Retsevmo · 4.5 Interaction with other medicinal products and other forms of interaction · 2

HOS-099585 · has-adverse-reaction-information · PDF-Seite 45

Summary of the safety profile The integrated frequency of adverse drug reactions (ADRs) reported in patients treated with selpercatinib from an open-label, multicentre, dose-escalation phase 1/2 study (LIBRETTO-001) and from two open-label, multicentre, randomised phase 3 comparative studies (LIBRETTO-431 and LIBRETTO-531) are summarised. The most common (≥ 1.0%) serious ADRs are pneumonia (5.3%), haemorrhage (2.4%), abdominal pain (2.1%), blood sodium decreased (2.0%), diarrhoea (1.5%), hypersensitivity (1.4%), vomiting (1.3%), blood creatinine increased (1.3%), pyrexia (1.3%), urinary tract infections (1.3%), ALT increased (1.0%) and AST increased (1.0%). Permanent discontinuation of Retsevmo for treatment emergent adverse events, regardless of attribution occurred in 8.8% of patients. The most common ADRs resulting in permanent discontinuation (3 or more patients) were increased ALT (0.7%), fatigue (0.5%), increased AST (0.4%), blood bilirubin increased (0.3%), pneumonia (0.3%), thrombocytopenia (0.3%), haemorrhage (0.3%), and hypersensitivity (0.3%). Tabulated list of adverse drug reactions The integrated frequency and severity of ADRs reported in patients treated with selpercatinib in Study LIBRETTO-001, Study LIBRETTO-431, and Study LIBRETTO-531 are shown in Table 5. The ADRs are classified according to the MedDRA system organ class and frequency. Frequency groups are defined by the following convention: 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), and not known (cannot be estimated from available data). Median time on treatment with selpercatinib was 30.09 months (Study LIBRETTO-001), 16.7 months (Study LIBRETTO-431), and 14.9 months (Study LIBRETTO-531). Table 5 Adverse drug reactions in patients receiving selpercatinib (N=1188) MedDRA system MedDRA preferred term Frequency of all Frequency of Grade organ class Grades ≥3 Infections and infestations Urinary tract infectionsa Very common Common Pneumonia b Very common Common Immune system disorders c Hypersensitivity d Common Common Endocrine disorders

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HOS-099579 · has-adverse-reaction-information · PDF-Seite 11

Summary of the safety profile The integrated frequency of adverse drug reactions (ADRs) reported in patients treated with selpercatinib from an open-label, multicentre, dose-escalation phase 1/2 study (LIBRETTO-001) and from two open-label, multicentre, randomised phase 3 comparative studies (LIBRETTO-431 and LIBRETTO-531) are summarised. The most common (≥ 1.0%) serious ADRs are pneumonia (5.3%), haemorrhage (2.4%), abdominal pain (2.1%), blood sodium decreased (2.0%), diarrhoea (1.5%), hypersensitivity (1.4%), vomiting (1.3%), blood creatinine increased (1.3%), pyrexia (1.3%), urinary tract infections (1.3%), ALT increased (1.0%) and AST increased (1.0%). Permanent discontinuation of Retsevmo for treatment emergent adverse events, regardless of attribution occurred in 8.8% of patients. The most common ADRs resulting in permanent discontinuation (3 or more patients) were increased ALT (0.7%), fatigue (0.5%), increased AST (0.4%), blood bilirubin increased (0.3%), pneumonia (0.3%), thrombocytopenia (0.3%), haemorrhage (0.3%), and hypersensitivity (0.3%). Tabulated list of adverse drug reactions The integrated frequency and severity of ADRs reported in patients treated with selpercatinib in Study LIBRETTO-001, Study LIBRETTO-431, and Study LIBRETTO-531 are shown in Table 5. The ADRs are classified according to the MedDRA system organ class and frequency. Frequency groups are defined by the following convention: 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), and not known (cannot be estimated from available data). Median time on treatment with selpercatinib was 30.09 months (Study LIBRETTO-001), 16.7 months (Study LIBRETTO-431), and 14.9 months (Study LIBRETTO-531). 11 Table 5 Adverse drug reactions in patients receiving selpercatinib (N=1188) MedDRA system MedDRA preferred term Frequency of all Frequency of Grade organ class Grades ≥3 Infections and infestations Urinary tract infectionsa Very common Common Pneumonia b Very common Common Immune system disorders c Hypersensitivity d

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HOS-099581 · has-contraindication-information · PDF-Seite 40

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

HOS-099575 · has-contraindication-information · PDF-Seite 7

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

HOS-099574 · has-indication-information · PDF-Seite 2

Retsevmo as monotherapy is indicated for the treatment of adults with: – advanced RET fusion-positive non-small cell lung cancer (NSCLC) not previously treated with a RET inhibitor. For biomarker-based patient selection, see section 4.2. Retsevmo as monotherapy is indicated for the treatment of adults and paediatric patients 2 years of age and older with: – advanced RET fusion-positive thyroid cancer who are radioactive iodine-refractory (if radioactive iodine is appropriate). For biomarker-based patient selection, see section 4.2. – advanced RET-mutant medullary thyroid cancer (MTC). For biomarker-based patient selection, see section 4.2. – advanced RET fusion-positive solid tumours, when treatment options not targeting RET provide limited clinical benefit, or have been exhausted (see sections 4.4 and 5.1). For biomarker-based patient selection, see section 4.2. 2

HOS-099580 · has-indication-information · PDF-Seite 36

Retsevmo as monotherapy is indicated for the treatment of adults with: – advanced RET fusion-positive non-small cell lung cancer (NSCLC) not previously treated with a RET inhibitor. For biomarker-based patient selection, see section 4.2. Retsevmo as monotherapy is indicated for the treatment of adults and paediatric patients 2 years of age and older with: – advanced RET fusion-positive thyroid cancer who are radioactive iodine-refractory (if radioactive iodine is appropriate). For biomarker-based patient selection, see section 4.2. – advanced RET-mutant medullary thyroid cancer (MTC). For biomarker-based patient selection, see section 4.2. – advanced RET fusion-positive solid tumours, when treatment options not targeting RET provide limited clinical benefit, or have been exhausted (see sections 4.4 and 5.1). For biomarker-based patient selection, see section 4.2.

HOS-099583 · has-interaction-information · PDF-Seite 43

Effects of other medicinal products on the pharmacokinetics of selpercatinib Selpercatinib metabolism is through CYP3A4. Therefore, medicinal products that can influence CYP3A4 enzyme activity may alter the pharmacokinetics of selpercatinib. Selpercatinib is a substrate for P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) in vitro, however these transporters do not appear to limit the oral absorption of selpercatinib, as its oral bioavailability is 73% and its exposure was increased minimally by co-administration of the P-gp inhibitor rifampicin (increase of approximately 6.5% and 19% in selpercatinib AUC0-24 and Cmax, respectively). Agents that may increase selpercatinib plasma concentrations Co-administration of a single 160 mg selpercatinib dose with itraconazole, a strong CYP3A inhibitor, increased the Cmax and AUC of selpercatinib by 30% and 130%, respectively, compared to selpercatinib given alone. If strong CYP3A and/or P-gp inhibitors, including, but not limited to, ketoconazole, itraconazole, voriconazole, ritonavir, saquinavir, telithromycin, posaconazole and nefazodone, have to be co-administered, the dose of selpercatinib should be reduced (see section 4.2). Agents that may decrease selpercatinib plasma concentrations Co-administration of rifampicin, a strong CYP3A4 inducer resulted in a decrease of approximately 87% and 70% in selpercatinib AUC and Cmax, respectively, compared to selpercatinib alone, therefore the concomitant use of strong CYP3A4 inducers including, but not limited to, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin and St. John’s Wort (Hypericum perforatum), should be avoided. Effects of selpercatinib on the pharmacokinetics of other medicinal products (increase in plasma concentration) Sensitive CYP2C8 substrates Selpercatinib increased the Cmax and AUC of repaglinide (a substrate of CYP2C8) by approximately 91% and 188% respectively. Therefore, co-administration with sensitive CYP2C8 substrates (e.g., amodiaquine, cerivastatin, enzalutamide, paclitaxel, repaglinide, torasemide, sorafenib, rosiglitazone, buprenorphine, selexipag, dasabuvir and montelukast), should be avoided. Sensitive CYP3A4 substrates Selpercatinib increased Cmax and AUC of midazolam (a CYP3A4 substrate) by approximately 39% and 54%, respectively. Therefore, concomitant use with sensitive CYP3A4 substrates, (e.g., alfentanil, avanafil, buspirone, conivaptan, darifenacin, darunavir, ebastine, lomitapide, lovastatin, mi

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HOS-099577 · has-interaction-information · PDF-Seite 9

Effects of other medicinal products on the pharmacokinetics of selpercatinib Selpercatinib metabolism is through CYP3A4. Therefore, medicinal products that can influence CYP3A4 enzyme activity may alter the pharmacokinetics of selpercatinib. Selpercatinib is a substrate for P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) in vitro, however these transporters do not appear to limit the oral absorption of selpercatinib, as its oral bioavailability is 73% and its exposure was increased minimally by co-administration of the P-gp inhibitor rifampicin (increase of approximately 6.5% and 19% in selpercatinib AUC0-24 and Cmax, respectively). Agents that may increase selpercatinib plasma concentrations Co-administration of a single 160 mg selpercatinib dose with itraconazole, a strong CYP3A inhibitor, increased the Cmax and AUC of selpercatinib by 30% and 130%, respectively, compared to selpercatinib given alone. If strong CYP3A and/or P-gp inhibitors, including, but not limited to, ketoconazole, itraconazole, voriconazole, ritonavir, saquinavir, telithromycin, posaconazole and nefazodone, have to be co-administered, the dose of selpercatinib should be reduced (see section 4.2). Agents that may decrease selpercatinib plasma concentrations Co-administration of rifampicin, a strong CYP3A4 inducer resulted in a decrease of approximately 87% and 70% in selpercatinib AUC and Cmax, respectively, compared to selpercatinib alone, therefore the concomitant use of strong CYP3A4 inducers including, but not limited to, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin and St. John’s Wort (Hypericum perforatum), should be avoided. Effects of selpercatinib on the pharmacokinetics of other medicinal products (increase in plasma concentration) Sensitive CYP2C8 substrates Selpercatinib increased the Cmax and AUC of repaglinide (a substrate of CYP2C8) by approximately 91% and 188% respectively. Therefore, co-administration with sensitive CYP2C8 substrates (e.g., 9 amodiaquine, cerivastatin, enzalutamide, paclitaxel, repaglinide, torasemide, sorafenib, rosiglitazone, buprenorphine, selexipag, dasabuvir and montelukast), should be avoided. Sensitive CYP3A4 substrates Selpercatinib increased Cmax and AUC of midazolam (a CYP3A4 substrate) by approximately 39% and 54%, respectively. Therefore, concomitant use with sensitive CYP3A4 substrates, (e.g., alfentanil, avanafil, buspirone, conivaptan, dari

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HOS-099578 · has-pregnancy-information · PDF-Seite 10

Women of childbearing potential/Contraception in females and males Women of childbearing potential have to use highly effective contraception during treatment and for at least one week after the last dose of selpercatinib. Men with female partners of childbearing potential should use effective contraception during treatment and for at least one week after the last dose of selpercatinib. Pregnancy 10 There are no available data from the use of selpercatinib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Retsevmo is not recommended during pregnancy and in women of childbearing potential not using contraception. It should only be used during pregnancy if the potential benefit justifies the potential risk to the foetus. Breast-feeding It is unknown whether selpercatinib is excreted in human milk. A risk to breast-fed newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Retsevmo and for at least one week after the last dose. Fertility No human data on the effect of selpercatinib on fertility are available. Based on findings from animal studies, male and female fertility may be compromised by treatment with Retsevmo (see section 5.3). Both men and women should seek advice on fertility preservation before treatment.

HOS-099584 · has-pregnancy-information · PDF-Seite 44

Women of childbearing potential/Contraception in females and males Women of childbearing potential have to use highly effective contraception during treatment and for at least one week after the last dose of selpercatinib. Men with female partners of childbearing potential should use effective contraception during treatment and for at least one week after the last dose of selpercatinib. Pregnancy There are no available data from the use of selpercatinib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Retsevmo is not recommended during pregnancy and in women of childbearing potential not using contraception. It should only be used during pregnancy if the potential benefit justifies the potential risk to the foetus. Breast-feeding It is unknown whether selpercatinib is excreted in human milk. A risk to breast-fed newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Retsevmo and for at least one week after the last dose. Fertility No human data on the effect of selpercatinib on fertility are available. Based on findings from animal studies, male and female fertility may be compromised by treatment with Retsevmo (see section 5.3). Both men and women should seek advice on fertility preservation before treatment. 44

HOS-099582 · has-warning-information · PDF-Seite 40

Efficacy across tumour types The benefit of selpercatinib has been established in single arm trials encompassing a relatively small sample of patients whose tumours exhibit RET gene fusions. Favourable effects of selpercatinib have been shown on the basis of objective 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, selpercatinib should only be used if there are no treatment options for which clinical benefit has been established, or where such treatment options have been exhausted (i.e., no satisfactory treatment options). Interstitial Lung Disease (ILD)/Pneumonitis Severe, life-threatening, or fatal cases of ILD/pneumonitis have been reported in patients treated with selpercatinib (see section 4.8). Patients should be monitored for pulmonary symptoms indicative of ILD/pneumonitis. Selpercatinib should be withheld, and patients should be promptly investigated for ILD if they present with acute or worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnoea, cough, and fever), and treated as medically appropriate. Based on the severity of 40 ILD/pneumonitis, the dose of selpercatinib should be interrupted, reduced, or permanently discontinued (see section 4.2). Increased alanine aminotransferase (ALT)/ aspartate aminotransferase (AST) Grade ≥3 increased ALT and Grade ≥3 increased AST were reported in patients receiving selpercatinib (see section 4.8). ALT and AST should be monitored prior to the start of selpercatinib therapy, every 2 weeks during the first 3 months of treatment, monthly for the next 3 months of treatment, and otherwise as clinically indicated. Based on the level of ALT or AST elevations, selpercatinib may require dose modification (see section 4.2). Hypertension Hypertension was reported in patients receiving selpercatinib (see section 4.8). Patient blood pressure should be controlled before starting selpercatinib treatment, monitored during selpercatinib treatment and treated as needed with standard anti-hypertensive therapy. Based on the level of increased blood pressure, selpercatinib may require dose modification (see section 4.2). Selpercatinib should be discontinued permanently if medically significant hypertension cannot be controlled with antihypertensive therapy. QT interval

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HOS-099576 · has-warning-information · PDF-Seite 7

Efficacy across tumour types The benefit of selpercatinib has been established in single arm trials encompassing a relatively small sample of patients whose tumours exhibit RET gene fusions. Favourable effects of selpercatinib have been shown on the basis of objective 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, selpercatinib should only be used if there are no treatment options for which clinical benefit has been established, or where such treatment options have been exhausted (i.e., no satisfactory treatment options). Interstitial Lung Disease (ILD)/Pneumonitis Severe, life-threatening, or fatal cases of ILD/pneumonitis have been reported in patients treated with selpercatinib (see section 4.8). Patients should be monitored for pulmonary symptoms indicative of ILD/pneumonitis. Selpercatinib should be withheld, and patients should be promptly investigated for ILD if they present with acute or worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnoea, cough, and fever), and treated as medically appropriate. Based on the severity of ILD/pneumonitis, the dose of selpercatinib should be interrupted, reduced, or permanently discontinued (see section 4.2). Increased alanine aminotransferase (ALT)/ aspartate aminotransferase (AST) Grade ≥3 increased ALT and Grade ≥3 increased AST were reported in patients receiving selpercatinib (see section 4.8). ALT and AST should be monitored prior to the start of selpercatinib therapy, every 2 weeks during the first 3 months of treatment, monthly for the next 3 months of treatment, and otherwise as clinically indicated. Based on the level of ALT or AST elevations, selpercatinib may require dose modification (see section 4.2). Hypertension Hypertension was reported in patients receiving selpercatinib (see section 4.8). Patient blood pressure should be controlled before starting selpercatinib treatment, monitored during selpercatinib treatment and treated as needed with standard anti-hypertensive therapy. Based on the level of increased blood pressure, selpercatinib may require dose modification (see section 4.2). Selpercatinib should be discontinued permanently if medically significant hypertension cannot be controlled with antihypertensive therapy. QT interval prolongation QT interval prolongation was reported in pa

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