine
section 4.5
updated information in rifabutin interaction

section 4.8- standard ADR reporting text

Section 5.1

addition of:  Resistance to rilpivirine was determined as a fold change in EC₅₀ value (FC) above the biological cut‑off (BCO) of the assay.

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