4.1. Therapeutic indications

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

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

4.2. Posology and method of administration

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

Posology

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

Dispersible tablets

EDURANT is also available as EDURANT 2.5 mg dispersible tablets for paediatric patients aged 2 to less than 18 years weighing at least 14 kg and less than 25 kg. The recommended dosage of EDURANT in these paediatric patients is based on body weight. A difference in bioavailability of 1 x 25 mg film‑coated tablets and 10 x 2.5 mg dispersible tablets was observed, therefore they are not interchangeable.

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 less than 2 years or weighing less than 14 kg have not been established. No data are available.

Pregnancy

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

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.

4.3. Contraindications

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).

4.4. Special warnings and precautions for use

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 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 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 and paediatric patients in trial TMC278-C213 were generally in line with these data. 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 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 and autoimmune hepatitis) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.8).

Pregnancy

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

Important information about some of the ingredients of EDURANT

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

4.5. Interaction 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 the recommended dose 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 therapeutic areas

Interaction

Geometric mean change (%)

Recommendations concerning co‑administration

ANTI‑INFECTIVES

Antiretrovirals

HIV NRTIs/N[t]RTIs

Didanosine*#

400 mg once daily

didanosine AUC ↑ 12%

didanosine Cmin NA

didanosine Cmax ↔

rilpivirine AUC ↔

rilpivirine Cmin ↔

rilpivirine Cmax ↔

No dose adjustment is required. Didanosine should be administered at least two hours before or at least four hours after rilpivirine.

Tenofovir disoproxil *#

245 mg once daily

tenofovir AUC ↑ 23%

tenofovir Cmin ↑ 24%

tenofovir Cmax ↑ 19%

rilpivirine AUC ↔

rilpivirine Cmin ↔

rilpivirine Cmax ↔

No dose adjustment is required.

Other NRTIs

(abacavir, emtricitabine, lamivudine, stavudine and zidovudine)

Not studied. No clinically relevant drug‑drug interactions are expected.

No dose adjustment is required.

HIV NNRTIs

NNRTIs

(delavirdine, efavirenz, etravirine, nevirapine)

Not studied.

It is not recommended to co‑administer rilpivirine with other NNRTIs.

HIV PIs – with co‑administration of low dose ritonavir

Darunavir/ritonavir*#

800/100 mg once daily

darunavir AUC ↔

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

(soft gel capsule)*#

400/100 mg twice daily

lopinavir AUC ↔

lopinavir Cmin ↓ 11%

lopinavir Cmax ↔

rilpivirine AUC ↑ 52%

rilpivirine Cmin ↑ 74%

rilpivirine Cmax ↑ 29%

(inhibition of CYP3A enzymes)

Other boosted PIs (atazanavir/ritonavir, fosamprenavir/ritonavir, saquinavir/ritonavir, tipranavir/ritonavir)

Not studied.

HIV PIs – without co‑administration of low dose ritonavir

Unboosted PIs (atazanavir, fosamprenavir, indinavir, nelfinavir)

Not studied. Increased exposure of rilpivirine is expected.

(inhibition of CYP3A enzymes)

No dose adjustment is required.

CCR5 Antagonists

Maraviroc

Not studied. No clinically relevant drug‑drug interaction is expected.

No dose adjustment is required.

HIV Integrase Strand Transfer Inhibitors

Raltegravir*

raltegravir AUC ↑ 9%

raltegravir Cmin ↑ 27%

raltegravir Cmax ↑ 10%

rilpivirine AUC ↔

rilpivirine Cmin ↔

rilpivirine Cmax ↔

No dose adjustment is required.

Other Antiviral Agents

Ribavirin

Not studied. No clinically relevant drug‑drug interaction is expected.

No dose adjustment is required.

Simeprevir*

simeprevir AUC ↔

simeprevir Cmin ↔

simeprevir Cmax ↑ 10%

rilpivirine AUC ↔

rilpivirine Cmin ↑ 25%

rilpivirine Cmax ↔

No dose adjustment is required.

OTHER AGENTS

ANTICONVULSANTS

Carbamazepine

Oxcarbazepine

Phenobarbital

Phenytoin

Not studied. Significant decreases in rilpivirine plasma concentrations are expected.

(induction of CYP3A enzymes)

Rilpivirine must not be used in combination with these anticonvulsants as co‑administration may result in loss of therapeutic effect of rilpivirine (see section 4.3).

AZOLE ANTIFUNGAL AGENTS

Ketoconazole*#

400 mg once daily

ketoconazole AUC ↓ 24%

ketoconazole Cmin ↓ 66%

ketoconazole Cmax ↔

(induction of CYP3A due to high rilpivirine dose in the study)

rilpivirine AUC ↑ 49%

rilpivirine Cmin ↑ 76%

rilpivirine Cmax ↑ 30%

(inhibition of CYP3A enzymes)

At the recommended dose of 25 mg once daily, no dose adjustment is required when rilpivirine is co‑administered with ketoconazole.

Fluconazole

Itraconazole

Posaconazole

Voriconazole

Not studied. Concomitant use of EDURANT with azole antifungal agents may cause an increase in the plasma concentrations of rilpivirine.

(inhibition of CYP3A enzymes)

No dose adjustment is required.

ANTIMYCOBACTERIALS

Rifabutin*

300 mg once daily†

rifabutin AUC ↔

rifabutin Cmin ↔

rifabutin Cmax ↔

25‑O‑desacetyl‑rifabutin AUC ↔

25‑O‑desacetyl‑rifabutin Cmin ↔

25‑O‑desacetyl‑rifabutin Cmax ↔

Throughout co‑administration of rilpivirine with rifabutin, the rilpivirine dose should be increased from 25 mg once daily to 50 mg once daily. When rifabutin co‑administration is stopped, the rilpivirine dose should be decreased to 25 mg once daily.

300 mg once daily

(+ 25 mg once daily rilpivirine)

rilpivirine AUC ↓ 42%

rilpivirine Cmin ↓ 48%

rilpivirine Cmax ↓ 31%

300 mg once daily

(+ 50 mg once daily rilpivirine)

rilpivirine AUC ↑ 16%*

rilpivirine Cmin ↔*

rilpivirine Cmax ↑ 43%*

* compared to 25 mg once daily rilpivirine alone

(induction of CYP3A enzymes)

Rifampicin*#

600 mg once daily

rifampicin AUC ↔

rifampicin Cmin NA

rifampicin Cmax ↔

25‑desacetyl‑rifampicin AUC ↓ 9%

25‑desacetyl‑rifampicin Cmin NA

25‑desacetyl‑rifampicin Cmax ↔

rilpivirine AUC ↓ 80%

rilpivirine Cmin ↓ 89%

rilpivirine Cmax ↓ 69%

(induction of CYP3A enzymes)

Rilpivirine must not be used in combination with rifampicin as co‑administration is likely to result in loss of therapeutic effect of rilpivirine (see section 4.3).

Rifapentine

Not studied. Significant decreases in rilpivirine plasma concentrations are expected.

(induction of CYP3A enzymes)

Rilpivirine must not be used in combination with rifapentine as co‑administration is likely to result in loss of therapeutic effect of rilpivirine (see section 4.3).

MACROLIDE ANTIBIOTICS

Clarithromycin

Erythromycin

Not studied. Increased exposure of rilpivirine is expected.

(inhibition of CYP3A enzymes)

Where possible, alternatives such as azithromycin should be considered.

GLUCOCORTICOIDS

Dexamethasone (systemic, except for single dose use)

Not studied. Dose dependent decreases in rilpivirine plasma concentrations are expected.

(induction of CYP3A enzymes)

Rilpivirine should not be used in combination with systemic dexamethasone (except as a single 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*#

20 mg once daily

omeprazole AUC ↓ 14%

omeprazole Cmin NA

omeprazole Cmax ↓ 14%

rilpivirine AUC ↓ 40%

rilpivirine Cmin ↓ 33%

rilpivirine Cmax ↓ 40%

(reduced absorption due to gastric pH increase)

Rilpivirine must not be used in combination with proton pump inhibitors as co‑administration is likely to result in loss of therapeutic effect of rilpivirine (see section 4.3).

Lansoprazole

Rabeprazole

Pantoprazole

Esomeprazole

Not studied. Significant decreases in rilpivirine plasma concentrations are expected.

(reduced absorption due to gastric pH increase)

H2‑RECEPTOR ANTAGONISTS

Famotidine*#

40 mg single dose taken 12 hours before rilpivirine

rilpivirine AUC ↓ 9%

rilpivirine Cmin NA

rilpivirine Cmax ↔

The combination of rilpivirine and H2‑receptor antagonists should be used with particular caution. Only H2‑receptor antagonists that can be dosed once daily should be used.

A strict dosing schedule, with intake of H2‑receptor antagonists at least 12 hours before or at least 4 hours after rilpivirine should be used.

Famotidine*#

40 mg single dose taken 2 hours before rilpivirine

rilpivirine AUC ↓ 76%

rilpivirine Cmin NA

rilpivirine Cmax ↓ 85%

(reduced absorption due to gastric pH increase)

Famotidine*#

40 mg single dose taken 4 hours after rilpivirine

rilpivirine AUC ↑ 13%

rilpivirine Cmin NA

rilpivirine Cmax ↑ 21%

Cimetidine

Nizatidine

Ranitidine

Not studied.

(reduced absorption due to gastric pH increase)

ANTACIDS

Antacids (e.g., aluminium or magnesium hydroxide, calcium carbonate)

Not studied. Significant decreases in rilpivirine plasma concentrations are expected.

(reduced absorption due to gastric pH increase)

The combination of rilpivirine and antacids should be used with particular caution. Antacids should only be administered either at least 2 hours before or at least 4 hours after rilpivirine.

NARCOTIC ANALGESICS

Methadone*

60‑100 mg once daily, individualised dose

R(‑) methadone AUC ↓ 16%

R(‑) methadone Cmin ↓ 22%

R(‑) methadone Cmax ↓ 14%

rilpivirine AUC ↔*

rilpivirine Cmin ↔*

rilpivirine Cmax ↔*

* based on historic controls

No dose adjustments are required when initiating co‑administration of methadone with rilpivirine. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.

ANTIARRHYTHMICS

Digoxin*

digoxin AUC ↔

digoxin Cmin NA

digoxin Cmax ↔

No dose adjustment is required.

ANTICOAGULANTS

Dabigatran etexilate

Not studied. A risk for increases in dabigatran plasma concentrations cannot be excluded.

(inhibition of intestinal P‑gp)

The combination of rilpivirine and dabigatran etexilate should be used with caution.

ANTIDIABETICS

Metformin*

850 mg single dose

metformin AUC ↔

metformin Cmin NA

metformin Cmax ↔

No dose adjustment is required.

HERBAL PRODUCTS

St John's wort (Hypericum perforatum)

Not studied. Significant decreases in rilpivirine plasma concentrations are expected.

(induction of CYP3A enzymes)

Rilpivirine must not be used in combination with products containing St John's wort as co‑administration may result in loss of therapeutic effect of rilpivirine (see section 4.3).

ANALGESICS

Paracetamol*#

500 mg single dose

paracetamol AUC ↔

paracetamol Cmin NA

paracetamol Cmax ↔

rilpivirine AUC ↔

rilpivirine Cmin ↑ 26%

rilpivirine Cmax ↔

No dose adjustment is required.

ORAL CONTRACEPTIVES

Ethinylestradiol*

0.035 mg once daily

Norethindrone*

1 mg once daily

ethinylestradiol AUC ↔

ethinylestradiol Cmin ↔

ethinylestradiol Cmax ↑ 17%

norethindrone AUC ↔

norethindrone Cmin ↔

norethindrone Cmax ↔

rilpivirine AUC ↔*

rilpivirine Cmin ↔*

rilpivirine Cmax ↔*

* based on historic controls

No dose adjustment is required.

HMG CO‑A REDUCTASE INHIBITORS

Atorvastatin*#

40 mg once daily

atorvastatin AUC ↔

atorvastatin Cmin ↓ 15%

atorvastatin Cmax ↑ 35%

rilpivirine AUC ↔

rilpivirine Cmin ↔

rilpivirine Cmax ↓ 9%

No dose adjustment is required.

PHOSPHODIESTERASE TYPE 5 (PDE‑5) INHIBITORS

Sildenafil*#

50 mg single dose

sildenafil AUC ↔

sildenafil Cmin NA

sildenafil Cmax ↔

rilpivirine AUC ↔

rilpivirine Cmin ↔

rilpivirine Cmax ↔

No dose adjustment is required.

Vardenafil

Tadalafil

Not studied.

No dose adjustment is required.

* 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.

4.6. Fertility, pregnancy and lactation

Pregnancy

A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative or feto/neonatal toxicity of rilpivirine (see sections 4.4, 5.1 and 5.2). Lower exposures of rilpivirine 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.

Breast‑feeding

It is not known whether rilpivirine is excreted in human milk. Rilpivirine is excreted in the milk of rats. Because of the potential for adverse reactions in breastfed infants, mothers should be instructed not 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 do not breast-feed.

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).

4.7. Effects 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.

4.8. Undesirable effects

Summary of the safety profile

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 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 3 ECHO and THRIVE trials)

N=686

System Organ Class (SOC)

Frequency Category

ADRs

(Rilpivirine + BR)

Blood and lymphatic system disorders

common

decreased white blood cell count

decreased haemoglobin

decreased platelet count

Immune system disorders

uncommon

immune reactivation syndrome

Metabolism and nutrition disorders

very common

increased total cholesterol (fasted)

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 disorders

common

rash

General disorders and administration site conditions

common

fatigue

BR=background regimen

N=number of subjects

Laboratory abnormalities

In the rilpivirine arm in the week 96 analysis of the phase 3 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 and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4).

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 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 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 ADRs of transaminase increased were reported.

There were no new safety concerns identified in the week 240 analysis of the TMC278-C213 Cohort 1 trial 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 the safety of the rilpivirine weight adjusted doses 12.5, 15 and 25 mg once daily in antiretroviral treatment-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%), AST increased (2/18, 11.1%), and rash (2/18, 11.1%). There were no patients who discontinued treatment due to ADRs. No new ADRs were identified compared to those seen in adults.

TMC278HTX2002

The single arm, open-label phase 2 trial, TMC278HTX2002, was designated to evaluate the safety of rilpivirine weight-adjusted doses 12.5, 15 and 25 mg once daily in virologically suppressed HIV-1 infected patients (2 to less12 years of age and weighing at least 10 kg) (see section 5.1). The median 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 no patients who discontinued treatment due to ADRs. No new ADRs were identified compared to those seen in adults.

The safety and efficacy of rilpivirine in children less than 2 years or weighing less than 14 kg have not been established.

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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