Edurant · 4.8 Undesirable effects · 2

HOS-155247 · has-adverse-reaction-information · PDF-Seite 33

Summary of the safety profile During the clinical development programme (1,368 patients in the phase 3 controlled trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE)), 55.7% of subjects experienced at least one adverse drug reaction (see section 5.1). The most frequently reported adverse drug reactions (ADRs) (≥ 2%) that were at least of moderate intensity were depression (4.1%), headache (3.5%), insomnia (3.5%), rash (2.3%), and abdominal pain (2.0%). The most frequent serious treatment-related ADRs were reported in 7 (1.0%) patients receiving rilpivirine. The median duration of exposure for patients 33 in the rilpivirine arm and efavirenz arm was 104.3 and 104.1 weeks, respectively. Most ADRs occurred in the first 48 weeks of treatment. Selected treatment-emergent clinical laboratory abnormalities (grade 3 or grade 4), considered as ADRs, reported in EDURANT treated patients were increased pancreatic amylase (3.8%), increased AST (2.3%), increased ALT (1.6%), increased LDL cholesterol (fasted, 1.5%), decreased white blood cell count (1.2%), increased lipase (0.9%), increased bilirubin (0.7%), increased triglycerides (fasted, 0.6%), decreased haemoglobin (0.1%), decreased platelet count (0.1%), and increased total cholesterol (fasted, 0.1%). Tabulated summary of adverse reactions ADRs reported in adult patients treated with rilpivirine are summarised in Table 3. 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 3: ADRs reported in antiretroviral treatment-naïve HIV-1 infected adult patients treated with Rilpivirine (pooled data from the week 96 analysis of the phase 3 ECHO and THRIVE trials) N=686 System Organ Class (SOC) Frequency Category ADRs (Rilpivirine + BR) Blood and lymphatic system common decreased white blood cell count disorders decreased haemoglobin decreased platelet count Immune system disorders uncommon immune reactivation syndrome Metabolism and nutrition very comm

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HOS-155241 · has-adverse-reaction-information · PDF-Seite 11

Summary of the safety profile During the clinical development programme (1,368 patients in the phase 3 controlled trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE)), 55.7% of subjects experienced at least one adverse drug reaction (see section 5.1). The most frequently reported adverse drug reactions (ADRs) (≥ 2%) that were at least of moderate intensity were depression (4.1%), headache (3.5%), insomnia (3.5%), rash (2.3%), and abdominal pain (2.0%). The most frequent serious treatment-related ADRs were reported in 7 (1.0%) patients receiving rilpivirine. The median duration of exposure for patients in the rilpivirine arm and efavirenz arm was 104.3 and 104.1 weeks, respectively. Most ADRs occurred in the first 48 weeks of treatment. Selected treatment-emergent clinical laboratory abnormalities (grade 3 or grade 4), considered as ADRs, reported in EDURANT treated patients were increased pancreatic amylase (3.8%), increased AST (2.3%), increased ALT (1.6%), increased LDL cholesterol (fasted, 1.5%), decreased white blood cell count (1.2%), increased lipase (0.9%), increased bilirubin (0.7%), increased triglycerides (fasted, 0.6%), decreased haemoglobin (0.1%), decreased platelet count (0.1%), and increased total cholesterol (fasted, 0.1%). Tabulated summary of adverse reactions ADRs reported in adult patients treated with rilpivirine are summarised in Table 2. The ADRs are listed by system organ class (SOC) and frequency. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1,000 to < 1/100). Within each frequency grouping, ADRs are presented in order of decreasing frequency. Table 2: ADRs reported in antiretroviral treatment-naïve HIV-1 infected adult patients treated with Rilpivirine (pooled data from the week 96 analysis of the phase 3 ECHO and THRIVE trials) N=686 System Organ Class (SOC) Frequency Category ADRs (Rilpivirine + BR) Blood and lymphatic system common decreased white blood cell count disorders decreased haemoglobin decreased platelet count Immune system disorders uncommon immune reactivation syndrome Metabolism and nutrition very common increased total cholesterol (fasted) disorders

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HOS-155243 · has-contraindication-information · PDF-Seite 27

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).

HOS-155237 · has-contraindication-information · PDF-Seite 3

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 3 - 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).

HOS-155236 · has-indication-information · PDF-Seite 2

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

HOS-155242 · has-indication-information · PDF-Seite 25

EDURANT, in combination with other antiretroviral medicinal products, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in paediatric patients 2 to less than 18 years of age and weighing at least 14 kg to less than 25 kg without known mutations associated with resistance to the non-nucleoside reverse transcriptase inhibitor (NNRTI) class, and with a viral load ≤ 100,000 HIV-1 RNA copies/ml (see sections 4.4 and 5.1). Genotypic resistance testing should guide the use of EDURANT (see sections 4.4 and 5.1).

HOS-155245 · has-interaction-information · PDF-Seite 28

Medicinal products that affect rilpivirine exposure Rilpivirine is primarily metabolised by cytochrome P450 (CYP)3A. Medicinal products that induce or inhibit CYP3A may thus affect the clearance of rilpivirine (see section 5.2). Co-administration of rilpivirine and medicinal products that induce CYP3A has been observed to decrease the plasma concentrations of rilpivirine, which could reduce the therapeutic effect of rilpivirine. Co-administration of rilpivirine and medicinal products that inhibit CYP3A has been observed to increase the plasma concentrations of rilpivirine. Co-administration of rilpivirine with medicinal products that increase gastric pH may result in decreased plasma concentrations of rilpivirine which could potentially reduce the therapeutic effect of EDURANT. Medicinal products that are affected by the use of rilpivirine Rilpivirine at the recommended dose is not likely to have a clinically relevant effect on the exposure of medicinal products metabolised by CYP enzymes. Rilpivirine inhibits P-glycoprotein in vitro (IC50 is 9.2 μM). In a clinical study, rilpivirine did not significantly affect the pharmacokinetics of digoxin. However, it may not be completely excluded that rilpivirine can increase the exposure to other medicines transported by P-glycoprotein that are more sensitive to intestinal P-gp inhibition, e.g., dabigatran etexilate. Rilpivirine is an in vitro inhibitor of the transporter MATE-2K with an IC50 of < 2.7 nM. The clinical implications of this finding are currently unknown. Established and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal products are listed in Table 2. Interaction table Interaction studies have only been performed in adults. 28 Interactions between rilpivirine and co-administered medicinal products are listed in Table 2(increase is indicated as “↑”, decrease as “↓”, no change as “↔”, not applicable as “NA”, confidence interval as “CI”). Table 2: INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL PRODUCTS Medicinal products by Interaction Recommendations concerning therapeutic areas Geometric mean change (%) co-administration ANTI-INFECTIVES Antiretrovirals HIV NRTIs/N[t]RTIs Didanosine*# didanosine AUC ↑ 12% No dose adjustmen

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HOS-155239 · has-interaction-information · PDF-Seite 5

Medicinal products that affect rilpivirine exposure Rilpivirine is primarily metabolised by cytochrome P450 (CYP)3A. Medicinal products that induce or inhibit CYP3A may thus affect the clearance of rilpivirine (see section 5.2). Co-administration of rilpivirine and medicinal products that induce CYP3A has been observed to decrease the plasma concentrations of rilpivirine, which could reduce the therapeutic effect of rilpivirine. Co-administration of rilpivirine and medicinal products that inhibit CYP3A has been observed to increase the plasma concentrations of rilpivirine. Co-administration of rilpivirine with medicinal products that increase gastric pH may result in decreased plasma concentrations of rilpivirine which could potentially reduce the therapeutic effect of EDURANT. Medicinal products that are affected by the use of rilpivirine Rilpivirine at the recommended dose is not likely to have a clinically relevant effect on the exposure of medicinal products metabolised by CYP enzymes. Rilpivirine inhibits P-glycoprotein in vitro (IC50 is 9.2 μM). In a clinical study, rilpivirine did not significantly affect the pharmacokinetics of digoxin. However, it may not be completely excluded that rilpivirine can increase the exposure to other medicines transported by P-glycoprotein that are more sensitive to intestinal P-gp inhibition, e.g., dabigatran etexilate. Rilpivirine is an in vitro inhibitor of the transporter MATE-2K with an IC50 of < 2.7 nM. The clinical implications of this finding are currently unknown. Established and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal products are listed in Table 1. Interaction table Interaction studies have only been performed in adults. Interactions between rilpivirine and co-administered medicinal products are listed in Table 1 (increase is indicated as “↑”, decrease as “↓”, no change as “↔”, not applicable as “NA”, confidence interval as “CI”). 5  Table 1: INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL PRODUCTS Medicinal products by Interaction Recommendations concerning therapeutic areas Geometric mean change (%) co-administration ANTI-INFECTIVES Antiretrovirals HIV NRTIs/N[t]RTIs Didanosine*# didanosine AUC ↑ 12% No dose adjustment is

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HOS-155246 · has-pregnancy-information · PDF-Seite 33

Pregnancy A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative or feto/neonatal toxicity of rilpivirine (see sections 4.4, 5.1 and 5.2). Lower exposures of rilpivirine were observed during pregnancy, therefore viral load should be monitored closely. Animal studies do not indicate reproductive toxicity (see section 5.3). The use of rilpivirine may be considered during pregnancy, if necessary. Breast-feeding It is not known whether rilpivirine is excreted in human milk. Rilpivirine is excreted in the milk of rats. Because of the potential for adverse reactions in breastfed infants, mothers should be instructed not to breast-feed if they are receiving rilpivirine. In order to avoid transmission of HIV to the infant it is recommended that women living with HIV do not breast-feed. Fertility No human data on the effect of rilpivirine on fertility are available. No clinically relevant effects on fertility were seen in animal studies (see section 5.3).

HOS-155240 · has-pregnancy-information · PDF-Seite 10

Pregnancy A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative or feto/neonatal toxicity of rilpivirine (see sections 4.4, 5.1 and 5.2). Lower exposures of rilpivirine were observed during pregnancy, therefore viral load should be monitored closely. Animal studies do not indicate reproductive toxicity (see section 5.3). The use of rilpivirine may be considered during pregnancy, if necessary. Breast-feeding It is not known whether rilpivirine is excreted in human milk. Rilpivirine is excreted in the milk of rats. Because of the potential for adverse reactions in breastfed infants, mothers should be instructed not to breast-feed if they are receiving rilpivirine. In order to avoid transmission of HIV to the infant it is recommended that women living with HIV do not breast-feed. Fertility No human data on the effect of rilpivirine on fertility are available. No clinically relevant effects on fertility were seen in animal studies (see section 5.3). 10

HOS-155244 · has-warning-information · PDF-Seite 27

Virologic failure and development of resistance EDURANT has not been evaluated in patients with previous virologic failure to any other antiretroviral therapy. The list of rilpivirine resistance-associated mutations presented in section 5.1 should only guide the use of EDURANT in the treatment-naïve population. In the pooled efficacy analysis from the phase 3 trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE) in adults through 96 weeks, patients treated with rilpivirine with a baseline viral load > 100,000 HIV-1 RNA copies/ml had a greater risk of virologic failure (18.2% with rilpivirine versus 7.9% with efavirenz) compared to patients with a baseline viral load ≤ 100,000 HIV-1 RNA copies/ml (5.7% with rilpivirine versus 3.6% with efavirenz). The greater risk of virologic failure for patients in the rilpivirine arm was observed in the first 48 weeks of these trials (see section 5.1). Patients with a baseline viral load > 100,000 HIV-1 RNA copies/ml who experienced virologic failure exhibited a higher rate of treatment-emergent resistance to the non-nucleoside reverse transcriptase inhibitor (NNRTI) class. More patients who failed virologically on rilpivirine than who failed virologically on efavirenz developed lamivudine/emtricitabine associated resistance (see section 5.1). Findings in adolescents and paediatric patients in trial TMC278-C213 were generally in line with these data. No virological failures were observed in trial TMC278HTX2002 (for details see section 5.1). Only patients deemed likely to have good adherence to antiretroviral therapy should be treated with rilpivirine, as suboptimal adherence can lead to development of resistance and the loss of future treatment options. As with other antiretroviral medicinal products, resistance testing should guide the use of rilpivirine (see section 5.1). Cardiovascular At supra-therapeutic doses (75 and 300 mg once daily), rilpivirine has been associated with prolongation of the QTc interval of the electrocardiogram (ECG) (see sections 4.5, 4.8 and 5.2). EDURANT at the recommended dose of 25 mg once daily is not associated with a clinically relevant effect on QTc. EDURANT should be used with caution when co-administered with medicinal products with a known risk of Torsade de Pointes. 27 Immune reactivation syndrome In HIV infected patients with severe immune deficiency at the time of initiation of CART, an inflammatory reaction to asymptoma

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HOS-155238 · has-warning-information · PDF-Seite 4

Virologic failure and development of resistance EDURANT has not been evaluated in patients with previous virologic failure to any other antiretroviral therapy. The list of rilpivirine resistance-associated mutations presented in section 5.1 should only guide the use of EDURANT in the treatment-naïve population. In the pooled efficacy analysis from the phase 3 trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE) in adults through 96 weeks, patients treated with rilpivirine with a baseline viral load > 100,000 HIV-1 RNA copies/ml had a greater risk of virologic failure (18.2% with rilpivirine versus 7.9% with efavirenz) compared to patients with a baseline viral load ≤ 100,000 HIV-1 RNA copies/ml (5.7% with rilpivirine versus 3.6% with efavirenz). The greater risk of virologic failure for patients in the rilpivirine arm was observed in the first 48 weeks of these trials (see section 5.1). Patients with a baseline viral load > 100,000 HIV-1 RNA copies/ml who experienced virologic failure exhibited a higher rate of treatment-emergent resistance to the non-nucleoside reverse transcriptase inhibitor (NNRTI) class. More patients who failed virologically on rilpivirine than who failed virologically on efavirenz developed lamivudine/emtricitabine associated resistance (see section 5.1). Findings in adolescents and paediatric patients in trial TMC278-C213 were generally in line with these data. No virological failures were observed in trial TMC278HTX2002 (for details see section 5.1). Only patients deemed likely to have good adherence to antiretroviral therapy should be treated with rilpivirine, as suboptimal adherence can lead to development of resistance and the loss of future treatment options. As with other antiretroviral medicinal products, resistance testing should guide the use of rilpivirine (see section 5.1). Cardiovascular At supra-therapeutic doses (75 and 300 mg once daily), rilpivirine has been associated with prolongation of the QTc interval of the electrocardiogram (ECG) (see sections 4.5, 4.8 and 5.2). EDURANT at the recommended dose of 25 mg once daily is not associated with a clinically relevant effect on QTc. EDURANT should be used with caution when co-administered with medicinal products with a known risk of Torsade de Pointes. Immune reactivation syndrome In HIV infected patients with severe immune deficiency at the time of initiation of CART, an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause

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