Revolade · 4.3 Contraindications · 1

HOS-095486 · has-adverse-reaction-information · PDF-Seite 55

Summary of the safety profile Immune thrombocytopenia in adult and paediatric patients The safety of Revolade was assessed in adult patients (N=763) using the pooled double-blind, placebo-controlled studies TRA100773A and B, TRA102537 (RAISE) and TRA113765, in which 403 patients were exposed to Revolade and 179 to placebo, in addition to data from the completed open-label studies (N=360) TRA108057 (REPEAT), TRA105325 (EXTEND) and TRA112940 (see section 5.1). Patients received study medication for up to 8 years (in EXTEND). The most important serious adverse reactions were hepatotoxicity and thrombotic/thromboembolic events. The most common adverse reactions occurring in at least 10% of patients included nausea, diarrhoea, increased alanine aminotransferase and back pain. 55 The safety of Revolade in paediatric patients (aged 1 to 17 years) with previously treated ITP has been demonstrated in two studies (N=171) (see section 5.1). PETIT2 (TRA115450) was a two-part, double- blind and open-label, randomised, placebo-controlled study. Patients were randomised 2:1 and received Revolade (n=63) or placebo (n=29) for up to 13 weeks in the randomised period of the study. PETIT (TRA108062) was a three-part, staggered-cohort, open-label and double-blind, randomised, placebo-controlled study. Patients were randomised 2:1 and received Revolade (n=44) or placebo (n=21), for up to 7 weeks. The profile of adverse reactions was comparable to that seen in adults with some additional adverse reactions, marked ♦ in the table below. The most common adverse reactions in paediatric ITP patients 1 year and older (≥3% and greater than placebo) were upper respiratory tract infection, nasopharyngitis, cough, pyrexia, abdominal pain, oropharyngeal pain, toothache and rhinorrhoea. Thrombocytopenia with HCV infection in adult patients ENABLE 1 (TPL103922 n=716, 715 treated with eltrombopag) and ENABLE 2 (TPL108390 n=805) were randomised, double-blind, placebo-controlled, multicentre studies to assess the efficacy and safety of Revolade in thrombocytopenic patients with HCV infection who were otherwise eligible to initiate antiviral therapy. In the HCV studies the safety population consisted of all randomised patients who received double-blind study medicinal product during Part 2 of ENABLE 1 (Revolade treatment n=450, placebo treatment n=232) and ENABLE 2 (Revolade treatment n=506, placebo treatment n=252). Patients are analys

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HOS-095480 · has-adverse-reaction-information · PDF-Seite 15

Summary of the safety profile Immune thrombocytopenia in adult and paediatric patients The safety of Revolade was assessed in adult patients (N=763) using the pooled double-blind, placebo-controlled studies TRA100773A and B, TRA102537 (RAISE) and TRA113765, in which 403 patients were exposed to Revolade and 179 to placebo, in addition to data from the completed open-label studies (N=360) TRA108057 (REPEAT), TRA105325 (EXTEND) and TRA112940 (see section 5.1). Patients received study medication for up to 8 years (in EXTEND). The most important serious adverse reactions were hepatotoxicity and thrombotic/thromboembolic events. The most common adverse reactions occurring in at least 10% of patients included nausea, diarrhoea, increased alanine aminotransferase and back pain. The safety of Revolade in paediatric patients (aged 1 to 17 years) with previously treated ITP has been demonstrated in two studies (N=171) (see section 5.1). PETIT2 (TRA115450) was a two-part, double- blind and open-label, randomised, placebo-controlled study. Patients were randomised 2:1 and received Revolade (n=63) or placebo (n=29) for up to 13 weeks in the randomised period of the study. PETIT (TRA108062) was a three-part, staggered-cohort, open-label and double-blind, randomised, placebo-controlled study. Patients were randomised 2:1 and received Revolade (n=44) or placebo (n=21), for up to 7 weeks. The profile of adverse reactions was comparable to that seen in adults with some additional adverse reactions, marked ♦ in the table below. The most common adverse reactions in paediatric ITP patients 1 year and older (≥3% and greater than placebo) were upper respiratory tract infection, nasopharyngitis, cough, pyrexia, abdominal pain, oropharyngeal pain, toothache and rhinorrhoea. Thrombocytopenia with HCV infection in adult patients ENABLE 1 (TPL103922 n=716, 715 treated with eltrombopag) and ENABLE 2 (TPL108390 n=805) were randomised, double-blind, placebo-controlled, multicentre studies to assess the efficacy and safety of Revolade in thrombocytopenic patients with HCV infection who were otherwise eligible to initiate antiviral therapy. In the HCV studies the safety population consisted of all randomised patients who received double-blind study medicinal product during Part 2 of ENABLE 1 (Revolade treatment n=450, placebo treatment n=232) and ENABLE 2 (Revolade treatment n=506, placebo treatment n=252). Patients are analysed according to the treatment received (total safety doubl

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HOS-095476 · has-contraindication-information · PDF-Seite 8

Hypersensitivity to eltrombopag or to any of the excipients listed in section 6.1.

HOS-095482 · has-contraindication-information · PDF-Seite 48

Hypersensitivity to eltrombopag or to any of the excipients listed in section 6.1.

HOS-095475 · has-indication-information · PDF-Seite 3

Revolade is indicated for the treatment of adult patients with primary immune thrombocytopenia (ITP) who are refractory to other treatments (e.g. corticosteroids, immunoglobulins) (see sections 4.2 and 5.1). Revolade is indicated for the treatment of paediatric patients aged 1 year and above with primary immune thrombocytopenia (ITP) lasting 6 months or longer from diagnosis and who are refractory to other treatments (e.g. corticosteroids, immunoglobulins) (see sections 4.2 and 5.1). Revolade is indicated in adult patients with chronic hepatitis C virus (HCV) infection for the treatment of thrombocytopenia, where the degree of thrombocytopenia is the main factor preventing the initiation or limiting the ability to maintain optimal interferon-based therapy (see sections 4.4 and 5.1). Revolade is indicated in adult patients with acquired severe aplastic anaemia (SAA) who were either refractory to prior immunosuppressive therapy or heavily pretreated and are unsuitable for haematopoietic stem cell transplantation (see section 5.1).

HOS-095481 · has-indication-information · PDF-Seite 43

Revolade is indicated for the treatment of adult patients with primary immune thrombocytopenia (ITP) who are refractory to other treatments (e.g. corticosteroids, immunoglobulins) (see sections 4.2 and 5.1). Revolade is indicated for the treatment of paediatric patients aged 1 year and above with primary immune thrombocytopenia (ITP) lasting 6 months or longer from diagnosis and who are refractory to other treatments (e.g. corticosteroids, immunoglobulins) (see sections 4.2 and 5.1). Revolade is indicated in adult patients with chronic hepatitis C virus (HCV) infection for the treatment of thrombocytopenia, where the degree of thrombocytopenia is the main factor preventing the initiation or limiting the ability to maintain optimal interferon-based therapy (see sections 4.4 and 5.1). Revolade is indicated in adult patients with acquired severe aplastic anaemia (SAA) who were either refractory to prior immunosuppressive therapy or heavily pretreated and are unsuitable for haematopoietic stem cell transplantation (see section 5.1).

HOS-095478 · has-interaction-information · PDF-Seite 12

Effects of eltrombopag on other medicinal products HMG CoA reductase inhibitors Administration of eltrombopag 75 mg once daily for 5 days with a single 10 mg dose of the OATP1B1 and BCRP substrate rosuvastatin to 39 healthy adult subjects increased plasma rosuvastatin Cmax 103% (90% confidence interval [CI]: 82%, 126%) and AUC0- 55% (90% CI: 42%, 69%). Interactions are also expected with other HMG-CoA reductase inhibitors, including atorvastatin, fluvastatin, lovastatin, pravastatin and simvastatin. When co-administered with eltrombopag, a reduced dose of statins should be considered and careful monitoring for statin adverse reactions should be undertaken (see section 5.2). OATP1B1 and BCRP substrates Concomitant administration of eltrombopag and OATP1B1 (e.g. methotrexate) and BCRP (e.g. topotecan and methotrexate) substrates should be undertaken with caution (see section 5.2). Cytochrome P450 substrates In studies utilising human liver microsomes, eltrombopag (up to 100 M) showed no in vitro inhibition of the CYP450 enzymes 1A2, 2A6, 2C19, 2D6, 2E1, 3A4/5, and 4A9/11 and was an inhibitor of CYP2C8 and CYP2C9 as measured using paclitaxel and diclofenac as the probe substrates. Administration of eltrombopag 75 mg once daily for 7 days to 24 healthy male subjects did not inhibit or induce the metabolism of probe substrates for 1A2 (caffeine), 2C19 (omeprazole), 2C9 (flurbiprofen), or 3A4 (midazolam) in humans. No clinically significant interactions are expected when eltrombopag and CYP450 substrates are co-administered (see section 5.2). HCV protease inhibitors Dose adjustment is not required when eltrombopag is co-administered with either telaprevir or boceprevir. Co-administration of a single dose of eltrombopag 200 mg with telaprevir 750 mg every 8 hours did not alter plasma telaprevir exposure. Co-administration of a single dose of eltrombopag 200 mg with boceprevir 800 mg every 8 hours did not alter plasma boceprevir AUC(0-), but increased Cmax by 20%, and decreased Cmin by 32%. The clinical relevance of the decrease in Cmin has not been established, increased clinical and laboratory monitoring for HCV suppression is recommended. 12 Effects of other medicinal products on eltrombopag Ciclosporin A decrease in eltrombopag exposure was observed with co-administration of 200 mg and 600 mg ciclosporin (a BCRP inhibitor). The co-administration of 200 mg ciclosporin decreased the Cmax and th

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HOS-095484 · has-interaction-information · PDF-Seite 52

Effects of eltrombopag on other medicinal products HMG CoA reductase inhibitors Administration of eltrombopag 75 mg once daily for 5 days with a single 10 mg dose of the OATP1B1 and BCRP substrate rosuvastatin to 39 healthy adult subjects increased plasma rosuvastatin Cmax 103% (90% confidence interval [CI]: 82%, 126%) and AUC0- 55% (90% CI: 42%, 69%). Interactions are also expected with other HMG-CoA reductase inhibitors, including atorvastatin, fluvastatin, lovastatin, pravastatin and simvastatin. When co-administered with eltrombopag, a reduced dose of statins should be considered and careful monitoring for statin adverse reactions should be undertaken (see section 5.2). 52 OATP1B1 and BCRP substrates Concomitant administration of eltrombopag and OATP1B1 (e.g. methotrexate) and BCRP (e.g. topotecan and methotrexate) substrates should be undertaken with caution (see section 5.2). Cytochrome P450 substrates In studies utilising human liver microsomes, eltrombopag (up to 100 M) showed no in vitro inhibition of the CYP450 enzymes 1A2, 2A6, 2C19, 2D6, 2E1, 3A4/5, and 4A9/11 and was an inhibitor of CYP2C8 and CYP2C9 as measured using paclitaxel and diclofenac as the probe substrates. Administration of eltrombopag 75 mg once daily for 7 days to 24 healthy male subjects did not inhibit or induce the metabolism of probe substrates for 1A2 (caffeine), 2C19 (omeprazole), 2C9 (flurbiprofen), or 3A4 (midazolam) in humans. No clinically significant interactions are expected when eltrombopag and CYP450 substrates are co-administered (see section 5.2). HCV protease inhibitors Dose adjustment is not required when eltrombopag is co-administered with either telaprevir or boceprevir. Co-administration of a single dose of eltrombopag 200 mg with telaprevir 750 mg every 8 hours did not alter plasma telaprevir exposure. Co-administration of a single dose of eltrombopag 200 mg with boceprevir 800 mg every 8 hours did not alter plasma boceprevir AUC(0-), but increased Cmax by 20%, and decreased Cmin by 32%. The clinical relevance of the decrease in Cmin has not been established, increased clinical and laboratory monitoring for HCV suppression is recommended. Effects of other medicinal products on eltrombopag Ciclosporin A decrease in eltrombopag exposure was observed with co-administration of 200 mg and 600 mg ciclosporin (a BCRP inhibitor). The co-administration of 200 mg ciclosporin decreased the Cmax and the

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HOS-095479 · has-pregnancy-information · PDF-Seite 14

Pregnancy There are no or limited amount of data from the use of eltrombopag in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Revolade is not recommended during pregnancy. Women of childbearing potential / Contraception in males and females Revolade is not recommended in women of childbearing potential not using contraception. Breast-feeding It is not known whether eltrombopag/metabolites are excreted in human milk. Studies in animals have shown that eltrombopag is likely secreted into milk (see section 5.3); therefore a risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to continue/abstain from Revolade therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility Fertility was not affected in male or female rats at exposures that were comparable to those in humans. However, a risk for humans cannot be ruled out (see section 5.3).

HOS-095485 · has-pregnancy-information · PDF-Seite 55

Pregnancy There are no or limited amount of data from the use of eltrombopag in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Revolade is not recommended during pregnancy. Women of childbearing potential / Contraception in males and females Revolade is not recommended in women of childbearing potential not using contraception. Breast-feeding It is not known whether eltrombopag/metabolites are excreted in human milk. Studies in animals have shown that eltrombopag is likely secreted into milk (see section 5.3); therefore a risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to continue/abstain from Revolade therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility Fertility was not affected in male or female rats at exposures that were comparable to those in humans. However, a risk for humans cannot be ruled out (see section 5.3).

HOS-095483 · has-warning-information · PDF-Seite 48

There is an increased risk for adverse reactions, including potentially fatal hepatic decompensation and thromboembolic events, in thrombocytopenic HCV patients with advanced chronic liver disease, as defined by low albumin levels ≤35 g/l or model for end stage liver disease (MELD) score ≥10, when treated with eltrombopag in combination with interferon-based therapy. In addition, the benefits of treatment in terms of the proportion achieving sustained virological response (SVR) compared with placebo were modest in these patients (especially for those with baseline albumin ≤35 g/l) compared with the group overall. Treatment with eltrombopag in these patients should be initiated only by physicians experienced in the management of advanced HCV, and only when the risks of thrombocytopenia or withholding antiviral therapy necessitate intervention. If treatment is considered clinically indicated, close monitoring of these patients is required. 48 Combination with direct-acting antiviral agents Safety and efficacy have not been established in combination with direct-acting antiviral agents approved for treatment of chronic hepatitis C infection. Risk of hepatotoxicity Eltrombopag administration can cause abnormal liver function and severe hepatotoxicity, which might be life-threatening (see section 4.8). Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin should be measured prior to initiation of eltrombopag, every 2 weeks during the dose adjustment phase and monthly following establishment of a stable dose. Eltrombopag inhibits UGT1A1 and OATP1B1, which may lead to indirect hyperbilirubinaemia. If bilirubin is elevated fractionation should be performed. Abnormal serum liver tests should be evaluated with repeat testing within 3 to 5 days. If the abnormalities are confirmed, serum liver tests should be monitored until the abnormalities resolve, stabilise, or return to baseline levels. Eltrombopag should be discontinued if ALT levels increase (3 times the upper limit of normal [x ULN] in patients with normal liver function, or ≥3 x baseline or >5 x ULN, whichever is the lower, in patients with pre-treatment elevations in transaminases) and are: • progressive, or • persistent for ≥4 weeks, or • accompanied by increased direct bilirubin, or • accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation. Caution is required whe

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HOS-095477 · has-warning-information · PDF-Seite 8

There is an increased risk for adverse reactions, including potentially fatal hepatic decompensation and thromboembolic events, in thrombocytopenic HCV patients with advanced chronic liver disease, as defined by low albumin levels ≤35 g/l or model for end stage liver disease (MELD) score ≥10, when treated with eltrombopag in combination with interferon-based therapy. In addition, the benefits of treatment in terms of the proportion achieving sustained virological response (SVR) compared with placebo were modest in these patients (especially for those with baseline albumin ≤35 g/l) compared with the group overall. Treatment with eltrombopag in these patients should be initiated only by physicians experienced in the management of advanced HCV, and only when the risks of thrombocytopenia or withholding antiviral therapy necessitate intervention. If treatment is considered clinically indicated, close monitoring of these patients is required. Combination with direct-acting antiviral agents Safety and efficacy have not been established in combination with direct-acting antiviral agents approved for treatment of chronic hepatitis C infection. Risk of hepatotoxicity Eltrombopag administration can cause abnormal liver function and severe hepatotoxicity, which might be life-threatening (see section 4.8). Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin should be measured prior to initiation of eltrombopag, every 2 weeks during the dose adjustment phase and monthly following establishment of a stable dose. Eltrombopag inhibits UGT1A1 and OATP1B1, which may lead to indirect hyperbilirubinaemia. If bilirubin is elevated fractionation should be performed. Abnormal serum liver tests should be evaluated with repeat testing within 3 to 5 days. If the abnormalities are confirmed, serum liver tests should be monitored until the abnormalities resolve, stabilise, or return to baseline levels. Eltrombopag should be discontinued if ALT levels increase (3 times the upper limit of normal [x ULN] in patients with normal liver function, or ≥3 x baseline or >5 x ULN, whichever is the lower, in patients with pre-treatment elevations in transaminases) and are: • progressive, or • persistent for ≥4 weeks, or • accompanied by increased direct bilirubin, or • accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation. Caution is required when administering eltrombopag to patients with hepatic disea

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