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Edurant (rilpivirine hydrochloride) – Summary of product characteristics - J05AG05

Updated on site: 06-Oct-2017

Medication nameEdurant
ATC CodeJ05AG05
Substancerilpivirine hydrochloride
ManufacturerJanssen-Cilag International N.V.   

1.NAME OF THE MEDICINAL PRODUCT

EDURANT 25 mg film-coated tablets

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

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

Excipient with known effect: each film-coated tablet contains 56 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM

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.

4.CLINICAL PARTICULARS

4.1Therapeutic 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 patients 12 years of age and older with a viral load ≤ 100,000 HIV-1 RNA copies/ml.

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

4.2Posology and method of administration

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

Posology

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

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).

Missed dose

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

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

Special populations

Elderly

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

Renal impairment

EDURANT has mainly been studied in patients with normal renal function. No dose adjustment of rilpivirine is required in patients with mild or moderate renal impairment. In patients with severe renal impairment or end-stage renal disease, rilpivirine should be used with caution. In patients with severe renal impairment or end-stage renal disease, the combination of rilpivirine with a strong CYP3A inhibitor (e.g., ritonavir-boosted HIV protease inhibitor) should only be used if the benefit outweighs the risk (see section 5.2).

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

Hepatic impairment

There is limited information regarding the use of EDURANT in patients with mild or moderate hepatic impairment (Child-Pugh score A or B). No dose adjustment of EDURANT is required in patients with mild or moderate hepatic impairment. EDURANT should be used with caution 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 (see section 5.2).

Paediatric population

The safety and efficacy of EDURANT in children aged < 12 years have not yet been established. No data are available.

Method of administration

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

4.3Contraindications

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 significant decreases in rilpivirine plasma concentrations may occur (due to CYP3A enzyme induction or gastric pH 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).

4.4Special 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.

Virologic failure and development of resistance

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

In the pooled efficacy analysis from the Phase III trials 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 versus 7.9% 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 in the rilpivirine arm was observed in the first 48 weeks of these trials (see section 5.1). Patients with a baseline viral load > 100,000 HIV-1 RNA copies/ml who experienced virologic failure exhibited a higher 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 on efavirenz developed lamivudine/emtricitabine associated resistance (see section 5.1).

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.

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

Cardiovascular

At supra-therapeutic doses (75 and 300 mg once daily), rilpivirine has been associated with prolongation of the QTc interval of the electrocardiogram (ECG) (see sections 4.5, 4.8 and 5.2). EDURANT at the recommended dose of 25 mg once daily is not associated with a clinically relevant effect on QTc. EDURANT should be used with caution when co-administered with medicinal products with a known risk of Torsade de Pointes.

Immune reactivation syndrome

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

Autoimmune disorders (such as Graves' disease) 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).

Important information about some of the ingredients of EDURANT

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

4.5Interaction with other medicinal products and other forms of interaction

Medicinal products that affect rilpivirine exposure

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

Co-administration of rilpivirine with medicinal products that increase gastric pH may result in decreased 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 a dose of 25 mg once daily is not likely to have a clinically relevant effect on the exposure of medicinal products metabolised by CYP enzymes.

Rilpivirine inhibits P-glycoprotein in vitro (IC50 is 9.2 μM). In a clinical study, rilpivirine did not significantly affect the pharmacokinetics of digoxin. However, it may not be completely excluded that rilpivirine can increase the exposure to other medicines transported by P-glycoprotein that are more sensitive 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 clinical implications of this finding are currently unknown.

Established and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal products are listed in table 1.

Interaction table

Interaction studies have only been performed in adults.

Interactions between rilpivirine and co-administered medicinal products are listed in table 1 (increase is 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 concerning

therapeutic 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 at

 

didanosine Cmax

least two hours before or at least four

 

rilpivirine AUC ↔

hours after rilpivirine.

 

rilpivirine Cmin

 

 

rilpivirine Cmax

 

Tenofovir disoproxil

tenofovir AUC ↑ 23%

No dose adjustment is required.

fumarate*#

tenofovir Cmin ↑ 24%

 

300 mg once daily

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, stavudine

 

 

and zidovudine)

 

 

HIV NNRTIs

 

 

NNRTIs

Not studied.

It is not recommended to

(delavirdine, efavirenz,

 

co-administer rilpivirine with other

etravirine, nevirapine)

 

NNRTIs.

HIV PIs – with co-administration of low dose ritonavir

Darunavir/ritonavir*#

darunavir AUC ↔

800/100 mg once daily

darunavir Cmin ↓ 11%

 

darunavir Cmax

 

rilpivirine AUC ↑ 130%

 

rilpivirine Cmin ↑ 178%

 

rilpivirine Cmax ↑ 79%

 

(inhibition of CYP3A enzymes)

Concomitant use of rilpivirine with ritonavir-boosted PIs causes an increase in the plasma concentrations of rilpivirine, but no dose adjustment is required.

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.

 

Telaprevir*

telaprevir AUC ↓ 5%

No dose adjustment is required.

750 mg every 8 hours

telaprevir Cmin ↓ 11%

 

 

telaprevir Cmax ↓ 3%

 

 

rilpivirine AUC ↑ 78%

 

 

rilpivirine Cmin ↑ 93%

 

 

rilpivirine Cmax ↑ 49%

 

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 mg

400 mg once daily

ketoconazole Cmin ↓ 66%

once daily, no dose adjustment is

 

ketoconazole Cmax

required when rilpivirine is

 

(induction of CYP3A due to high

co-administered with ketoconazole.

 

 

 

rilpivirine 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 of

300 mg once daily

rifabutin Cmin

rilpivirine with rifabutin, the rilpivirine

 

rifabutin Cmax

dose should be increased from 25 mg

 

25-O-desacetyl-rifabutin AUC ↔

once daily to 50 mg once daily. When

 

25-O-desacetyl-rifabutin Cmin

rifabutin co-administration is stopped,

 

25-O-desacetyl-rifabutin Cmax

the rilpivirine dose should be

300 mg once daily

rilpivirine AUC ↓ 42%

decreased to 25 mg once daily.

 

(+ 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 rilpivirine

 

 

alone

 

 

(induction of CYP3A enzymes)

 

Rifampicin*#

rifampicin AUC ↔

Rilpivirine must not be used in

600 mg once daily

rifampicin Cmin NA

combination with rifampicin as

 

rifampicin Cmax

co-administration is likely to result in

 

25-desacetyl-rifampicin AUC ↓ 9%

loss of therapeutic effect of rilpivirine

 

25-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 in

 

in rilpivirine plasma concentrations

combination with rifapentine as

 

are expected.

co-administration is likely to result in

 

 

loss 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 systemic

single dose use)

concentrations are expected.

dexamethasone (except as a single

 

(induction of CYP3A enzymes)

dose) as co-administration may result

 

in loss of therapeutic effect of

 

 

rilpivirine (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 in

20 mg once daily

omeprazole Cmin NA

combination with proton pump

 

omeprazole Cmax ↓ 14%

inhibitors as co-administration is likely

 

rilpivirine AUC ↓ 40%

to result in loss of therapeutic effect of

 

rilpivirine Cmin ↓ 33%

rilpivirine (see section 4.3).

 

rilpivirine Cmax ↓ 40%

 

 

(reduced absorption due to gastric

 

 

pH increase)

 

 

Lansoprazole

Not studied. Significant decreases

 

Rabeprazole

in rilpivirine plasma concentrations

 

Pantoprazole

are expected.

 

Esomeprazole

(reduced absorption due to gastric

 

 

 

 

pH increase)

 

 

H2-RECEPTOR ANTAGONISTS

 

 

Famotidine*#

rilpivirine AUC ↓ 9%

The combination of rilpivirine and

40 mg single dose taken

rilpivirine Cmin NA

H2-receptor antagonists should be used

12 hours before

rilpivirine Cmax

with particular caution. Only

rilpivirine

 

 

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 of

2 hours before rilpivirine

rilpivirine Cmax ↓ 85%

H2-receptor antagonists at least

 

 

 

12 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 NA

 

4 hours after rilpivirine

rilpivirine Cmax ↑ 21%

 

Cimetidine

Not studied.

 

 

Nizatidine

(reduced absorption due to gastric

 

Ranitidine

 

 

pH increase)

 

 

ANTACIDS

 

 

 

Antacids (e.g.,

Not studied. Significant decreases

The combination of rilpivirine and

aluminium or magnesium

in rilpivirine plasma concentrations

antacids should be used with particular

hydroxide, calcium

are expected.

caution. Antacids should only be

carbonate)

(reduced absorption due to gastric

administered either at least 2 hours

 

before or at least 4 hours after

 

pH increase)

 

rilpivirine.

NARCOTIC ANALGESICS

 

 

 

Methadone*

R(-) methadone AUC ↓ 16%

No dose adjustments are required

60-100 mg once daily,

R(-) methadone Cmin ↓ 22%

when initiating co-administration of

individualised dose

R(-) methadone Cmax ↓ 14%

methadone with rilpivirine. However,

 

rilpivirine AUC ↔*

clinical monitoring is recommended as

 

rilpivirine Cmin ↔*

methadone maintenance therapy may

 

rilpivirine Cmax ↔*

need to be adjusted in some patients.

 

* based on historic controls

 

ANTIARRHYTHMICS

 

 

 

Digoxin*

digoxin AUC ↔

No dose adjustment is required.

 

digoxin Cmin

NA

 

 

digoxin Cmax

 

ANTICOAGULANTS

 

 

 

Dabigatran etexilate

Not studied. A risk for increases in

The combination of rilpivirine and

 

dabigatran plasma concentrations

dabigatran etexilate should be used

 

cannot be excluded.

with caution.

 

(inhibition of intestinal P-gp)

 

ANTIDIABETICS

Metformin*

 

metformin AUC ↔

 

No dose adjustment is required.

850 mg single dose

 

metformin Cmin NA

 

 

 

 

metformin 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 containing

 

 

are expected.

 

 

 

 

St John’s wort as co-administration

 

 

 

 

 

 

 

may 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

NA

 

 

 

paracetamol 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

NA

 

 

 

 

 

sildenafil 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 interactions

#

shown are predicted.

This interaction study has been performed with a dose higher than the recommended dose for rilpivirine assessing the maximal effect

 

 

on the co-administered medicinal product. The dosing recommendation is applicable to the recommended dose of rilpivirine of 25 mg

once 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 between rilpivirine and medicinal products that prolong the QTc interval of the ECG. In a study of healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the ECG (see section 5.1). EDURANT should be used with caution when co-administered with a medicinal product with a known risk of Torsade de Pointes.

4.6Fertility, 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.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of EDURANT during pregnancy.

Breast-feeding

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

Fertility

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

4.7Effects on ability to drive and use machines

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 be considered when assessing a patient’s ability to drive or operate machinery.

4.8Undesirable effects

Summary of the safety profile

During the clinical development program (1,368 patients in the Phase III controlled trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE)), 55.7% of subjects experienced at least one adverse 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 ADRs were reported in 7 (1.0%) patients receiving rilpivirine. The median duration of exposure for patients in the rilpivirine arm and efavirenz arm was 104.3 and 104.1 weeks, respectively. Most ADRs occurred 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 blood cell 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%).

Tabulated summary of adverse reactions

ADRs reported in adult patients treated with rilpivirine are summarised in Table 2. The ADRs are listed 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 patients treated with Rilpivirine

(pooled data from the week 96 analysis of the Phase III ECHO and THRIVE trials) N=686

System Organ Class (SOC)

Frequency Category

ADRs

 

 

(Rilpivirine + BR)

Blood and lymphatic system

common

decreased white blood cell count

disorders

 

decreased haemoglobin

 

 

decreased 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 appetite

 

 

increased triglycerides (fasted)

Psychiatric disorders

very common

insomnia

 

common

abnormal dreams

 

 

depression

 

 

sleep disorders

 

 

depressed mood

Nervous system disorders

very common

headache

 

 

dizziness

 

common

somnolence

Gastrointestinal disorders

very common

nausea

 

 

increased pancreatic amylase

 

common

abdominal pain

 

 

vomiting

 

 

increased lipase

 

 

abdominal discomfort

 

 

dry mouth

Hepatobiliary disorders

very common

increased transaminases

 

common

increased bilirubin

Skin and subcutaneous tissue

common

rash

disorders

 

 

General disorders and

common

fatigue

administration site conditions

 

 

BR=background regimen

 

 

N=number of subjects

 

 

Laboratory abnormalities

In the rilpivirine arm in the week 96 analysis of the Phase III ECHO and THRIVE trials, mean change from baseline in total cholesterol (fasted) was 5 mg/dl, in HDL cholesterol (fasted) 4 mg/dl, in LDL cholesterol (fasted) 1 mg/dl, and in triglycerides (fasted) -7 mg/dl.

Description of selected adverse reactions

Immune reactivation 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) 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).

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 rilpivirine (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 rilpivirine in children aged < 12 years have not yet been established. No data are available.

Other special populations

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 hepatic enzyme elevation was higher than in patients receiving rilpivirine who were not co-infected. This observation was the same in the efavirenz arm. The pharmacokinetic exposure of rilpivirine in co-infected patients was comparable to that in patients without co-infection.

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 the national reporting system listed in Appendix V.

4.9Overdose

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. Since rilpivirine is highly bound to plasma protein, dialysis is unlikely to result in significant removal of the active substance.

5.PHARMACOLOGICAL PROPERTIES

5.1Pharmacodynamic properties

Pharmacotherapeutic group: Antiviral for systemic use, non-nucleoside reverse transcriptase inhibitors, ATC code: J05AG05.

Mechanism of action

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

Antiviral activity in vitro

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 rilpivirine demonstrated limited in vitro activity against HIV-2 with EC50 values ranging from 2,510 to

10,830 nM (920 to 3,970 ng/ml), treatment of HIV-2 infection with rilpivirine is not recommended in the 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).

Resistance

In cell culture

Rilpivirine-resistant strains were selected in cell culture starting from wild-type HIV-1 of different origins and subtypes as well as NNRTI resistant HIV-1. The most commonly observed resistance-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 biological cut-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 primary efficacy analysis. In the week 48 pooled resistance analysis from the Phase III trials, 62 (of a total of 72) virologic failures in the rilpivirine arm had resistance data at baseline and time of failure. In this analysis, the resistance-associated mutations (RAMs) associated with NNRTI resistance that developed 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, at baseline, did not affect response. The E138K substitution emerged most frequently during rilpivirine treatment, commonly in combination with the M184I substitution. In the week 48 analysis, 31 out of 62 of rilpivirine virologic failures had concomitant NNRTI and NRTI RAMs; 17 of those 31 had the combination of E138K and M184I. The most common mutations were the same in the week 48 and week 96 analyses.

In the week 96 pooled resistance analysis, lower rates of virologic failure were observed in the second 48 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.

Considering all of the available in vitro and in vivo data in treatment-naïve subjects, the following resistance-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 the use of EDURANT in the treatment-naïve population. These resistance-associated mutations were derived from in vivo data involving treatment-naïve subjects only and therefore cannot be used to predict the activity of rilpivirine in subjects who have virologically failed an antiretroviral-containing regimen.

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

Cross-resistance

Site-directed NNRTI mutant virus

In a panel of 67 HIV-1 recombinant laboratory strains with one resistance-associated mutation at RT positions 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-associated mutations 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 combination of 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 isolates resistant to efavirenz and/or nevirapine.

Treatment-naïve HIV-1 infected adult patients

In the week 96 pooled resistance analysis of the Phase III trials (ECHO and THRIVE), 42 out of 86 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 as

follows: 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 showed treatment-emergent resistance to rilpivirine (genotypic analysis), with the following frequency of phenotypic cross-resistance: etravirine 4/9, efavirenz 3/9, and nevirapine 1/9.

Effects on electrocardiogram

The effect of rilpivirine at the recommended dose of 25 mg once daily on the QTcF interval was evaluated in a randomised, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 60 healthy adults, with 13 measurements over 24 hours at steady-state. EDURANT at the recommended 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 in healthy adults, the maximum mean time-matched (95% upper confidence bound) differences in QTcF interval 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 Cmax observed with the recommended 25 mg once daily dose of rilpivirine.

Clinical efficacy and safety

Treatment-naïve HIV-1 infected adult patients

The evidence of efficacy of rilpivirine is based on the analyses of 96 week data from 2 randomised, double-blinded, active-controlled, Phase III trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE). The trials were identical in design, with the exception of the background regimen (BR). In the 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 in addition to a BR versus patients receiving efavirenz 600 mg once daily in addition to a BR. Similar efficacy for rilpivirine was seen in each trial demonstrating non-inferiority to efavirenz.

Antiretroviral treatment-naïve HIV-1 infected patients were enrolled who had a plasma HIV-1 RNA ≥ 5,000 copies/ml and were screened for susceptibility to N(t)RTIs and for absence of specific 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 of 2 investigator-selected N(t)RTIs: tenofovir disoproxil fumarate plus emtricitabine or zidovudine plus lamivudine or abacavir plus lamivudine. In ECHO, randomisation was stratified by screening viral load. 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 completed 96 weeks of treatment or discontinued earlier.

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

Table 3: Baseline disease characteristics of antiretroviral treatment-naïve HIV-1 infected adult subjects 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

5.0

log10 copies/ml

(2-7)

(3-7)

Median baseline CD4+ cell count (range),

x 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 following

 

 

background regimens:

 

 

tenofovir disoproxil fumarate plus

80.2%

80.1%

emtricitabine

 

 

zidovudine 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 treated with rilpivirine and patients treated with efavirenz from the pooled data from the ECHO and THRIVE trials. The response rate (confirmed undetectable viral load < 50 HIV-1 RNA copies/ml) at week 96 was comparable between the rilpivirine arm and the efavirenz arm. The incidence of virologic failure was higher in the rilpivirine arm than the efavirenz arm at week 96; however, most of the virologic failures occurred within the first 48 weeks of treatment. Discontinuations due to adverse events were higher in the efavirenz arm at week 96 than the rilpivirine arm. Most of these discontinuations occurred 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%

< 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%

ND

adverse event (AE)

(14/686)

(46/682)

 

(26/682)

(52/682)

 

Discontinued for non-AE

4.5%

5.7%

ND

7.0%

8.1%

ND

reason

(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 (x 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)

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 factors

and study.

Virologic failure in pooled efficacy analysis: includes subjects who were rebounder (confirmed viral load ≥ 50 copies/ml after being

 

 

responder) or who were never suppressed (no confirmed viral load < 50 copies/ml, either ongoing or discontinued due to lack or loss of

efficacy).

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

 

At week 96, the mean change from baseline in CD4+ cell count was +228 x 106 cells/l in the rilpivirine arm and +219 x 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 defined virological 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 IIb trial in antiretroviral treatment-naïve HIV-1 infected adult patients consisting of 2 parts: an initial partially blinded dose-finding part [(rilpivirine) doses blinded] up to 96 weeks, followed by a long-term, open label part. In the open label part of the trial, patients originally randomised to one of the three doses of rilpivirine were all treated with rilpivirine 25 mg once daily in addition to a BR, once the dose for the Phase III studies was selected. Patients in the control arm received efavirenz 600 mg once daily in addition 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 enrolled 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 or protease inhibitor, had no prior use of NNRTIs and were screened for susceptibility to N(t)RTI and for absence 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 mean

increase from baseline in CD4+ counts was 146 x 106 cells/l in patients receiving rilpivirine 25 mg and 160 x 106 cells/l in patients receiving efavirenz.

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

Paediatric population

The pharmacokinetics, safety, tolerability and efficacy of rilpivirine 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.

The European Medicines Agency has deferred the obligation to submit the results of studies with rilpivirine in one or more subsets of the paediatric population in the treatment of Human Immunodeficiency Virus (HIV-1) infection (see section 4.2 for information on paediatric use).

5.2Pharmacokinetic properties

The pharmacokinetic properties of rilpivirine have been evaluated in adult healthy subjects and in antiretroviral treatment-naïve HIV-1 infected patients 12 years of age and older. Exposure to rilpivirine was generally lower in HIV-1 infected patients than in healthy subjects.

Absorption

After oral administration, the maximum plasma concentration of rilpivirine is generally achieved within 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 fasted condition 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% lower than 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 plasma concentrations of rilpivirine, which could potentially reduce the therapeutic effect of EDURANT (see section 4.2).

Distribution

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

Biotransformation

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

Elimination

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

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.

The pharmacokinetics of rilpivirine in paediatric patients less than 12 years of age are under investigation. Dosing recommendations for paediatric patients less than 12 years of age cannot be made due to insufficient data (see section 4.2).

Older people

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

Gender

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

Race

Population pharmacokinetic analysis of rilpivirine in HIV infected patients indicated that race had no clinically relevant effect on the exposure to rilpivirine.

Hepatic impairment

Rilpivirine is primarily metabolised and eliminated by the liver. In a study comparing 8 patients with mild hepatic impairment (Child-Pugh score A) to 8 matched controls, and 8 patients with moderate hepatic impairment (Child-Pugh score B) to 8 matched controls, the multiple dose exposure of rilpivirine was 47% higher in patients with mild hepatic impairment and 5% higher in patients with moderate 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 (see

section 4.2).

Hepatitis B and/or hepatitis C virus co-infection

Population pharmacokinetic analysis indicated that hepatitis B and/or C virus co-infection had no clinically relevant effect on the exposure to rilpivirine.

Renal impairment

The pharmacokinetics of rilpivirine have not been studied in patients with renal insufficiency. Renal elimination of rilpivirine is negligible. No dose adjustment is needed for patients with mild or moderate 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 alteration of drug absorption, distribution and/or metabolism secondary to renal dysfunction. In patients with severe 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 bound to plasma proteins, it is unlikely that it will be significantly removed by haemodialysis or peritoneal dialysis (see section 4.2).

5.3Preclinical safety data

Repeated dose toxicity

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 on reproductive function. There was no teratogenicity with rilpivirine in rats and rabbits. The exposures at the embryo-foetal No Observed Adverse Effects Levels (NOAELs) in rats and rabbits were respectively 15 and 70 times higher than the exposure in humans 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 up to 104 weeks. At the lowest tested doses in the carcinogenicity studies, the systemic exposures (based on AUC) to rilpivirine were 21-fold (mice) and 3-fold (rats), relative to those observed in humans at the recommended dose (25 mg once daily). In rats, there were no drug-related neoplasms. 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 the in 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.

6.PHARMACEUTICAL PARTICULARS

6.1List of excipients

Tablet core

Lactose monohydrate

Croscarmellose sodium

Povidone K30

Polysorbate 20

Silicified microcrystalline cellulose

Magnesium stearate

Tablet coating

Lactose monohydrate

Hypromellose 2910 6 mPa.s

Titanium dioxide E171

Macrogol 3000

Triacetin

6.2Incompatibilities

Not applicable.

6.3Shelf life

3 years

6.4Special precautions for storage

Store in the original bottle in order to protect from light.

6.5Nature and contents of container

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

6.6Special precautions for disposal

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

7.MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

8.MARKETING AUTHORISATION NUMBER

EU/1/11/736/001

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 28 November 2011

Date of latest renewal: DD Month YYYY

10.DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/.

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