英文药名：EDURANT（Rilpivirine film-coated tablets） 中文药名：利匹韦林片 生产厂家：德国强生制药 药品介绍 近日，强生公司的Edurant(rilpivirine)用于初治成人的人类免疫缺陷病毒-1(HIV-1)感染。Edurant是一种非核苷类逆转录酶抑制剂(NNRTI)，适合与其他抗逆转录病毒药联用。 基于两项Ⅲ期临床试验(涉及1368例成人HIV感染者)和一项历时96周的试验(延伸至192周)的48周数据，FDA确定了Edurant的安全性和有效性。这些研究选取了既往未接受任何HIV治疗的患者，给予Edurant或依法韦仑(经FDA批准用于治疗HIV感染的另一种NNRTI)治疗。两种药物均与其他抗逆转录病毒药联用。 研究表明，Edurant在降低病毒载量方面与依法韦仑等效。Edurant治疗组与依法韦仑治疗组分别有83%和80%的患者在48周治疗后显示病毒载量降至无法检出的水平。Edurant治疗组中治疗开始时病毒载量较高的患者对治疗无应答的几率，高于治疗开始时病毒载量较低者，另外，对Edurant治疗无应答者的耐药率高于对依法韦仑无应答者。 包装规格 30片x25mg 厂家：德国Janssen-Cilag Edurant 25mg tablets 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 4.1 Therapeutic indications EDURANT, in combination with other antiretroviral medicinal products, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-naïve adult patients with a viral load ≤ 100,000 HIV-1 RNA copies/ml. As with other antiretroviral medicinal products, 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 EDURANT must always be given in combination with other antiretroviral medicinal products. Adults 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 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. Special populations Older people 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. Paediatric population The safety and efficacy of EDURANT in children aged < 18 years have not yet been established. No data are available. 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). Renal impairment EDURANT 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 administration EDURANT 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 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 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 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). As with other antiretroviral medicinal products, resistance testing should guide the use of EDURANT (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. Fat redistribution Combination antiretroviral therapy (CART) has been associated with redistribution of body fat (lipodystrophy) in HIV infected patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and protease inhibitors (PIs) and lipoatrophy and nucleoside reverse transcriptase inhibitors (NRTIs) has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age and with drug-related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution (see section 4.8). 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. 4.5 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 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 rilpivirine EDURANT 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 table 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 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. HIV NNRTIs 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. 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. 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. OTHER AGENTS ANTICONVULSANTS 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. ANTIMYCOBACTERIALS 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. 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) 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) H2-RECEPTOR ANTAGONISTS 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 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. 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 EDURANT. 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 EDURANT 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) 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. 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 EDURANT 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 EDURANT assessing the maximal effect on the co-administered medicinal product. The dosing recommendation is applicable to the recommended dose of EDURANT of 25 mg once daily. This interaction study has been performed with a dose higher than the recommended dose for EDURANT. 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 There 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-feeding It 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 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. No studies on the effects of EDURANT on the ability to drive and use machines have been performed. 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 The 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 reactions ADRs 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 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 In the week 96 analysis of the Phase III controlled trials ECHO and THRIVE, 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%). Selected treatment emergent clinical laboratory abnormalities (grade 3 or grade 4), considered as ADRs, reported in EDURANT-treated patients from the 96 week pooled data from the ECHO and THRIVE trials 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%). No new ADR terms were identified in adult patients in the Phase III ECHO and THRIVE trials between 48 weeks and 96 weeks nor in the Phase IIb TMC278-C204 trial through 240 weeks. Laboratory abnormalities In 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 Lipodystrophy CART has been associated with redistribution of body fat (lipodystrophy) in HIV infected patients, including loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump) (see section 4.4). 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 The safety and efficacy of EDURANT in children aged < 18 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 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 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: United Kingdom Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard Ireland Pharmacovigilance Section Irish Medicines Board Kevin O'Malley House Earlsfort Centre Earlsfort Terrace IRL - Dublin 2 Tel: +353 1 6764971 Fax: +353 1 6762517 Website: www.imb.ie e-mail: imbpharmacovigilance@imb.ie 4.9 Overdose There is no specific antidote for overdose with EDURANT. Human experience of overdose with EDURANT is limited. Treatment of overdose with EDURANT 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 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antiviral for systemic use, NNRTI (non-nucleoside reverse transcriptase inhibitor), 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 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). 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 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 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. 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 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 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 electrocardiogram The 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 safety Treatment-naïve HIV-1 infected patients The 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) EDURANT + BR N=686 Efavirenz + BR N=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 emtricitabine zidovudine plus lamivudine abacavir plus lamivudine 80.2% 14.7% 5.1% 80.1% 15.1% 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 EDURANT 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 EDURANT arm and the efavirenz arm. The incidence of virologic failure was higher in the EDURANT 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 EDURANT arm. Most of these discontinuations occurred in the first 48 weeks of treatment. Table 4: Virologic outcome 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 + BR N=686  Efavirenz + BR N=682  Observed difference (95% CI) ± EDURANT + BR N=686  Efavirenz + BR N=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) Non-response             Virologic failure†             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) 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 EDURANT 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/emtricitabine zidovudine/lamivudine abacavir/lamivudine All* EDURANT-treated 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) Efavirenz-treated 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) The number of patients with virologic failure and paired genotypes (baseline and failure) were 71, 11, and 4 for EDURANT 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 EDURANT and who developed resistance to EDURANT, 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 [(EDURANT) 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 EDURANT were all treated with EDURANT 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 EDURANT 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 EDURANT 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 EDURANT 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 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 in ARV-naïve patients (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties The pharmacokinetic properties of rilpivirine have been evaluated in adult healthy subjects and in adult antiretroviral treatment-naïve HIV-1 infected patients. 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 The pharmacokinetics of rilpivirine in pediatric patients are under investigation. Dosing recommendations for pediatric patients 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). 5.3 Preclinical 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 6.1 List 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 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years 6.4 Special precautions for storage Store in the original bottle in order to protect from light. 6.5 Nature 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. 6.6 Special precautions for disposal and other handling 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(s) EU/1/11/736/001 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 28 November 2011 10. Date of revision of the text 20 March 2014 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/.