- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.
PosologyEDURANT must always be given in combination with other antiretroviral medicinal products.
Adults and adolescents (12 to less than 18 years of age)The recommended dose of EDURANT is one 25 mg tablet taken once daily. EDURANT must be taken with a meal (see section 5.2).
Dose adjustmentFor 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 doseIf the patient misses a dose of EDURANT within 12 hours of the time it is usually taken, the patient must take EDURANT 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 EDURANT, another EDURANT tablet should be taken with a meal. If a patient vomits more than 4 hours after taking EDURANT, the patient does not need to take another dose of EDURANT until the next regularly scheduled dose.
Older peopleThere 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.
Paediatric populationThe safety and efficacy of EDURANT in children aged < 12 years have not yet been established.No data are available.
Hepatic impairmentThere 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).
Renal impairmentEDURANT has mainly been studied in patients with normal renal function. No dose adjustment of EDURANT is required in patients with mild or moderate renal impairment. In patients with severe renal impairment or end-stage renal disease, EDURANT should be used with caution. In patients with severe renal impairment or end-stage renal disease, the combination of EDURANT 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 EDURANT 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).
Method of administrationEDURANT must be taken orally, once daily with a meal (see section 5.2). It is recommended that the EDURANT film-coated tablet be swallowed whole with water and not be chewed or crushed.
Virologic failure and development of resistanceEDURANT 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 EDURANT with a baseline viral load > 100,000 HIV-1 RNA copies/ml had a greater risk of virologic failure (18.2% with EDURANT versus 7.9% with efavirenz) compared to patients with a baseline viral load ≤ 100,000 HIV-1 RNA copies/ml (5.7% with EDURANT versus 3.6% with efavirenz). The greater risk of virologic failure for patients in the EDURANT 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 EDURANT 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 EDURANT (see section 5.1).
CardiovascularAt 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 syndromeIn 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 EDURANTEDURANT contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Medicinal products that affect rilpivirine exposureRilpivirine 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 EDURANT and medicinal products that induce CYP3A has been observed to decrease the plasma concentrations of rilpivirine, which could reduce the therapeutic effect of EDURANT.Co-administration of EDURANT and medicinal products that inhibit CYP3A has been observed to increase the plasma concentrations of rilpivirine.Co-administration of EDURANT 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 rilpivirineEDURANT 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 drugs 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 tableInteraction 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||InteractionGeometric mean change (%)||Recommendations concerning co-administration|
|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 EDURANT.|
|Tenofovir disoproxil fumarate*#300 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.|
|NNRTIs (delavirdine, efavirenz, etravirine, nevirapine)||Not studied.||It is not recommended to co-administer EDURANT 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 EDURANT 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.|
|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.|
|Telaprevir* 750 mg every 8 hours||telaprevir AUC ↓ 5% telaprevir Cmin ↓ 11% telaprevir Cmax ↓ 3% rilpivirine AUC ↑ 78% rilpivirine Cmin ↑ 93% rilpivirine Cmax ↑ 49%||No dose adjustment is required.|
|Carbamazepine Oxcarbazepine Phenobarbital Phenytoin||Not studied. Significant decreases in rilpivirine plasma concentrations are expected. (induction of CYP3A enzymes)||EDURANT must not be used in combination with these anticonvulsants as co-administration may result in loss of therapeutic effect of EDURANT.|
|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 EDURANT 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.|
|Rifabutin* 300 mg once daily 300 mg once daily (+ 25 mg once daily rilpivirine) 300 mg once daily (+ 50 mg once daily rilpivirine)||rifabutin AUC ↔rifabutin Cmin ↔rifabutin Cmax ↔25-O-desacetyl-rifabutin AUC ↔25-O-desacetyl-rifabutin Cmin ↔25-O-desacetyl-rifabutin Cmax ↔rilpivirine AUC ↓ 42% rilpivirine Cmin ↓ 48% rilpivirine Cmax ↓ 31% rilpivirine AUC ↑ 16%* rilpivirine Cmin ↔* rilpivirine Cmax ↑ 43%* * compared to 25 mg once daily rilpivirine alone (induction of CYP3A enzymes)||Throughout co-administration of EDURANT with rifabutin, the EDURANT dose should be increased from 25 mg once daily to 50 mg once daily. When rifabutin co-administration is stopped, the EDURANT dose should be decreased to 25 mg once daily.|
|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)||EDURANT must not be used in combination with rifampicin as co-administration is likely to result in loss of therapeutic effect of EDURANT.|
|Rifapentine||Not studied. Significant decreases in rilpivirine plasma concentrations are expected. (induction of CYP3A enzymes)||EDURANT must not be used in combination with rifapentine as co-administration is likely to result in loss of therapeutic effect of EDURANT.|
|Clarithromycin Erythromycin||Not studied. Increased exposure of rilpivirine is expected. (inhibition of CYP3A enzymes)||Where possible, alternatives such as azithromycin should be considered.|
|Dexamethasone (systemic, except for single dose use)||Not studied. Dose dependent decreases in rilpivirine plasma concentrations are expected. (induction of CYP3A enzymes)||EDURANT 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 EDURANT. 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)||EDURANT must not be used in combination with proton pump inhibitors as co-administration is likely to result in loss of therapeutic effect of EDURANT.|
|Lansoprazole Rabeprazole Pantoprazole Esomeprazole||Not studied. Significant decreases in rilpivirine plasma concentrations are expected. (reduced absorption due to gastric pH increase)|
|Famotidine*#40 mg single dose taken 12 hours before rilpivirine||rilpivirine AUC ↓ 9% rilpivirine Cmin NA rilpivirine Cmax ↔||The combination of EDURANT 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 EDURANT 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 (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 EDURANT 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 EDURANT.|
|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 EDURANT. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.|
|Digoxin*||digoxin AUC ↔digoxin Cmin NA digoxin Cmax ↔||No dose adjustment is required.|
|Dabigatran etexilate||Not studied. A risk for increases in dabigatran plasma concentrations cannot be excluded. (inhibition of intestinal P-gp)||The combination of EDURANT and dabigatran etexilate should be used with caution.|
|Metformin* 850 mg single dose||metformin AUC ↔metformin Cmin NA metformin Cmax ↔||No dose adjustment is required.|
|St John's wort (Hypericum perforatum)||Not studied. Significant decreases in rilpivirine plasma concentrations are expected. (induction of CYP3A enzymes)||EDURANT must not be used in combination with products containing St John's wort as co-administration may result in loss of therapeutic effect of EDURANT.|
|Paracetamol*#500 mg single dose||paracetamol AUC ↔paracetamol Cmin NA paracetamol Cmax ↔rilpivirine AUC ↔rilpivirine Cmin ↑ 26% rilpivirine Cmax ↔||No dose adjustment is required.|
|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.|
QT prolonging medicinal productsThere 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.
PregnancyThere are no adequate and well controlled or pharmacokinetic studies with EDURANT in pregnant women. Studies in animals have shown no reproductive toxicity (see section 5.3) and limited placenta passage. It is not known whether placental transfer of EDURANT occurs in pregnant women. There was no teratogenicity with rilpivirine in rats and rabbits.EDURANT should not be used during pregnancy unless clearly needed.
Breast-feedingIt is not known whether rilpivirine is excreted in human milk. EDURANT 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 EDURANT.
FertilityNo 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).
Summary of the safety profileThe safety assessment is based on the week 96 pooled data from 1,368 patients in the Phase III controlled trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE) in antiretroviral treatment-naïve HIV-1 infected adult patients, 686 of whom received EDURANT (25 mg once daily) (see section 5.1). The median duration of exposure for patients in the EDURANT arm and efavirenz arm was 104.3 and 104.1 weeks, respectively. Most ADRs occurred in the first 48 weeks of treatment.
Tabulated summary of adverse reactionsADRs reported in adult patients treated with EDURANT are summarised in table 2. Selected treatment emergent clinical laboratory abnormalities (grade 3 or grade 4), considered as ADRs, are included in a footnote to 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 EDURANT(pooled data from the week 96 analysis of the Phase III ECHO and THRIVE trials) N=686|
|System Organ Class (SOC)||Frequency Category||ADRs(EDURANT + 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|
|Gastrointestinal disorders||very common||nausea increased pancreatic amylase#|
|common||abdominal pain* vomiting increased lipase#abdominal discomfort dry mouth|
|Hepatobiliary disorders||very common||increased transaminases#|
|Skin and subcutaneous tissue disorders||common||rash*|
|General disorders and administration site conditions||common||fatigue|
Laboratory abnormalitiesIn the EDURANT 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.In the pooled Phase III ECHO and THRIVE trials, serum creatinine increased minimally over 96 weeks of treatment with EDURANT. Most of this increase occurred within the first four weeks of treatment, with a mean change of 0.1 mg/dl (range: -0.3 mg/dl to 0.6 mg/dl) observed overall. In subjects who entered the trials with mild or moderate renal impairment, the serum creatinine increase observed was similar to that seen in subjects with normal renal function. These changes are not considered to be clinically relevant since they do not reflect a change in glomerular filtration rate and no subject discontinued treatment due to increases in serum creatinine. Creatinine increases were comparable by background N(t)RTIs.In the pooled Phase III ECHO and THRIVE trials, at week 96, there was an overall mean change from baseline in basal cortisol of -19.1 (-30.85; -7.37) nmol/l in the EDURANT arm and of -0.6 (-13.29; 12.17) nmol/l in the efavirenz arm. At week 96, the mean change from baseline in ACTH-stimulated cortisol levels was lower in the EDURANT group (+18.4 ± 8.36 nmol/l) than in the efavirenz group (+54.1 ± 7.24 nmol/l). Mean values for both basal and ACTH-stimulated cortisol values at week 96 were within the normal range. These changes in adrenal safety parameters were not clinically relevant. There were no clinical signs or symptoms suggestive of adrenal or gonadal dysfunction in adults.
Description of selected adverse reactions
Immune reactivation syndromeIn 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 EDURANT (25 mg once daily) in combination with other antiretroviral agents (see section 5.1). The median duration of exposure for patients was 63.5 weeks. There were no patients who discontinued treatment due to ADRs. No new ADRs were identified compared to those seen in adults.Most ADRs were Grade 1 or 2. The most common ADRs (all grades, greater than or equal to 10%) were headache (19.4%), depression (19.4%), somnolence (13.9%), and nausea (11.1%). No grade 3-4 laboratory abnormalities for AST/ALT or grade 3-4 ADRs of transaminase increased were reported. The safety and efficacy of EDURANT in children aged < 12 years have not yet been established. No data are available.
Other special populations
Patients co-infected with hepatitis B and/or hepatitis C virusIn patients co-infected with hepatitis B or C virus receiving EDURANT, the incidence of hepatic enzyme elevation was higher than in patients receiving EDURANT 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 reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:United KingdomYellow Card Scheme Website: www.mhra.gov.uk/yellowcard. Ireland HPRA Pharmacovigilance Earlsfort Terrace IRL - Dublin 2 Tel: +353 1 6764971 Fax: +353 1 6762517 Website: www.hpra.ieE-mail: firstname.lastname@example.org
Mechanism of actionRilpivirine 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 vitroRilpivirine 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 EDURANT 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).
In cell cultureRilpivirine-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 subjectsFor 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 EDURANT 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 EDURANT 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.
Site-directed NNRTI mutant virusIn 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 isolatesRilpivirine 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 patientsIn the week 96 pooled resistance analysis of the Phase III trials (ECHO and THRIVE), 42 out of 86 subjects with virologic failure on EDURANT 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 EDURANT 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 electrocardiogramThe effect of EDURANT 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 EDURANT 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 EDURANT 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 EDURANT.
Clinical efficacy and safetyTreatment-naïve HIV-1 infected adult patientsThe evidence of efficacy of EDURANT 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 EDURANT 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 EDURANT 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 EDURANT arm and the efavirenz arm. Table 3 displays selected baseline disease characteristics of the patients in the EDURANT 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|
|EDURANT + BRN=686||Efavirenz + BRN=682|
|Baseline disease characteristics|
|Median baseline plasma HIV-1 RNA (range), log10 copies/ml||5.0 (2-7)||5.0 (3-7)|
|Median baseline CD4+ cell count (range), x 106 cells/l||249 (1-888)||260 (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 emtricitabinezidovudine plus lamivudineabacavir plus lamivudine||80.2%14.7%5.1%||80.1%15.1%4.8%|
|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|
|EDURANT + BRN=686||Efavirenz + BRN=682||Observed difference (95% CI) ±||EDURANT + BRN=686||Efavirenz + BRN=682||Observed difference (95% CI) ±|
|Response (confirmed < 50 HIV-1 RNA copies/ml)§#||84.3% (578/686)||82.3% (561/682)||2.0 (-2.0; 6.0)||77.6% (532/686)||77.6% (529/682)||0 (-4.4; 4.4)|
|Overall||9.0% (62/686)||4.8% (33/682)||ND||11.5% (79/686)||5.9% (40/682)||ND|
|≤ 100,000||3.8% (14/368)||3.3% (11/330)||ND||5.7% (21/368)||3.6% (12/329)||ND|
|> 100,000||15.1% (48/318)||6.3% (22/352)||ND||18.2% (58/318)||7.9% (28/353)||ND|
|Death||0.1% (1/686)||0.4% (3/682)||ND||0.1% (1/686)||0.9% (6/682)||ND|
|Discontinued due to adverse event (AE)||2.0% (14/686)||6.7% (46/682)||ND||3.8% (26/682)||7.6% (52/682)||ND|
|Discontinued for non-AE reason¶||4.5% (31/686)||5.7% (39/682)||ND||7.0% (48/682)||8.1% (55/682)||ND|
|Response by subcategory|
|By background NRTI|
|Tenofovir/emtricitabine||83.5% (459/550)||82.4% (450/546)||1.0 (-3.4; 5.5)||76.9% (423/550)||77.3% (422/546)||-0.4% (-5.4; 4.6)|
|Zidovudine/lamivudine||87.1% (88/101)||80.6% (83/103)||6.5 (-3.6; 16.7)||81.2% (82/101)||76.7% (79/103)||4.5% (-6.8; 15.7)|
|Abacavir/lamivudine||88.6% (31/35)||84.8% (28/33)||3.7 (-12.7; 20.1)||77.1% (27/35)||84.8% (28/33)||-7.7% (-26.7; 11.3)|
|By baseline viral load (copies/ml)|
|≤ 100,000||90.2% (332/368)||83.6% (276/330)||6.6 (1.6; 11.5)||84.0% (309/368)||79.9% (263/329)||4.0 (-1.7; 9.7)|
|> 100,000||77.4% (246/318)||81.0% (285/352)||-3.6 (-9.8; 2.5)||70.1% (223/318)||75.4% (266/353)||-5.2 (-12.0;1.5)|
|By baseline CD4 count (x 106 cells/l)|
|< 50||58.8% (20/34)||80.6% (29/36)||-21.7 (-43.0; -0.5)||55.9% (19/34)||69.4% (25/36)||-13.6 (-36.4; 9.3)|
|≥ 50-< 200||80.4% (156/194)||81.7% (143/175)||-1.3 (-9.3; 6.7)||71.1% (138/194)||74.9% (131/175)||-3.7 (-12.8; 5.4)|
|≥ 200-< 350||86.9% (272/313)||82.4% (253/307)||4.5 (-1.2; 10.2)||80.5% (252/313)||79.5% (244/307)||1.0 (-5.3; 7.3)|
|≥ 350||90.3% (130/144)||82.9% (136/164)||7.4 (-0.3; 15.0)||85.4% (123/144)||78.7% (129/164)||6.8 (-1.9; 15.4)|
|Table 5: Resistance outcome by background NRTI regimen used(pooled data from the ECHO and THRIVE trials in the week 96 resistance analysis)|
|tenofovir/ emtricitabine||zidovudine/ lamivudine||abacavir/ lamivudine||All*|
|Resistance# to emtricitabine/lamivudine % (n/N)||6.9 (38/550)||3.0 (3/101)||8.6 (3/35)||6.4 (44/686)|
|Resistance to rilpivirine % (n/N)||6.5 (36/550)||3.0 (3/101)||8.6 (3/35)||6.1 (42/686)|
|Resistance to emtricitabine/lamivudine % (n/N)||1.1 (6/546)||1.9 (2/103)||3.0 (1/33)||1.3 (9/682)|
|Resistance to efavirenz % (n/N)||2.4 (13/546)||2.9 (3/103)||3.0 (1/33)||2.5 (17/682)|
Paediatric populationThe pharmacokinetics, safety, tolerability and efficacy of EDURANT 25 mg once daily, in combination with an investigator-selected BR containing two NRTIs, was evaluated in trial TMC278-C213, a single-arm, open-label Phase 2 trial in antiretroviral treatment-naïve HIV-1 infected adolescent subjects weighing at least 32 kg. This analysis included 36 patients who had completed at least 48 weeks of treatment or discontinued earlier. The 36 subjects had a median age of 14.5 years (range: 12 to 17 years), and were 55.6% female, 88.9% Black and 11.1% Asian. The median baseline plasma HIV-1 RNA was 4.8 log10 copies per mL, and the median baseline CD4+ cell count was 414 x 106 cells/l (range: 25 to 983 x 106 cells/l). The proportion of subjects with HIV-1 RNA < 50 copies/mL at week 48 (TLOVR) was 72.2% (26/36). The proportion of responders was higher in subjects with a baseline viral load ≤ 100,000 copies/mL (78.6%, 22/28) as compared to those with a baseline viral load > 100,000 copies/mL (50.0%, 4/8). The proportion of virological failures was 22.2% (8/36). The proportion of virologic failures was lower in subjects with a baseline viral load ≤ 100,000 copies/mL (17.9%, 5/28) as compared to those with a baseline viral load > 100,000 copies/mL (37.5%, 3/8). Rilpivirine resistance mutations were observed in 62.5% (5/8) of subjects with virological failure. In 4 of those 5 subjects, NRTI resistance was observed as well. One subject discontinued due to an adverse event and 1 subject discontinued due to reasons other than an adverse event or virological failure. At week 48, the mean increase in CD4+ cell count from baseline was 201.2 x 106 cells/l. The European Medicines Agency has deferred the obligation to submit the results of studies with EDURANT 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).
AbsorptionAfter 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 absorptionThe 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).
DistributionRilpivirine 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.
BiotransformationIn vitro experiments indicate that rilpivirine primarily undergoes oxidative metabolism mediated by the cytochrome P450 (CYP) 3A system.
EliminationThe 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 peoplePopulation 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).
GenderNo clinically relevant differences in the pharmacokinetics of rilpivirine have been observed between men and women.
RacePopulation pharmacokinetic analysis of rilpivirine in HIV infected patients indicated that race had no clinically relevant effect on the exposure to rilpivirine.
Hepatic impairmentRilpivirine 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-infectionPopulation pharmacokinetic analysis indicated that hepatitis B and/or C virus co-infection had no clinically relevant effect on the exposure to rilpivirine.
Renal impairmentThe 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).
Repeated dose toxicityLiver toxicity associated with liver enzyme induction was observed in rodents. In dogs, cholestasis-like effects were noted.
Reproductive toxicology studiesStudies 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 mutagenesisRilpivirine 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.
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