EDURANT 25mg tablets medication leaflet

EDURANT 25 mg film-coated tablets

Each film-coated tablet contains rilpivirine hydrochloride equivalent to 25 mg rilpivirine.

Each film-coated tablet contains 56 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

Film-coated tablet

White to off-white, round, biconvex, film-coated tablet with a diameter of 6.4 mm, debossed with“TMC” on one side and “25” on the other side.

EDURANT, in combination with other antiretroviral medicinal products, is indicated for the treatmentof human immunodeficiency virus type 1 (HIV-1) infection in adults and paediatric patients weighingat least 25 kg without known mutations associated with resistance to the non-nucleoside reversetranscriptase inhibitor (NNRTI) class, and with a viral load ≤ 100,000 HIV-1 RNA copies/ml (seesections 4.4 and 5.1).

Genotypic resistance testing should guide the use of EDURANT (see sections 4.4 and 5.1).

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

The recommended dose of EDURANT in adult and paediatric patients weighing at least 25 kg is one25 mg tablet taken once daily. EDURANT must be taken with a meal (see section 5.2).

Dispersible tablets

EDURANT is also available as 2.5 mg dispersible tablets for paediatric patients aged 2 to less than18 years weighing at least 14 kg and less than 25 kg. The recommended dosage of EDURANT in thesepaediatric patients is based on body weight. A difference in bioavailability of 1 x 25 mg film-coatedtablet and 10 x 2.5 mg dispersible tablets was observed, therefore they are not interchangeable.

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

If the patient misses a dose of EDURANT within 12 hours of the time it is usually taken, the patientmust take the medicine with a meal as soon as possible and resume the normal dosing schedule. If apatient misses a dose of EDURANT by more than 12 hours, the patient should not take the misseddose, but resume the usual dosing schedule.

If a patient vomits within 4 hours of taking the medicine, another EDURANT tablet should be takenwith a meal. If a patient vomits more than 4 hours after taking the medicine, the patient does not needto take another dose of EDURANT until the next regularly scheduled dose.

There is limited information regarding the use of EDURANT in patients > 65 years of age. No doseadjustment of EDURANT is required in older patients (see section 5.2). EDURANT should be usedwith caution in this population.

EDURANT has mainly been studied in patients with normal renal function. No dose adjustment ofrilpivirine is required in patients with mild or moderate renal impairment. In patients with severe renalimpairment or end-stage renal disease, rilpivirine should be used with caution. In patients with severerenal impairment or end-stage renal disease, the combination of rilpivirine with a strong CYP3Ainhibitor (e.g., ritonavir-boosted HIV protease inhibitor) should only be used if the benefit outweighsthe risk (see section 5.2).

Treatment with rilpivirine resulted in an early small increase of mean serum creatinine levels whichremained stable over time and is not considered clinically relevant (see section 4.8).

There is limited information regarding the use of EDURANT in patients with mild or moderate hepaticimpairment (Child-Pugh score A or B). No dose adjustment of EDURANT is required in patients withmild or moderate hepatic impairment. EDURANT should be used with caution in patients withmoderate hepatic impairment. EDURANT has not been studied in patients with severe hepaticimpairment (Child-Pugh score C). Therefore, EDURANT is not recommended in patients with severehepatic impairment (see section 5.2).

The safety and efficacy of EDURANT in children less than 2 years or weighing less than 14 kg havenot been established. No data are available.

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

EDURANT must be taken orally, once daily with a meal (see section 5.2). It is recommended that thefilm-coated tablet be swallowed whole with water and not be chewed or crushed.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

EDURANT should not be co-administered with the following medicinal products, as significantdecreases in rilpivirine plasma concentrations may occur (due to CYP3A enzyme induction or gastricpH increase), which may result in loss of therapeutic effect of EDURANT (see section 4.5):

- the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin

- the antimycobacterials rifampicin, rifapentine

- proton pump inhibitors, such as omeprazole, esomeprazole, lansoprazole, pantoprazole,rabeprazole

- the systemic glucocorticoid dexamethasone, except as a single dose treatment

- St John’s wort (Hypericum perforatum).

Virologic failure and development of resistance

EDURANT has not been evaluated in patients with previous virologic failure to any otherantiretroviral therapy. The list of rilpivirine resistance-associated mutations presented in section 5.1should only guide the use of EDURANT in the treatment-naïve population.

In the pooled efficacy analysis from the phase 3 trials TMC278-C209 (ECHO) and TMC278-C215(THRIVE) in adults through 96 weeks, patients treated with rilpivirine with a baseline viral load> 100,000 HIV-1 RNA copies/ml had a greater risk of virologic failure (18.2% with rilpivirine versus7.9% with efavirenz) compared to patients with a baseline viral load ≤ 100,000 HIV-1 RNA copies/ml(5.7% with rilpivirine versus 3.6% with efavirenz). The greater risk of virologic failure for patients inthe rilpivirine arm was observed in the first 48 weeks of these trials (see section 5.1). Patients with abaseline viral load > 100,000 HIV-1 RNA copies/ml who experienced virologic failure exhibited ahigher rate of treatment-emergent resistance to the non-nucleoside reverse transcriptase inhibitor(NNRTI) class. More patients who failed virologically on rilpivirine than who failed virologically onefavirenz developed lamivudine/emtricitabine associated resistance (see section 5.1).

Findings in adolescents and paediatric patients in trial TMC278-C213 were generally in line with thesedata. No virological failures were observed in trial TMC278HTX2002 (for details see section 5.1).

Only patients deemed likely to have good adherence to antiretroviral therapy should be treated withrilpivirine, as suboptimal adherence can lead to development of resistance and the loss of futuretreatment options.

As with other antiretroviral medicinal products, resistance testing should guide the use of rilpivirine(see section 5.1).

At supra-therapeutic doses (75 and 300 mg once daily), rilpivirine has been associated withprolongation of the QTc interval of the electrocardiogram (ECG) (see sections 4.5, pct. 4.8 and 5.2).

EDURANT at the recommended dose of 25 mg once daily is not associated with a clinically relevanteffect on QTc. EDURANT should be used with caution when co-administered with medicinal productswith a known risk of Torsade de Pointes.

In HIV infected patients with severe immune deficiency at the time of initiation of CART, aninflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and causeserious clinical conditions or aggravation of symptoms. Typically, such reactions have been observedwithin the first weeks or months of initiation of CART. Relevant examples are cytomegalovirusretinitis, generalised and/or focal mycobacterial infections and Pneumocystis jiroveci pneumonia. Anyinflammatory symptoms should be evaluated and treatment instituted when necessary.

Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported tooccur in the setting of immune reactivation; however, the reported time to onset is more variable andthese events can occur many months after initiation of treatment (see section 4.8).

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 duringpregnancy. 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 bemonitored closely (see sections 4.6, 5.1 and 5.2). Alternatively, switching to another ART regimencould be considered.

Important information about some of the ingredients of EDURANT

EDURANT contains lactose. Patients with rare hereditary problems of galactose intolerance, totallactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Medicinal products that affect rilpivirine exposure

Rilpivirine is primarily metabolised by cytochrome P450 (CYP)3A. Medicinal products that induce orinhibit CYP3A may thus affect the clearance of rilpivirine (see section 5.2). Co-administration ofrilpivirine and medicinal products that induce CYP3A has been observed to decrease the plasmaconcentrations of rilpivirine, which could reduce the therapeutic effect of rilpivirine.

Co-administration of rilpivirine and medicinal products that inhibit CYP3A has been observed toincrease the plasma concentrations of rilpivirine.

Co-administration of rilpivirine with medicinal products that increase gastric pH may result indecreased plasma concentrations of rilpivirine which could potentially reduce the therapeutic effect of

EDURANT.

Medicinal products that are affected by the use of rilpivirine

Rilpivirine at the recommended dose is not likely to have a clinically relevant effect on the exposure ofmedicinal products metabolised by CYP enzymes.

Rilpivirine inhibits P-glycoprotein in vitro (IC50 is 9.2 μM). In a clinical study, rilpivirine did notsignificantly affect the pharmacokinetics of digoxin. However, it may not be completely excluded thatrilpivirine can increase the exposure to other medicines transported by P-glycoprotein that are moresensitive to intestinal P-gp inhibition, e.g., dabigatran etexilate.

Rilpivirine is an in vitro inhibitor of the transporter MATE-2K with an IC50 of < 2.7 nM. The clinicalimplications of this finding are currently unknown.

Established and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinalproducts are listed in Table 1.

Interaction studies have only been performed in adults.

Interactions between rilpivirine and co-administered medicinal products are listed in Table 1 (increaseis indicated as “↑”, decrease as “↓”, no change as “↔”, not applicable as “NA”, confidence interval as“CI”).

Table 1: INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL

PRODUCTS

Medicinal products by Interaction Recommendations concerningtherapeutic areas Geometric mean change (%) co-administration

ANTI-INFECTIVES

Antiretrovirals

HIV NRTIs/N[t]RTIs

Didanosine*# didanosine AUC ↑ 12% No dose adjustment is required.400 mg once daily didanosine Cmin NA Didanosine should be administered atdidanosine Cmax ↔ least two hours before or at least fourrilpivirine AUC ↔ hours after rilpivirine.rilpivirine Cmin ↔rilpivirine Cmax ↔

Tenofovir disoproxil *# tenofovir AUC ↑ 23% No dose adjustment is required.245 mg once daily tenofovir Cmin ↑ 24%tenofovir Cmax ↑ 19%rilpivirine AUC ↔rilpivirine Cmin ↔rilpivirine Cmax ↔

Other NRTIs Not studied. No clinically relevant No dose adjustment is required.(abacavir, emtricitabine, drug-drug interactions are expected.lamivudine, stavudineand zidovudine)

HIV NNRTIs

NNRTIs Not studied. It is not recommended to(delavirdine, efavirenz, co-administer rilpivirine with otheretravirine, nevirapine) NNRTIs.

HIV PIs - with co-administration of low dose ritonavir

Darunavir/ritonavir*# darunavir AUC ↔ Concomitant use of rilpivirine with800/100 mg once daily darunavir Cmin ↓ 11% ritonavir-boosted PIs causes andarunavir Cmax ↔ increase in the plasma concentrationsrilpivirine AUC ↑ 130% of rilpivirine, but no dose adjustmentrilpivirine Cmin ↑ 178% is required.rilpivirine Cmax ↑ 79%(inhibition of CYP3A enzymes)

Lopinavir/ritonavir lopinavir AUC ↔(soft gel capsule)*# lopinavir Cmin ↓ 11%400/100 mg twice daily lopinavir Cmax ↔rilpivirine AUC ↑ 52%rilpivirine Cmin ↑ 74%rilpivirine Cmax ↑ 29%(inhibition of CYP3A enzymes)

Other boosted PIs Not studied.(atazanavir/ritonavir,fosamprenavir/ritonavir,saquinavir/ritonavir,tipranavir/ritonavir)

HIV PIs - without co-administration of low dose ritonavir

Unboosted PIs Not studied. Increased exposure of No dose adjustment is required.(atazanavir, rilpivirine is expected.fosamprenavir, indinavir,nelfinavir) (inhibition of CYP3A enzymes)

CCR5 Antagonists

Maraviroc Not studied. No clinically relevant No dose adjustment is required.

drug-drug interaction is expected.

HIV Integrase Strand Transfer Inhibitors

Raltegravir* raltegravir AUC ↑ 9% No dose adjustment is required.

raltegravir Cmin ↑ 27%raltegravir Cmax ↑ 10%rilpivirine AUC ↔rilpivirine Cmin ↔rilpivirine Cmax ↔

Other Antiviral Agents

Ribavirin Not studied. No clinically relevant No dose adjustment is required.

drug-drug interaction is expected.

Simeprevir* simeprevir AUC ↔ No dose adjustment is required.

simeprevir Cmin ↔simeprevir Cmax ↑ 10%rilpivirine AUC ↔rilpivirine Cmin ↑ 25%rilpivirine Cmax ↔

OTHER AGENTS

ANTICONVULSANTS

Carbamazepine Not studied. Significant decreases Rilpivirine must not be used in

Oxcarbazepine in rilpivirine plasma concentrations combination with these

Phenobarbital are expected. anticonvulsants as co-administration

Phenytoin may result in loss of therapeutic effect(induction of CYP3A enzymes) of rilpivirine (see section 4.3).

AZOLE ANTIFUNGAL AGENTS

Ketoconazole*# ketoconazole AUC ↓ 24% At the recommended dose of 25 mg400 mg once daily ketoconazole Cmin ↓ 66% once daily, no dose adjustment isketoconazole Cmax ↔ required when rilpivirine isco-administered with ketoconazole.

(induction of CYP3A due to highrilpivirine dose in the study)rilpivirine AUC ↑ 49%rilpivirine Cmin ↑ 76%rilpivirine Cmax ↑ 30%(inhibition of CYP3A enzymes)

Fluconazole Not studied. Concomitant use of No dose adjustment is required.

Itraconazole EDURANT with azole antifungal

Posaconazole agents may cause an increase in the

Voriconazole plasma concentrations of rilpivirine.

(inhibition of CYP3A enzymes)

ANTIMYCOBACTERIALS

Rifabutin* rifabutin AUC ↔ Throughout co-administration of300 mg once daily† rifabutin Cmin ↔ rilpivirine with rifabutin, the rilpivirinerifabutin Cmax ↔ dose should be increased from 25 mg25-O-desacetyl-rifabutin AUC ↔ once daily to 50 mg once daily. When25-O-desacetyl-rifabutin Cmin ↔ rifabutin co-administration is stopped,25-O-desacetyl-rifabutin Cmax ↔ the rilpivirine dose should bedecreased to 25 mg once daily.300 mg once daily rilpivirine AUC ↓ 42%(+ 25 mg once daily rilpivirine Cmin ↓ 48%rilpivirine) rilpivirine Cmax ↓ 31%300 mg once daily rilpivirine AUC ↑ 16%*(+ 50 mg once daily rilpivirine Cmin ↔*rilpivirine) rilpivirine Cmax ↑ 43%*

* compared to 25 mg once daily rilpivirinealone(induction of CYP3A enzymes)

Rifampicin*# rifampicin AUC ↔ Rilpivirine must not be used in600 mg once daily rifampicin Cmin NA combination with rifampicin asrifampicin Cmax ↔ co-administration is likely to result in25-desacetyl-rifampicin AUC ↓ 9% loss of therapeutic effect of rilpivirine25-desacetyl-rifampicin Cmin NA (see section 4.3).25-desacetyl-rifampicin Cmax ↔rilpivirine AUC ↓ 80%rilpivirine Cmin ↓ 89%rilpivirine Cmax ↓ 69%(induction of CYP3A enzymes)

Rifapentine Not studied. Significant decreases Rilpivirine must not be used inin rilpivirine plasma concentrations combination with rifapentine asare expected. co-administration is likely to result inloss of therapeutic effect of rilpivirine(induction of CYP3A enzymes) (see section 4.3).

MACROLIDE ANTIBIOTICS

Clarithromycin Not studied. Increased exposure of Where possible, alternatives such as

Erythromycin rilpivirine is expected. azithromycin should be considered.

(inhibition of CYP3A enzymes)

GLUCOCORTICOIDS

Dexamethasone Not studied. Dose dependent Rilpivirine should not be used in(systemic, except for decreases in rilpivirine plasma combination with systemicsingle dose use) concentrations are expected. dexamethasone (except as a singledose) as co-administration may result(induction of CYP3A enzymes) in loss of therapeutic effect ofrilpivirine (see section 4.3).

Alternatives should be considered,particularly for long-term use.

PROTON PUMP INHIBITORS

Omeprazole*# omeprazole AUC ↓ 14% Rilpivirine must not be used in20 mg once daily omeprazole Cmin NA combination with proton pumpomeprazole Cmax ↓ 14% inhibitors as co-administration is likelyrilpivirine AUC ↓ 40% to result in loss of therapeutic effect ofrilpivirine Cmin ↓ 33% rilpivirine (see section 4.3).rilpivirine Cmax ↓ 40%(reduced absorption due to gastricpH increase)

Lansoprazole Not studied. Significant decreases

Rabeprazole in rilpivirine plasma concentrations

Pantoprazole are expected.

Esomeprazole(reduced absorption due to gastricpH increase)

H2-RECEPTOR ANTAGONISTS

Famotidine*# rilpivirine AUC ↓ 9% The combination of rilpivirine and40 mg single dose taken rilpivirine Cmin NA H2-receptor antagonists should be used12 hours before rilpivirine Cmax ↔ with particular caution. Onlyrilpivirine H2-receptor antagonists that can be

Famotidine*# rilpivirine AUC ↓ 76% dosed once daily should be used.40 mg single dose taken rilpivirine Cmin NA A strict dosing schedule, with intake of2 hours before rilpivirine rilpivirine Cmax ↓ 85% H2-receptor antagonists at least12 hours before or at least 4 hours(reduced absorption due to gastric after rilpivirine should be used.pH increase)

Famotidine*# rilpivirine AUC ↑ 13%40 mg single dose taken rilpivirine Cmin NA4 hours after rilpivirine rilpivirine Cmax ↑ 21%

Cimetidine Not studied.

Nizatidine

Ranitidine (reduced absorption due to gastricpH increase)

ANTACIDS

Antacids (e.g., Not studied. Significant decreases The combination of rilpivirine andaluminium or magnesium in rilpivirine plasma concentrations antacids should be used with particularhydroxide, calcium are expected. caution. Antacids should only becarbonate) administered either at least 2 hours(reduced absorption due to gastric before or at least 4 hours afterpH increase) rilpivirine.

NARCOTIC ANALGESICS

Methadone* R(-) methadone AUC ↓ 16% No dose adjustments are required60-100 mg once daily, R(-) methadone Cmin ↓ 22% when initiating co-administration ofindividualised dose R(-) methadone Cmax ↓ 14% methadone with rilpivirine. However,rilpivirine AUC ↔* clinical monitoring is recommended asrilpivirine Cmin ↔* methadone maintenance therapy mayrilpivirine Cmax ↔* need to be adjusted in some patients.

* based on historic controls

ANTIARRHYTHMICS

Digoxin* digoxin AUC ↔ No dose adjustment is required.

digoxin Cmin NAdigoxin Cmax ↔

ANTICOAGULANTS

Dabigatran etexilate Not studied. A risk for increases in The combination of rilpivirine anddabigatran plasma concentrations dabigatran etexilate should be usedcannot be excluded. with caution.

(inhibition of intestinal P-gp)

ANTIDIABETICS

Metformin* metformin AUC ↔ No dose adjustment is required.850 mg single dose metformin Cmin NAmetformin Cmax ↔

HERBAL PRODUCTS

St John’s wort Not studied. Significant decreases Rilpivirine must not be used in(Hypericum perforatum) in rilpivirine plasma concentrations combination with products containingare expected. St John’s wort as co-administrationmay result in loss of therapeutic effect(induction of CYP3A enzymes) of rilpivirine (see section 4.3).

ANALGESICS

Paracetamol*# paracetamol AUC ↔ No dose adjustment is required.500 mg single dose paracetamol Cmin NAparacetamol Cmax ↔rilpivirine AUC ↔rilpivirine Cmin ↑ 26%rilpivirine Cmax ↔

ORAL CONTRACEPTIVES

Ethinylestradiol* ethinylestradiol AUC ↔ No dose adjustment is required.0.035 mg once daily ethinylestradiol Cmin ↔

Norethindrone* ethinylestradiol Cmax ↑ 17%1 mg once daily norethindrone AUC ↔norethindrone Cmin ↔norethindrone Cmax ↔rilpivirine AUC ↔*rilpivirine Cmin ↔*rilpivirine Cmax ↔*

* based on historic controls

HMG CO-A REDUCTASE INHIBITORS

Atorvastatin*# atorvastatin AUC ↔ No dose adjustment is required.40 mg once daily atorvastatin Cmin ↓ 15%atorvastatin Cmax ↑ 35%rilpivirine AUC ↔rilpivirine Cmin ↔rilpivirine Cmax ↓ 9%

PHOSPHODIESTERASE TYPE 5 (PDE-5) INHIBITORS

Sildenafil*# sildenafil AUC ↔ No dose adjustment is required.50 mg single dose sildenafil Cmin NAsildenafil Cmax ↔rilpivirine AUC ↔rilpivirine Cmin ↔rilpivirine Cmax ↔

Vardenafil Not studied. No dose adjustment is required.

Tadalafil

* The interaction between rilpivirine and the medicinal product was evaluated in a clinical study. All other drug-drug interactionsshown are predicted.

# This interaction study has been performed with a dose higher than the recommended dose for rilpivirine assessing the maximal effecton the co-administered medicinal product. The dosing recommendation is applicable to the recommended dose of rilpivirine of 25 mgonce daily.

† This interaction study has been performed with a dose higher than the recommended dose for rilpivirine.

QT prolonging medicinal products

There is limited information available on the potential for a pharmacodynamic interaction betweenrilpivirine and medicinal products that prolong the QTc interval of the ECG. In a study of healthysubjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have beenshown to prolong the QTc interval of the ECG (see section 5.1). EDURANT should be used withcaution when co-administered with a medicinal product with a known risk of Torsade de Pointes.

A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicate nomalformative or feto/neonatal toxicity of rilpivirine (see sections 4.4, 5.1 and 5.2). Lower exposures ofrilpivirine were observed during pregnancy, therefore viral load should be monitored closely.

Animal studies do not indicate reproductive toxicity (see section 5.3).

The use of rilpivirine may be considered during pregnancy, if necessary.

It is not known whether rilpivirine is excreted in human milk. Rilpivirine is excreted in the milk ofrats. Because of the potential for adverse reactions in breastfed infants, mothers should be instructednot to breast-feed if they are receiving rilpivirine.

In order to avoid transmission of HIV to the infant it is recommended that women living with HIV donot breast-feed.

No human data on the effect of rilpivirine on fertility are available. No clinically relevant effects onfertility were seen in animal studies (see section 5.3).

EDURANT has no or negligible influence on the ability to drive and use machines. However, fatigue,dizziness and somnolence have been reported in some patients taking EDURANT and should beconsidered when assessing a patient’s ability to drive or operate machinery.

During the clinical development programme (1,368 patients in the phase 3 controlled trials

TMC278-C209 (ECHO) and TMC278-C215 (THRIVE)), 55.7% of subjects experienced at least oneadverse drug reaction (see section 5.1). The most frequently reported adverse drug reactions (ADRs)(≥ 2%) that were at least of moderate intensity were depression (4.1%), headache (3.5%), insomnia(3.5%), rash (2.3%), and abdominal pain (2.0%). The most frequent serious treatment-related ADRswere reported in 7 (1.0%) patients receiving rilpivirine. The median duration of exposure for patientsin the rilpivirine arm and efavirenz arm was 104.3 and 104.1 weeks, respectively. Most ADRsoccurred in the first 48 weeks of treatment.

Selected treatment-emergent clinical laboratory abnormalities (grade 3 or grade 4), considered as

ADRs, reported in EDURANT treated patients were increased pancreatic amylase (3.8%), increased

AST (2.3%), increased ALT (1.6%), increased LDL cholesterol (fasted, 1.5%), decreased white bloodcell count (1.2%), increased lipase (0.9%), increased bilirubin (0.7%), increased triglycerides (fasted,0.6%), decreased haemoglobin (0.1%), decreased platelet count (0.1%), and increased total cholesterol(fasted, 0.1%).

ADRs reported in adult patients treated with rilpivirine are summarised in Table 2. The ADRs arelisted by system organ class (SOC) and frequency. Frequencies are defined as very common (≥ 1/10),common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1,000 to < 1/100). Within each frequency grouping,

ADRs are presented in order of decreasing frequency.

Table 2: ADRs reported in antiretroviral treatment-naïve HIV-1 infected adult patientstreated with Rilpivirine(pooled data from the week 96 analysis of the phase 3 ECHO and THRIVE trials) N=686

System Organ Class (SOC) Frequency Category ADRs(Rilpivirine + BR)

Blood and lymphatic system common decreased white blood cell countdisorders decreased haemoglobindecreased platelet count

Immune system disorders uncommon immune reactivation syndrome

Metabolism and nutrition very common increased total cholesterol (fasted)disorders increased LDL cholesterol (fasted)common decreased appetiteincreased triglycerides (fasted)

Psychiatric disorders very common insomniacommon abnormal dreamsdepressionsleep disordersdepressed mood

Nervous system disorders very common headachedizzinesscommon somnolence

Gastrointestinal disorders very common nauseaincreased pancreatic amylasecommon abdominal painvomitingincreased lipaseabdominal discomfortdry mouth

Hepatobiliary disorders very common increased transaminasescommon increased bilirubin

Skin and subcutaneous tissue common rashdisorders

General disorders and common fatigueadministration site conditions

BR=background regimen

N=number of subjects

In the rilpivirine arm in the week 96 analysis of the phase 3 ECHO and THRIVE trials, mean changefrom baseline in total cholesterol (fasted) was 5 mg/dl, in HDL cholesterol (fasted) 4 mg/dl, in LDLcholesterol (fasted) 1 mg/dl, and in triglycerides (fasted) -7 mg/dl.

In HIV infected patients with severe immune deficiency at the time of initiation of combinationantiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunisticinfections may arise. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) havealso been reported; however, the reported time to onset is more variable and these events can occurmany months after initiation of treatment (see section 4.4).

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

TMC278-C213 Cohort 1

The safety assessment is based on the week 48 analysis of the single-arm, open-label, phase 2 trial,

TMC278-C213 Cohort 1, in which 36 antiretroviral treatment-naïve HIV-1 infected adolescentpatients weighing at least 32 kg received rilpivirine (25 mg once daily) in combination with otherantiretroviral 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 identifiedcompared to those seen in adults.

Most ADRs were grade 1 or 2. The most common ADRs reported in Study TMC278-C213 Cohort 1(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 ADRsof transaminase increased were reported.

There were no new safety concerns identified in the week 240 analysis of the TMC278-C213 Cohort 1trial in adolescents.

Paediatric population (2 to less than 12 years of age)

TMC278-C213 Cohort 2

Cohort 2 of the single-arm, open-label phase 2 trial, TMC278-C213 was designed to evaluate thesafety of the rilpivirine weight adjusted doses 12.5, 15, and 25 mg once daily in antiretroviraltreatment-naïve HIV-1 infected patients (6 to less than 12 years of age and weighing at least 17 kg)(see section 5.1). The median duration of exposure for patients in the week 48 analysis (including post-week 48 extension) was 69.5 (range 35 to 218) weeks.

All ADRs were mild or moderate. ADRs reported in at least 2 participants, regardless of severity,were: decreased appetite (3/18, 16.7%), vomiting (2/18, 11.1%), ALT increased (2/18, 11.1%), ASTincreased (2/18, 11.1%), and rash (2/18, 11.1%). There were no patients who discontinued treatmentdue to ADRs. No new ADRs were identified compared to those seen in adults.

TMC278HTX2002

The single arm, open-label phase 2 trial, TMC278HTX2002, was designed to evaluate the safety ofrilpivirine weight-adjusted doses 12.5, 15, and 25 mg once daily in virologically suppressed HIV-1infected patients (2 to less than 12 years of age and weighing at least 10 kg) (see section 5.1). Themedian duration of exposure for patients in the week 48 analysis was 48.4 (range 47 to 52) weeks.

All ADRs were mild or moderate. ADRs reported in at least 2 participants, regardless of severity,were: vomiting (4/26, 15.4%), abdominal pain (3/26, 11.5%), nausea (2/26, 7.7%), ALT increased(3/26, 11.5%), AST increased (2/26, 7.7%), and decreased appetite (2/26, 7.7%). There were nopatients who discontinued treatment due to ADRs. No new ADRs were identified compared to thoseseen in adults.

The safety and efficacy of rilpivirine in children less than 2 years or weighing less than 14 kg have notbeen established.

Patients co-infected with hepatitis B and/or hepatitis C virus

In patients co-infected with hepatitis B or C virus receiving rilpivirine, the incidence of hepaticenzyme elevation was higher than in patients receiving rilpivirine who were not co-infected. Thisobservation was the same in the efavirenz arm. The pharmacokinetic exposure of rilpivirine inco-infected patients was comparable to that in patients without co-infection.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no specific antidote for overdose with EDURANT. Human experience of overdose withrilpivirine is limited. Symptoms of overdose may include headache, nausea, dizziness and/or abnormaldreams. Treatment of overdose with rilpivirine consists of general supportive measures includingmonitoring of vital signs and ECG (QT interval) as well as observation of the clinical status of thepatient. Further management should be as clinically indicated or as recommended by the nationalpoisons centre, where available. Since rilpivirine is highly bound to plasma protein, dialysis is unlikelyto result in significant removal of the active substance.

Pharmacotherapeutic group: Antiviral for systemic use, non-nucleoside reverse transcriptase inhibitors,

ATC code: J05AG05.

Rilpivirine is a diarylpyrimidine NNRTI of HIV-1. Rilpivirine activity is mediated by non-competitiveinhibition of HIV-1 reverse transcriptase (RT). Rilpivirine does not inhibit the human cellular DNApolymerases α, β and γ.

Rilpivirine exhibited activity against laboratory strains of wild-type HIV-1 in an acutely infected

T-cell line with a median EC50 value for HIV-1/IIIB of 0.73 nM (0.27 ng/ml). Although rilpivirinedemonstrated limited in vitro activity against HIV-2 with EC50 values ranging from 2,510 to10,830 nM (920 to 3,970 ng/ml), treatment of HIV-2 infection with rilpivirine is not recommended inthe absence of clinical data.

Rilpivirine also demonstrated antiviral activity against a broad panel of HIV-1 group M (subtype A, B,

C, D, F, G, H) primary isolates with EC50 values ranging from 0.07 to 1.01 nM (0.03 to 0.37 ng/ml)and group O primary isolates with EC50 values ranging from 2.88 to 8.45 nM (1.06 to 3.10 ng/ml).

Rilpivirine-resistant strains were selected in cell culture starting from wild-type HIV-1 of differentorigins and subtypes as well as NNRTI resistant HIV-1. The most commonly observedresistance-associated mutations that emerged included L100I, K101E, V108I, E138K, V179F, Y181C,

H221Y, F227C and M230I.

Resistance to rilpivirine was determined as a fold change in EC50 value (FC) above the biologicalcut-off (BCO) of the assay.

In treatment-naïve adult subjects

For the resistance analysis, a broader definition of virologic failure was used than in the primaryefficacy analysis. In the week 48 pooled resistance analysis from the phase 3 trials, 62 (of a total of 72)virologic failures in the rilpivirine arm had resistance data at baseline and time of failure. In thisanalysis, the resistance-associated mutations (RAMs) associated with NNRTI resistance thatdeveloped in at least 2 rilpivirine virologic failures were: V90I, K101E, E138K, E138Q, V179I,

Y181C, V189I, H221Y, and F227C. In the trials, the presence of the mutations V90I and V189I, atbaseline, did not affect response. The E138K substitution emerged most frequently during rilpivirinetreatment, commonly in combination with the M184I substitution. In the week 48 analysis, 31 out of62 of rilpivirine virologic failures had concomitant NNRTI and NRTI RAMs; 17 of those 31 had thecombination of E138K and M184I. The most common mutations were the same in the week 48 andweek 96 analyses.

In the week 96 pooled resistance analysis, lower rates of virologic failure were observed in the second48 weeks than in the first 48 weeks of treatment. From the week 48 to the week 96 analysis, 24 (3.5%)and 14 (2.1%) additional virologic failures occurred in the rilpivirine and efavirenz arm, respectively.

Of these virologic failures, 9 out of 24 and 4 out of 14 were in subjects with a baseline viral load< 100,000 copies/ml, respectively.

In treatment-naïve paediatric subjects 12 to less than 18 years

In the week 240 resistance analysis of TMC278-C213 Cohort 1, rilpivirine resistance-associatedmutations (RAMs) were observed in 46.7% (7/15) of subjects with virologic failure and post-baselinegenotypic data. All subjects with rilpivirine RAMs also had at least 1 treatment-emergent NRTI RAMat the last post-baseline time point with genotypic data.

In treatment-naïve paediatric subjects 6 to less than 12 years of age

In the final resistance analysis of TMC278-C213 Cohort 2, rilpivirine RAMs were observed in 83.3%(5/6) of subjects with post-baseline genotypic data; of these, 2/6 occurred within the first 48 weeks and4 subjects with rilpivirine RAMs also had at least 1 treatment-emergent NRTI RAM at the last post-baseline time point with genotypic data.

In virologically suppressed paediatric subjects 2 to less than 12 years of age

In the TMC278HTX2002 trial, no subjects experienced virologic failure and no treatment-emergentresistance was observed.

Considering all of the available in vitro and in vivo data in treatment-naïve subjects, the followingresistance-associated mutations, when present at baseline, may affect the activity of rilpivirine: K101E,

K101P, E138A, E138G, E138K, E138R, E138Q, V179L, Y181C, Y181I, Y181V, Y188L, H221Y,

F227C, M230I, and M230L. These rilpivirine resistance-associated mutations should only guide theuse of EDURANT in the treatment-naïve population. These resistance-associated mutations werederived from in vivo data involving treatment-naïve subjects only and therefore cannot be used topredict the activity of rilpivirine in subjects who have virologically failed an antiretroviral-containingregimen.

As with other antiretroviral medicinal products, resistance testing should guide the use of EDURANT.

Site-directed NNRTI mutant virus

In a panel of 67 HIV-1 recombinant laboratory strains with one resistance-associated mutation at RTpositions associated with NNRTI resistance, including the most commonly found K103N and Y181C,rilpivirine showed antiviral activity against 64 (96%) of these strains. The single resistance-associatedmutations associated with a loss of susceptibility to rilpivirine were: K101P, Y181I and Y181V. The

K103N substitution did not result in reduced susceptibility to rilpivirine by itself, but the combinationof K103N and L100I resulted in a 7-fold reduced susceptibility to rilpivirine.

Recombinant clinical isolates

Rilpivirine retained sensitivity (FC ≤ BCO) against 62% of 4,786 HIV-1 recombinant clinical isolatesresistant to efavirenz and/or nevirapine.

Treatment-naïve HIV-1 infected adult patients

In the week 96 pooled resistance analysis of the phase 3 trials (ECHO and THRIVE), 42 out of86 subjects with virologic failure on rilpivirine showed treatment-emergent resistance to rilpivirine(genotypic analysis). In these patients, phenotypic cross-resistance to other NNRTIs was noted asfollows: etravirine 32/42, efavirenz 30/42, and nevirapine 16/42. In patients with a baseline viral load≤ 100,000 copies/ml, 9 out of 27 patients with virologic failure on rilpivirine showedtreatment-emergent resistance to rilpivirine (genotypic analysis), with the following frequency ofphenotypic cross-resistance: etravirine 4/9, efavirenz 3/9, and nevirapine 1/9.

The effect of rilpivirine at the recommended dose of 25 mg once daily on the QTcF interval wasevaluated in a randomised, placebo and active (moxifloxacin 400 mg once daily) controlled crossoverstudy in 60 healthy adults, with 13 measurements over 24 hours at steady-state. EDURANT at therecommended dose of 25 mg once daily is not associated with a clinically relevant effect on QTc.

When supratherapeutic doses of 75 mg once daily and 300 mg once daily of rilpivirine were studied inhealthy adults, the maximum mean time-matched (95% upper confidence bound) differences in QTcFinterval from placebo after baseline correction were 10.7 (15.3) and 23.3 (28.4) ms, respectively.

Steady-state administration of rilpivirine 75 mg once daily and 300 mg once daily resulted in a mean

Cmax approximately 2.6-fold and 6.7-fold, respectively, higher than the mean steady-state Cmaxobserved with the recommended 25 mg once daily dose of rilpivirine.

Adult population

Treatment-naïve adult subjects

The evidence of efficacy of rilpivirine is based on the analysis of 96 week data from 2 randomised,double-blinded, active-controlled, phase 3 trials TMC278-C209 (ECHO) and TMC278-C215(THRIVE). The trials were identical in design, with the exception of the background regimen (BR). Inthe week 96 efficacy analysis, the virologic response rate [confirmed undetectable viral load(< 50 HIV-1 RNA copies/ml)] was evaluated in patients receiving rilpivirine 25 mg once daily inaddition to a BR versus patients receiving efavirenz 600 mg once daily in addition to a BR. Similarefficacy for rilpivirine was seen in each trial demonstrating non-inferiority to efavirenz.

Antiretroviral treatment-naïve HIV-1 infected patients were enroled who had a plasma

HIV-1 RNA ≥ 5,000 copies/ml and were screened for susceptibility to N(t)RTIs and for absence ofspecific NNRTI resistance-associated mutations. In ECHO, the BR was fixed to the N(t)RTIs,tenofovir disoproxil fumarate plus emtricitabine. In THRIVE, the BR consisted of2 investigator-selected N(t)RTIs: tenofovir disoproxil fumarate plus emtricitabine or zidovudine pluslamivudine or abacavir plus lamivudine. In ECHO, randomisation was stratified by screening viralload. In THRIVE, randomisation was stratified by screening viral load and by N(t)RTI BR.

This analysis included 690 patients in ECHO and 678 patients in THRIVE who had completed96 weeks of treatment or discontinued earlier.

In the pooled analysis for ECHO and THRIVE, demographics and baseline characteristics werebalanced between the rilpivirine arm and the efavirenz arm. Table 3 displays selected baseline diseasecharacteristics of the patients in the rilpivirine and efavirenz arms.

Table 3: Baseline disease characteristics of antiretroviral treatment-naïve HIV-1 infected adultsubjects in the ECHO and THRIVE trials (pooled analysis)

Pooled data from the ECHO and THRIVE trials

Rilpivirine + BR Efavirenz + BR

N=686 N=682

Baseline disease characteristics

Median baseline plasma HIV-1 RNA (range), 5.0 5.0log10 copies/ml (2-7) (3-7)

Median baseline CD4+ cell count (range), 249 260x 106 cells/l (1-888) (1-1,137)

Percentage of subjects with:

hepatitis B/C virus co-infection 7.3% 9.5%

Percentage of patients with the followingbackground regimens:

tenofovir disoproxil fumarate plus 80.2% 80.1%emtricitabinezidovudine plus lamivudine 14.7% 15.1%abacavir plus lamivudine 5.1% 4.8%

BR=background regimen

Table 4 below shows the results of the week 48 and the week 96 efficacy analysis for patients treatedwith rilpivirine and patients treated with efavirenz from the pooled data from the ECHO and THRIVEtrials. The response rate (confirmed undetectable viral load < 50 HIV-1 RNA copies/ml) at week 96was comparable between the rilpivirine arm and the efavirenz arm. The incidence of virologic failurewas higher in the rilpivirine arm than the efavirenz arm at week 96; however, most of the virologicfailures occurred within the first 48 weeks of treatment. Discontinuations due to adverse events werehigher in the efavirenz arm at week 96 than the rilpivirine arm. Most of these discontinuationsoccurred in the first 48 weeks of treatment.

Table 4: Virologic outcome in adult subjects in the ECHO and THRIVE trials(pooled data in the week 48 (primary) and week 96 analysis; ITT-TLOVR*)

Outcome in the week 48 analysis Outcome in the week 96 analysis

Rilpivirine Efavirenz Observed Rilpivirine Efavirenz Observed+ BR + BR difference + BR + BR difference

N=686 N=682 (95% CI) ± N=686 N=682 (95% CI) ±

Response (confirmed 84.3% 82.3% 2.0 77.6% 77.6% 0< 50 HIV-1 RNA (578/686) (561/682) (-2.0; 6.0) (532/686) (529/682) (-4.4; 4.4)copies/ml)§#

Non-response

Virologic failure†

Overall 9.0% 4.8% ND 11.5% 5.9% ND(62/686) (33/682) (79/686) (40/682)≤ 100,000 3.8% 3.3% ND 5.7% 3.6% ND(14/368) (11/330) (21/368) (12/329)> 100,000 15.1% 6.3% ND 18.2% 7.9% ND(48/318) (22/352) (58/318) (28/353)

Death 0.1% 0.4% ND 0.1% 0.9% ND(1/686) (3/682) (1/686) (6/682)

Discontinued due to 2.0% 6.7% ND 3.8% 7.6% NDadverse event (AE) (14/686) (46/682) (26/682) (52/682)

Discontinued for non-AE 4.5% 5.7% ND 7.0% 8.1% NDreason¶ (31/686) (39/682) (48/682) (55/682)

Response by subcategory

By background NRTI

Tenofovir/emtricitabine 83.5% 82.4% 1.0 76.9% 77.3% -0.4%(459/550) (450/546) (-3.4; 5.5) (423/550) (422/546) (-5.4; 4.6)

Zidovudine/lamivudine 87.1% 80.6% 6.5 81.2% 76.7% 4.5%(88/101) (83/103) (-3.6; 16.7) (82/101) (79/103) (-6.8; 15.7)

Abacavir/lamivudine 88.6% 84.8% 3.7 77.1% 84.8% -7.7%(31/35) (28/33) (-12.7; 20.1) (27/35) (28/33) (-26.7; 11.3)

By baseline viral load (copies/ml)≤ 100,000 90.2% 83.6% 6.6 84.0% 79.9% 4.0(332/368) (276/330) (1.6; 11.5) (309/368) (263/329) (-1.7; 9.7)> 100,000 77.4% 81.0% -3.6 70.1% 75.4% -5.2(246/318) (285/352) (-9.8; 2.5) (223/318) (266/353) (-12.0;1.5)

By baseline CD4 count (× 106 cells/l)< 50 58.8% 80.6% -21.7 55.9% 69.4% -13.6(20/34) (29/36) (-43.0; -0.5) (19/34) (25/36) (-36.4; 9.3)≥ 50-< 200 80.4% 81.7% -1.3 71.1% 74.9% -3.7(156/194) (143/175) (-9.3; 6.7) (138/194) (131/175) (-12.8; 5.4)≥ 200-< 350 86.9% 82.4% 4.5 80.5% 79.5% 1.0(272/313) (253/307) (-1.2; 10.2) (252/313) (244/307) (-5.3; 7.3)≥ 350 90.3% 82.9% 7.4 85.4% 78.7% 6.8(130/144) (136/164) (-0.3; 15.0) (123/144) (129/164) (-1.9; 15.4)

BR=background regimen; CI=confidence interval; N=number of subjects per treatment group; ND=not determined.

* Intent-to-treat time to loss of virologic response.± Based on normal approximation.§ Subjects achieved virologic response (two consecutive viral loads < 50 copies/ml) and maintained it through week 48/96.# Predicted difference of response rates (95% CI) for the week 48 analysis: 1.6% (-2.2%; 5.3%) and for the week 96 analysis: -0.4%(-4.6%; 3.8%); both p-value < 0.0001 (non-inferiority at 12% margin) from logistic regression model, including stratification factorsand study.

† Virologic failure in pooled efficacy analysis: includes subjects who were rebounder (confirmed viral load ≥ 50 copies/ml after beingresponder) or who were never suppressed (no confirmed viral load < 50 copies/ml, either ongoing or discontinued due to lack or loss ofefficacy).

¶ e.g., lost to follow-up, non-compliance, withdrew consent.

At week 96, the mean change from baseline in CD4+ cell count was +228 × 106 cells/l in therilpivirine arm and +219 × 106 cells/l in the efavirenz arm in the pooled analysis of the ECHO and

THRIVE trials [estimated treatment difference (95% CI): 11.3 (-6.8; 29.4)].

From the week 96 pooled resistance analysis, the resistance outcome for patients with protocol definedvirological failure, and paired genotypes (baseline and failure) is shown in Table 5.

Table 5: Resistance outcome by background NRTI regimen used(pooled data from the ECHO and THRIVE trials in the week 96 resistance analysis)tenofovir/ zidovudine/ abacavir/ All*emtricitabine lamivudine lamivudine

Rilpivirine-treated

Resistance# to 6.9 (38/550) 3.0 (3/101) 8.6 (3/35) 6.4 (44/686)emtricitabine/lamivudine% (n/N)

Resistance to rilpivirine 6.5 (36/550) 3.0 (3/101) 8.6 (3/35) 6.1 (42/686)% (n/N)

Efavirenz-treated

Resistance to 1.1 (6/546) 1.9 (2/103) 3.0 (1/33) 1.3 (9/682)emtricitabine/lamivudine% (n/N)

Resistance to efavirenz 2.4 (13/546) 2.9 (3/103) 3.0 (1/33) 2.5 (17/682)% (n/N)

* The number of patients with virologic failure and paired genotypes (baseline and failure) were 71, 11, and 4 for rilpivirine and 30, 10,and 2 for efavirenz, for the tenofovir/emtricitabine, zidovudine/lamivudine, and abacavir/lamivudine regimens, respectively.# Resistance was defined as the emergence of any resistance-associated mutation at failure.

For those patients failing therapy with rilpivirine and who developed resistance to rilpivirine,cross-resistance to other approved NNRTIs (etravirine, efavirenz, nevirapine) was generally seen.

Study TMC278-C204 was a randomised, active-controlled, phase 2b trial in antiretroviraltreatment-naïve HIV-1 infected adult patients consisting of 2 parts: an initial partially blindeddose-finding part [(rilpivirine) doses blinded] up to 96 weeks, followed by a long-term, open-labelpart. In the open-label part of the trial, patients originally randomised to one of the three doses ofrilpivirine were all treated with rilpivirine 25 mg once daily in addition to a BR, once the dose for thephase 3 studies was selected. Patients in the control arm received efavirenz 600 mg once daily inaddition to a BR in both parts of the study. The BR consisted of 2 investigator-selected N(t)RTIs:zidovudine plus lamivudine or tenofovir disoproxil fumarate plus emtricitabine.

Study TMC278-C204 enroled 368 HIV-1 infected treatment-naïve adult patients who had a plasma

HIV-1 RNA ≥ 5,000 copies/ml, previously received ≤ 2 weeks of treatment with an N(t)RTI orprotease inhibitor, had no prior use of NNRTIs and were screened for susceptibility to N(t)RTI and forabsence of specific NNRTI resistance-associated mutations.

At 96 weeks, the proportion of patients with < 50 HIV-1 RNA copies/ml receiving rilpivirine 25 mg(N=93) compared to patients receiving efavirenz (N=89) was 76% and 71%, respectively. The meanincrease from baseline in CD4+ counts was 146 × 106 cells/l in patients receiving rilpivirine 25 mg and160 × 106 cells/l in patients receiving efavirenz.

Of those patients who were responders at week 96, 74% of patients receiving rilpivirine remained withundetectable viral load (< 50 HIV-1 RNA copies/ml) at week 240 compared to 81% of patientsreceiving efavirenz. There were no safety concerns identified in the week 240 analyses.

In treatment-naïve paediatric subjects 12 to less than 18 years

The pharmacokinetics, safety, tolerability and efficacy of rilpivirine 25 mg once daily, in combinationwith an investigator-selected BR containing two NRTIs, was evaluated in trial TMC278-C213

Cohort 1, a single-arm, open-label phase 2 trial in antiretroviral treatment-naïve HIV-1 infectedadolescent subjects weighing at least 32 kg. This analysis included 36 patients who had completed atleast 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 themedian baseline CD4+ cell count was 414 × 106 cells/l (range: 25 to 983 × 106 cells/l).

Table 6 summarises the week 48 and week 240 virologic outcome results for trial TMC278-C213

Cohort 1. Six subjects discontinued due to virological failure up to week 48 and 3 subjectsdiscontinued beyond week 48. One subject discontinued due to an adverse event at week 48, and noadditional subjects discontinued due to adverse events in the week 240 analysis.

Table 6: Virologic outcome in adolescent subjects in TMC278-C213 Cohort 1 - week 48 andweek 240 analysis; ITT-TLOVR*

Week 48 Week 240

N=36 N=32

Response (confirmed < 50 HIV-1 72.2% 43.8%

RNA copies/ml)§ (26/36) (14/32)78.6% 48%≤ 100,000 (22/28) (12/25)50% 28.6%> 100,000(4/8) (2/7)

Non-response

Virologic failure±22.2% 50%

Overall(8/36) (16/32)17.9% 48%≤ 100,000(5/28) (12/25)37.5% 57.1%> 100,000(3/8) (4/7)

Increase in CD4+ cell count201.2 × 106 cells/l 113.6 × 106 cells/l(mean)

N=number of subjects per treatment group.

* Intent-to-treat time to loss of virologic response.§ Subjects achieved virologic response (two consecutive viral loads < 50 copies/ml) and maintained it through week 48 and week 240.± Virologic failure in efficacy analysis: includes subjects who were rebounder (confirmed viral load ≥ 50 copies/ml after beingresponder) or who were never suppressed (no confirmed viral load < 50 copies/ml, either ongoing or discontinued due to lack or lossof efficacy).

Treatment-naïve paediatric subjects 6 to less than 12 years of age

The pharmacokinetics, safety, tolerability and efficacy of rilpivirine weight-adjusted doses 12.5, 15,and 25 mg once daily, in combination with an investigator-selected BR containing two NRTIs, wasevaluated in trial TMC278-C213 Cohort 2, a single-arm, open-label phase 2 trial in antiretroviraltreatment-naïve HIV-1 infected paediatric subjects 6 to less than 12 years of age and weighing at least17 kg. The week 48 analysis included 18 subjects, 17 (94.4%) subjects completed the 48-weektreatment period, and 1 (5.6%) subject discontinued the study early due to reaching a virologicendpoint. The 18 subjects had a median age of 9.0 years (range 6 to 11 years) and the median weight atbaseline was 25 kg (range 17 to 51 kg). 88.9% were Black and 38.9% were female. The medianbaseline plasma viral load was 55 400 (range 567-149 000) copies/ml, and the median absolutebaseline CD4+ cell count was 432.5 × 106 cells/l (range 12-2 068 × 106 cells/l).

The number of subjects with HIV-1 RNA <50 copies/ ml at week 48 was 13/18 (72.2%), while 3/18(16.7%) subjects had HIV-1 RNA ≥50 copies/ml at week 48. Two subjects had missing viral load dataat week 48 but remained on study. The viral load for these 2 subjects was <50 copies/ml, post-week 48. The median increase in CD4+ from baseline was 220 × 106 cells/l (range -520 to 635 x 106cells/l) at week 48.

Virologically suppressed paediatric subjects 2 to less than 12 years of age

The pharmacokinetics, safety, tolerability and efficacy of rilpivirine weight-adjusted doses 12.5, 15,and 25 mg, in combination with an investigator-selected BR, was evaluated in TMC278HTX2002, asingle-arm, open-label phase 2 trial in virologically suppressed HIV-1 infected paediatric subjects 2 toless than 12 years of age and weighing at least 10 kg. All participants completed the 48-weektreatment.

The 26 subjects had a median age of 9.9 years, 61.5% male, 50% Black, 26.9% Asian and 23.1%

White. The median weight at baseline was 28.1 kg (range 16 to 60 kg). Baseline plasma HIV-1 viralload was undetectable (<50 copies/ml) in 25 (96.2%) subjects and 1 (3.8%) subject had a baselineplasma viral load ≥50 copies/ml (125 copies/ml). The median absolute baseline CD4+ cell count was881.5 × 106 cells/l (range 458 to 1327 × 106 cells/l).

All 26 subjects treated with rilpivirine (in combination with BR) were virologically suppressed(plasma viral load <50 copies/ml) at week 48. The median change in CD4+ cell count from baselinewas - 27.5 × 106 cells/l (range -275 to 279 x 106 cells/l) at week 48.

Rilpivirine in combination with a background regimen was evaluated in a clinical trial of 19 pregnantwomen during the second and third trimesters, and postpartum. The pharmacokinetic data demonstratethat 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 wasgenerally preserved throughout the study: of the 12 subjects that completed the study, 10 subjects weresuppressed at the end of the study; in the other 2 subjects an increase in viral load was observed onlypostpartum, for at least 1 subject due to suspected suboptimal adherence. No mother to childtransmission 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 wereno new safety findings compared with the known safety profile of rilpivirine in HIV-1 infected adults(see sections 4.2, pct. 4.4 and 5.2).

The pharmacokinetic properties of rilpivirine have been evaluated in adult healthy subjects and inantiretroviral treatment-naïve and virologically suppressed HIV-1 infected patients ≥6 years of age andweighing ≥ 16 kg. Exposure to rilpivirine was generally lower in HIV-1 infected patients than inhealthy subjects.

After oral administration, the maximum plasma concentration of rilpivirine is generally achievedwithin 4-5 hours. The absolute bioavailability of EDURANT is unknown.

Effect of food on absorption

The exposure to rilpivirine was approximately 40% lower when EDURANT was taken in a fastedcondition as compared to a normal caloric meal (533 kcal) or high-fat high-caloric meal (928 kcal).

When EDURANT was taken with only a protein-rich nutritional drink, exposures were 50% lowerthan when taken with a meal. EDURANT must be taken with a meal to obtain optimal absorption.

Taking EDURANT in fasted condition or with only a nutritional drink may result in decreased plasmaconcentrations of rilpivirine, which could potentially reduce the therapeutic effect of EDURANT (seesection 4.2).

Rilpivirine is approximately 99.7% bound to plasma proteins in vitro, primarily to albumin. Thedistribution of rilpivirine into compartments other than plasma (e.g., cerebrospinal fluid, genital tractsecretions) has not been evaluated in humans.

In vitro experiments indicate that rilpivirine primarily undergoes oxidative metabolism mediated bythe cytochrome P450 (CYP) 3A system.

The terminal elimination half-life of rilpivirine is approximately 45 hours. After single dose oraladministration of 14C-rilpivirine, on average 85% and 6.1% of the radioactivity could be retrieved infaeces and urine, respectively. In faeces, unchanged rilpivirine accounted for on average 25% of theadministered dose. Only trace amounts of unchanged rilpivirine (< 1% of dose) were detected in urine.

Additional information on special populations

The pharmacokinetics of rilpivirine in antiretroviral treatment-naïve or virologically suppressed HIV-1infected paediatric patients aged 6 years to less than 18 years of age weighing at least 16 kg receivingthe recommended weight-based dosing regimen of rilpivirine were comparable or higher (i.e., AUC is39% higher, based on pharmacokinetic modeling) than those obtained in treatment-naïve HIV-1infected adult patients.

The pharmacokinetics of rilpivirine in paediatric patients less than 6 years of age or weighing less than16 kg have not been formally evaluated in patients.

Older people

Population pharmacokinetic analysis in HIV infected patients showed that rilpivirine pharmacokineticsare not different across the age range (18 to 78 years) evaluated, with only 3 subjects aged 65 years orolder. No dose adjustment of EDURANT is required in older patients. EDURANT should be used withcaution in this population (see section 4.2).

No clinically relevant differences in the pharmacokinetics of rilpivirine have been observed betweenmen and women.

Population pharmacokinetic analysis of rilpivirine in HIV infected patients indicated that race had noclinically relevant effect on the exposure to rilpivirine.

Rilpivirine is primarily metabolised and eliminated by the liver. In a study comparing 8 patients withmild hepatic impairment (Child-Pugh score A) to 8 matched controls, and 8 patients with moderatehepatic impairment (Child-Pugh score B) to 8 matched controls, the multiple dose exposure ofrilpivirine was 47% higher in patients with mild hepatic impairment and 5% higher in patients withmoderate hepatic impairment. However, it may not be excluded that the pharmacologically active,unbound, rilpivirine exposure is significantly increased in moderate hepatic impairment.

No dose adjustment is suggested but caution is advised in patients with moderate hepatic impairment.

EDURANT has not been studied in patients with severe hepatic impairment (Child-Pugh score C).

Therefore, EDURANT is not recommended in patients with severe hepatic impairment (seesection 4.2).

Population pharmacokinetic analysis indicated that hepatitis B and/or C virus co-infection had noclinically relevant effect on the exposure to rilpivirine.

The pharmacokinetics of rilpivirine have not been studied in patients with renal insufficiency. Renalelimination of rilpivirine is negligible. No dose adjustment is needed for patients with mild ormoderate renal impairment. In patients with severe renal impairment or end-stage renal disease,

EDURANT should be used with caution, as plasma concentrations may be increased due to alterationof drug absorption, distribution and/or metabolism secondary to renal dysfunction. In patients withsevere renal impairment or end-stage renal disease, the combination of EDURANT with a strong

CYP3A inhibitor should only be used if the benefit outweighs the risk. As rilpivirine is highly boundto plasma proteins, it is unlikely that it will be significantly removed by haemodialysis or peritonealdialysis (see section 4.2).

Pregnancy and Postpartum

The exposure to total rilpivirine after intake of rilpivirine 25 mg once daily as part of an antiretroviralregimen was lower during pregnancy (similar for the 2nd and 3rd trimester) compared with postpartum(see Table 7). The decrease in unbound (i.e., active) rilpivirine pharmacokinetic parameters duringpregnancy 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 Cmax, AUC24h and Cmin values were, respectively, 21%, 29% and35% lower as compared to postpartum; during the 3rd trimester of pregnancy, Cmax, AUC24h and Cminvalues were, respectively, 20%, 31% and 42% lower as compared to postpartum.

Table 7: Pharmacokinetic Results of Total Rilpivirine After Administration of Rilpivirine 25 mg

Once Daily as Part of an Antiretroviral Regimen, During the 2nd Trimester of Pregnancy, the 3rd

Trimester of Pregnancy and Postpartum

Pharmacokinetics of total Postpartum 2nd Trimester 3rd Trimesterrilpivirine (6-12 Weeks) of pregnancy of pregnancy(mean ± SD, tmax: median [range]) (n=11) (n=15) (n=13)

Cmin, ng/ml 84.0 ± 58.8 54.3 ± 25.8 52.9 ± 24.4

Cmax, ng/ml 167 ± 101 121 ± 45.9 123 ± 47.5tmax, h 4.00 (2.03-25.08) 4.00 (1.00-9.00) 4.00 (2.00-24.93)

AUC24h, ng.h/ml 2714 ± 1535 1792 ± 711 1762 ± 662

Liver toxicity associated with liver enzyme induction was observed in rodents. In dogs,cholestasis-like effects were noted.

Reproductive toxicology studies

Studies in animals have shown no evidence of relevant embryonic or foetal toxicity or an effect onreproductive function. There was no teratogenicity with rilpivirine in rats and rabbits. The exposures(based on AUC) at the embryo-foetal No Observed Adverse Effects Levels (NOAELs) in rats andrabbits were respectively 15 and 70 times higher than the exposure in humans (minimum 12 years ofage and weighing more than 32 kg) at the recommended dose of 25 mg once daily.

Carcinogenesis and mutagenesis

Rilpivirine was evaluated for carcinogenic potential by oral gavage administration to mice and rats upto 104 weeks. At the lowest tested doses in the carcinogenicity studies, the systemic exposures (basedon AUC) to rilpivirine were greater than 12-fold (mice) and greater than 1.4-fold (rats), relative to theexpected exposure in humans at a dose of 25 mg once daily. In rats, there were no drug-relatedneoplasms. In mice, rilpivirine was positive for hepatocellular neoplasms in both males and females.

The observed hepatocellular findings in mice may be rodent-specific.

Rilpivirine has tested negative in the absence and presence of a metabolic activation system in thein vitro Ames reverse mutation assay and the in vitro clastogenicity mouse lymphoma assay.

Rilpivirine did not induce chromosomal damage in the in vivo micronucleus test in mice.

Lactose monohydrate

Croscarmellose sodium (E468)

Povidone K30 (E1201)

Polysorbate 20

Silicified microcrystalline cellulose (E460)

Magnesium stearate (E470b)

Lactose monohydrate

Hypromellose 2910 6 mPa.s (E464)

Titanium dioxide (E171)

Macrogol 3000

Triacetin (E1518)

Not applicable.

3 years

Store in the original bottle in order to protect from light. This medicinal product does not require anyspecial temperature storage conditions.

75 ml high density polyethylene (HDPE) bottle with a polypropylene (PP) child resistant closure andinduction seal liner. Each carton contains one bottle of 30 tablets.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

EU/1/11/736/001

Date of first authorisation: 28 November 2011

Date of latest renewal: 22 July 2016

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

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