Rozlytrek · 4.6 Fertility, pregnancy and lactation · 2

HOS-098925 · has-adverse-reaction-information · PDF-Seite 12

Summary of the safety profile The most common adverse reactions (≥20%) were fatigue, constipation, diarrhoea, dizziness, dysgeusia, oedema, increased weight, anaemia, increased blood creatinine, nausea, dysaesthesia, pain, vomiting, pyrexia, arthralgia, increased aspartate aminotransferase and dyspnoea, cognitive disorders, cough, and increased alanine aminotransferase. The most frequent serious adverse reactions (≥2%) were lung infection (5.3%), fractures (4.1%), dyspnoea (3.6%), cognitive impairment (2.9%), pleural 12 effusion (2.5%) and pyrexia (2.5%). Permanent discontinuation due to an adverse reaction occurred in 6.0% of patients. Tabulated list of adverse reactions Table 4 summarises the adverse drug reactions (ADRs) occurring in 762 adult and 91 paediatric patients treated with Rozlytrek in three clinical trials in adults (ALKA, STARTRK-1, and STARTRK-2) and one clinical trial in paediatric patients (STARTRK-NG) and one clinical trial in adult and paediatric patients (TAPISTRY). The median duration of exposure was 8.6 months. Table 5 includes paediatric patients from three clinical studies; STARTRK-NG, STARTRK-2 and TAPISTRY. The median duration of exposure was 11.1 months. Paediatric data in the description of selected adverse reactions reflect exposure to Rozlytrek in this expanded paediatric safety population (n=91). The safety profile observed in the expanded paediatric population was consistent with the known paediatric safety profile from the integrated safety population in Table 4 below. Adverse drug reactions are listed by MedDRA system organ class. The following categories of frequency have been used: very common ≥1/10, common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000). Within each system organ class, the adverse reactions are presented in order of decreasing frequency. Table 4: Adverse drug reactions occurring in adult and paediatric patients treated with Rozlytrek in clinical trials (n=853) System organ All grades Frequency Grade ≥3 class Adverse reaction (%) category (%) (all grades) Infections and Urinary tract infection 15.7 Very common 2.7 infestations Lung infection1

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HOS-098931 · has-adverse-reaction-information · PDF-Seite 43

Summary of the safety profile The most common adverse reactions (≥20%) were fatigue, constipation, diarrhoea, dizziness, dysgeusia, oedema, increased weight, anaemia, increased blood creatinine, nausea, dysaesthesia, pain, vomiting, pyrexia, arthralgia, increased aspartate aminotransferase and dyspnoea, cognitive disorders, cough, and increased alanine aminotransferase. The most frequent serious adverse reactions (≥2%) were lung infection (5.3%), fractures (4.1%), dyspnoea (3.6%), cognitive impairment (2.9%), pleural effusion (2.5%) and pyrexia (2.5%). Permanent discontinuation due to an adverse reaction occurred in 6.0% of patients. Tabulated list of adverse reactions Table 4 summarises the adverse drug reactions (ADRs) occurring in 762 adult and 91 paediatric patients treated with Rozlytrek in three clinical trials in adults (ALKA, STARTRK-1, and STARTRK-2) and one clinical trial in paediatric patients (STARTRK-NG) and one clinical trial in adult and paediatric patients (TAPISTRY). The median duration of exposure was 8.6 months. Table 5 includes paediatric patients from three clinical studies; STARTRK-NG, STARTRK-2 and TAPISTRY. The median duration of exposure was 11.1 months. Paediatric data in the description of selected adverse reactions reflect exposure to Rozlytrek in this expanded paediatric safety population (n=91). The safety profile observed in the expanded paediatric population was consistent with the known paediatric safety profile from the integrated safety population in Table 4 below. Adverse drug reactions are listed by MedDRA system organ class. The following categories of frequency have been used: very common ≥1/10, common (≥1/100 to <1/10), uncommon (≥1/1 000 to 43 <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000). Within each system organ class, the adverse reactions are presented in order of decreasing frequency. Table 4: Adverse drug reactions occurring in adult and paediatric patients treated with Rozlytrek in clinical trials (n=853) Frequency System organ All grades Grade ≥3 Adverse reaction category class (%) (%) (all grades)

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HOS-098927 · has-contraindication-information · PDF-Seite 38

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 38

HOS-098921 · has-contraindication-information · PDF-Seite 8

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

HOS-098926 · has-indication-information · PDF-Seite 33

Neurotrophic tyrosine receptor kinase (NTRK) gene fusion Rozlytrek as monotherapy is indicated for the treatment of adult and paediatric patients older than 1 month with solid tumours that have a NTRK gene fusion, • who have a disease that is locally advanced, metastatic or where surgical resection is likely to result in severe morbidity, and • who have not received a prior NTRK inhibitor • who have no satisfactory treatment options (see sections 4.4 and 5.1). ROS1 gene fusion Rozlytrek as monotherapy is indicated for the treatment of adult patients with ROS1-positive, advanced non-small cell lung cancer (NSCLC) not previously treated with ROS1 inhibitors.

HOS-098920 · has-indication-information · PDF-Seite 3

Neurotrophic tyrosine receptor kinase (NTRK) gene fusion Rozlytrek as monotherapy is indicated for the treatment of adult and paediatric patients older than 1 month with solid tumours that have a NTRK gene fusion, • who have a disease that is locally advanced, metastatic or where surgical resection is likely to result in severe morbidity, and • who have not received a prior NTRK inhibitor • who have no satisfactory treatment options (see sections 4.4 and 5.1). ROS1 gene fusion Rozlytrek as monotherapy is indicated for the treatment of adult patients with ROS1-positive, advanced non-small cell lung cancer (NSCLC) not previously treated with ROS1 inhibitors.

HOS-098929 · has-interaction-information · PDF-Seite 41

Effects of entrectinib on other medicinal products Effect of entrectinib on CYP substrates Entrectinib is a weak inhibitor of CYP3A4. Co-administration of entrectinib 600 mg once daily with oral midazolam (a sensitive CYP3A substrate) in patients increased the midazolam AUC by 50% but reduced midazolam Cmax by 21%. Caution is advised when entrectinib is administered together with sensitive CYP3A4 substrates with a narrow therapeutic range (e.g., cisapride, cyclosporin, ergotamine, fentanyl, pimozide, quinidine, tacrolimus, alfentanil and sirolimus), due to the increased risk of adverse drug reactions. Effect of entrectinib on P-gp substrates In vitro data suggest that entrectinib has inhibitory potential towards P-glycoprotein (P-gp). Co-administration of a single 600 mg dose of entrectinib with digoxin (a sensitive P-gp substrate) increased digoxin Cmax by 28% and AUC by 18%. The renal clearance of digoxin was similar between treatments of digoxin alone and digoxin co-administered with entrectinib, indicating minimal effect of entrectinib on renal clearance of digoxin. The effect of entrectinib on digoxin absorption is not considered clinically relevant, but it is unknown whether the effect of entrectinib may be larger on more sensitive oral P-gp substrates such as dabigatran etexilate. Effect of entrectinib on BCRP substrates Inhibition of BCRP was observed in in vitro studies. The clinical relevance of this inhibition is unknown, but caution is advised when sensitive oral BCRP substrates (e.g. methotrexate, mitoxantrone, topotecan, lapatinib) are co-administered with entrectinib, due to the risk of increased absorption. Effect of entrectinib on other transporter substrates In vitro data indicate that entrectinib has weak inhibitory potential towards organic anion-transporting polypeptide (OATP)1B1. The clinical relevance of this inhibition is unknown, but caution is advised when sensitive oral OATP1B1 substrates (e.g. atorvastatin, pravastatin, rosuvastatin repaglinide, bosentan) are co-administered with entrectinib, due to the risk of increased absorption. Effect of entrectinib on substrates of PXR regulated enzymes In vitro studies indicate that entrectinib may induce pregnane X receptor (PXR) regulated enzymes (e.g. CYP2C family and UGT). Co-administration of entrectinib with CYP2C8, CYP2C9 or CYP2C19 substrates (e.g. repaglinide, warfarin, tolbutamide or omeprazole) may decrease their exposure. Oral contraceptives It is currently unknown whe

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HOS-098923 · has-interaction-information · PDF-Seite 10

Effects of entrectinib on other medicinal products Effect of entrectinib on CYP substrates Entrectinib is a weak inhibitor of CYP3A4. Co-administration of entrectinib 600 mg once daily with oral midazolam (a sensitive CYP3A substrate) in patients increased the midazolam AUC by 50% but reduced midazolam Cmax by 21%. Caution is advised when entrectinib is administered together with sensitive CYP3A4 substrates with a narrow therapeutic range (e.g., cisapride, cyclosporin, ergotamine, fentanyl, pimozide, quinidine, tacrolimus, alfentanil and sirolimus), due to the increased risk of adverse drug reactions. Effect of entrectinib on P-gp substrates In vitro data suggest that entrectinib has inhibitory potential towards P-glycoprotein (P-gp). Co-administration of a single 600 mg dose of entrectinib with digoxin (a sensitive P-gp substrate) increased digoxin Cmax by 28% and AUC by 18%. The renal clearance of digoxin was similar between treatments of digoxin alone and digoxin co-administered with entrectinib, indicating minimal effect of entrectinib on renal clearance of digoxin. The effect of entrectinib on digoxin absorption is not considered clinically relevant, but it is unknown whether the effect of entrectinib may be larger on more sensitive oral P-gp substrates such as dabigatran etexilate. Effect of entrectinib on BCRP substrates Inhibition of BCRP was observed in in vitro studies. The clinical relevance of this inhibition is unknown, but caution is advised when sensitive oral BCRP substrates (e.g. methotrexate, mitoxantrone, topotecan, lapatinib) are co-administered with entrectinib, due to the risk of increased absorption. 10 Effect of entrectinib on other transporter substrates In vitro data indicate that entrectinib has weak inhibitory potential towards organic anion-transporting polypeptide (OATP)1B1. The clinical relevance of this inhibition is unknown, but caution is advised when sensitive oral OATP1B1 substrates (e.g. atorvastatin, pravastatin, rosuvastatin repaglinide, bosentan) are co-administered with entrectinib, due to the risk of increased absorption. Effect of entrectinib on substrates of PXR regulated enzymes In vitro studies indicate that entrectinib may induce pregnane X receptor (PXR) regulated enzymes (e.g. CYP2C family and UGT). Co-administration of entrectinib with CYP2C8, CYP2C9 or CYP2C19 substrates (e.g. repaglinide, warfarin, tolbutamide or omeprazole) may decrease their

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HOS-098930 · has-pregnancy-information · PDF-Seite 42

Women of childbearing potential / Contraception in males and females Female patients of childbearing potential should have medically supervised pregnancy testing prior to initiating Rozlytrek therapy. Female patients of childbearing potential must use highly effective contraceptive methods during treatment and for at least 5 weeks following the last dose of Rozlytrek. It is currently unknown whether entrectinib may reduce the effectiveness of systemically acting hormonal contraceptives (see section 4.5). Therefore, women using systemically acting hormonal contraceptives should be advised to add a barrier method. Male patients with female partners of childbearing potential must use highly effective contraceptive methods during treatment and for at least 3 months following the last dose of Rozlytrek (see section 5.3). 42 Pregnancy There are no available data from the use of entrectinib in pregnant women. Based on animal studies and its mechanism of action, entrectinib may cause foetal harm when administered to a pregnant woman (see sections 4.4 and 5.3). Rozlytrek is not recommended during pregnancy and in women of childbearing potential not using contraception. Female patients receiving Rozlytrek should be advised of the potential harm to the foetus. Female patients should be advised to contact the doctor, should pregnancy occur. Breast-feeding It is unknown whether entrectinib or its metabolites are excreted in human milk. A risk to breast-fed children cannot be excluded. Breast-feeding should be discontinued during treatment with Rozlytrek. Fertility No fertility studies in animals have been performed to evaluate the effect of entrectinib (see section 5.3).

HOS-098924 · has-pregnancy-information · PDF-Seite 12

Women of childbearing potential / Contraception in males and females Female patients of childbearing potential should have medically supervised pregnancy testing prior to initiating Rozlytrek therapy. Female patients of childbearing potential must use highly effective contraceptive methods during treatment and for at least 5 weeks following the last dose of Rozlytrek. It is currently unknown whether entrectinib may reduce the effectiveness of systemically acting hormonal contraceptives (see section 4.5). Therefore, women using systemically acting hormonal contraceptives should be advised to add a barrier method. Male patients with female partners of childbearing potential must use highly effective contraceptive methods during treatment and for at least 3 months following the last dose of Rozlytrek (see section 5.3). Pregnancy There are no available data from the use of entrectinib in pregnant women. Based on animal studies and its mechanism of action, entrectinib may cause foetal harm when administered to a pregnant woman (see sections 4.4 and 5.3). Rozlytrek is not recommended during pregnancy and in women of childbearing potential not using contraception. Female patients receiving Rozlytrek should be advised of the potential harm to the foetus. Female patients should be advised to contact the doctor, should pregnancy occur. Breast-feeding It is unknown whether entrectinib or its metabolites are excreted in human milk. A risk to breast-fed children cannot be excluded. Breast-feeding should be discontinued during treatment with Rozlytrek. Fertility No fertility studies in animals have been performed to evaluate the effect of entrectinib (see section 5.3).

HOS-098928 · has-warning-information · PDF-Seite 39

Efficacy across tumour types The benefit of Rozlytrek has been established in single-arm trials encompassing a relatively small sample of patients whose tumours exhibit NTRK gene fusions. Favourable effects of Rozlytrek have been shown based on overall response rate and response duration in a limited number of tumour types. The effect may be quantitatively different depending on tumour type, as well as on concomitant genomic alterations (see section 5.1). For these reasons, Rozlytrek should only be used if there are no satisfactory treatment options (i.e., for which clinical benefit has not been established, or where such treatment options have been exhausted). Cognitive disorders Cognitive disorders, including confusion, mental status changes, memory impairment, and hallucinations, were reported in clinical trials with Rozlytrek (see section 4.8). Patients over the age of 65 years experienced a higher incidence of these events than younger patients. Patients should be monitored for signs of cognitive changes. Based on the severity of cognitive disorders, Rozlytrek treatment should be modified as described in Table 3 in section 4.2. Patients should be counselled on the potential for cognitive changes with Rozlytrek treatment. Patients should be instructed not to drive or use machines until symptoms resolve if they experience cognitive disorders (see section 4.7). Fractures Fractures have been reported in 29.7% (27/91) of paediatric patients treated with Rozlytrek in clinical trials (see section 4.8). Bone fractures mostly occurred in paediatric patients less than 12 years of age and were localised in the lower extremity (with a predilection for femur, tibia, foot, and fibula). In both adult and paediatric patients, some fractures occurred in the setting of a fall or other trauma to the affected area. Fourteen paediatric patients had more than one occurrence of a fracture. Fractures resolved in the majority of paediatric patients (see section 4.8). Five paediatric patients had Rozlytrek treatment interrupted due to a fracture. Six paediatric patients discontinued treatment due to fractures. Patients with signs or symptoms of fractures (e.g., pain, abnormal gait, changes in mobility, deformity) should be evaluated promptly. Hyperuricemia Hyperuricemia has been observed in patients treated with entrectinib. Serum uric acid levels should be assessed prior to initiating Rozlytrek and periodically during treatment. Patients should be monitored for sig

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HOS-098922 · has-warning-information · PDF-Seite 8

Efficacy across tumour types The benefit of Rozlytrek has been established in single-arm trials encompassing a relatively small sample of patients whose tumours exhibit NTRK gene fusions. Favourable effects of Rozlytrek have been shown based on overall response rate and response duration in a limited number of tumour types. The effect may be quantitatively different depending on tumour type, as well as on concomitant genomic alterations (see section 5.1). For these reasons, Rozlytrek should only be used if there are no satisfactory treatment options (i.e., for which clinical benefit has not been established, or where such treatment options have been exhausted). Cognitive disorders Cognitive disorders, including confusion, mental status changes, memory impairment, and hallucinations, were reported in clinical trials with Rozlytrek (see section 4.8). Patients over the age of 65 years experienced a higher incidence of these events than younger patients. Patients should be monitored for signs of cognitive changes. Based on the severity of cognitive disorders, Rozlytrek treatment should be modified as described in Table 3 in section 4.2. Patients should be counselled on the potential for cognitive changes with Rozlytrek treatment. Patients should be instructed not to drive or use machines until symptoms resolve if they experience cognitive disorders (see section 4.7). Fractures Fractures have been reported in 29.7% (27/91) of paediatric patients treated with Rozlytrek in clinical trials (see section 4.8). Bone fractures mostly occurred in paediatric patients less than 12 years of age and were localised in the lower extremity (with a predilection for femur, tibia, foot, and fibula). In both adult and paediatric patients, some fractures occurred in the setting of a fall or other trauma to the affected area. Fourteen paediatric patients had more than one occurrence of a fracture. Fractures resolved in the majority of paediatric patients (see section 4.8). Five paediatric patients had Rozlytrek treatment interrupted due to a fracture. Six paediatric patients discontinued treatment due to fractures. 8 Patients with signs or symptoms of fractures (e.g., pain, abnormal gait, changes in mobility, deformity) should be evaluated promptly. Hyperuricemia Hyperuricemia has been observed in patients treated with entrectinib. Serum uric acid levels should be assessed prior to initiating Rozlytrek and periodicall

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