Teysuno · 4.6 Fertility, pregnancy and lactation · 2

HOS-095728 · has-adverse-reaction-information · PDF-Seite 14

Summary of safety profile The overall safety profile of Teysuno in combination with cisplatin is based primarily on clinical study data from 593 patients with advanced gastric cancer treated with this regimen. In addition, there is post-marketing experience in over 866,000 Asian (mainly Japanese) patients. Among 593 patients treated with Teysuno in combination with cisplatin, the most common severe adverse reactions (Grade 3 or higher with frequency of at least 10%) were neutropaenia, anaemia, and fatigue. Tabulated list of adverse reactions 14 The following headings are used to rank the adverse reactions by frequency: 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 the available data). The frequencies of very common, common, and uncommon adverse reactions are from 593 patients treated with Teysuno in combination with cisplatin in clinical trials. The frequencies of medically relevant rare and very rare adverse reactions are estimated from post-marketing surveillance of 866,000 patients in Asia (mostly Japanese) treated with Teysuno-based therapy. Each term is presented in its most common category only and within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 9: Adverse reactions reported by decreasing seriousness in each frequency grouping System Organ Very Common Uncommon Rare / Very Classa common rare Infections and Neutropenic sepsis, septic shock, sepsis, Hepatitis B infestations infection, pneumonia, bacteremia, reactivation respiratory tract infection, upper respiratory tract infection, pyelonephritis acute, urinary tract infection, pharyngitis, nasopharyngitis, rhinitis, tooth infection, candidiasis, oral herpes,

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HOS-095734 · has-adverse-reaction-information · PDF-Seite 39

Summary of safety profile The overall safety profile of Teysuno in combination with cisplatin is based primarily on clinical study data from 593 patients with advanced gastric cancer treated with this regimen. In addition, there is post-marketing experience in over 866,000 Asian (mainly Japanese) patients. Among 593 patients treated with Teysuno in combination with cisplatin, the most common severe adverse reactions (Grade 3 or higher with frequency of at least 10%) were neutropaenia, anaemia, and fatigue. Tabulated list of adverse reactions The following headings are used to rank the adverse reactions by frequency: 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 the available data). The frequencies of very common, common, and uncommon adverse reactions are from 593 patients treated with Teysuno in 39 combination with cisplatin in clinical trials. The frequencies of medically relevant rare and very rare adverse reactions are estimated from post-marketing surveillance of 866,000 patients in Asia (mostly Japanese) treated with Teysuno-based therapy. Each term is presented in its most common category only and within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 9: Adverse reactions reported by decreasing seriousness in each frequency grouping System Organ Very Common Uncommon Rare / Very Classa common rare Infections and Neutropenic sepsis, septic shock, sepsis, Hepatitis B Infestations infection, pneumonia, bacteremia, reactivation respiratory tract infection, upper respiratory tract infection, pyelonephritis acute, urinary tract infection, pharyngitis, nasopharyngitis, rhinitis, tooth infection, candidiasis, oral herpes,

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HOS-095724 · has-contraindication-information · PDF-Seite 8

• Hypersensitivity to any of the active substances (tegafur, gimeracil, and oteracil) or to any of the excipients listed in 6.1. • History of severe and unexpected reactions to fluoropyrimidine therapy. • Known complete dihydropyrimidine dehydrogenase (DPD) deficiency (see section 4.4). • Pregnancy and breast-feeding. • Severe bone marrow suppression (severe leukopaenia, neutropaenia, or thrombocytopaenia; see section 4.2, Table 7). • End stage renal disease patients requiring dialysis. • Co-administration of other fluoropyrimidines with Teysuno. • Recent or concomitant treatment with brivudine (see section 4.4 and 4.5 for drug-drug interaction). • Contraindications for cisplatin; oxaliplatin, irinotecan and bevacizumab refer to the corresponding SmPCs. 8

HOS-095730 · has-contraindication-information · PDF-Seite 33

• Hypersensitivity to any of the active substances (tegafur, gimeracil, and oteracil) or to any of the excipients listed in section 6.1. • History of severe and unexpected reactions to fluoropyrimidine therapy. • Known complete dihydropyrimidine dehydrogenase (DPD) deficiency (see section 4.4). • Pregnancy and breast-feeding. • Severe bone marrow suppression (severe leukopaenia, neutropaenia, or thrombocytopaenia; see section 4.2, Table 7). • End stage renal disease patients requiring dialysis. • Co-administration of other fluoropyrimidines with Teysuno. • Recent or concomitant treatment with brivudine (see section 4.4 and 4.5 for drug-drug interaction). • Contraindications for cisplatin, oxaliplatin, irinotecan and bevacizumab; refer to the corresponding SmPCs.

HOS-095723 · has-indication-information · PDF-Seite 2

Teysuno is indicated in adults: - for the treatment of advanced gastric cancer when given in combination with cisplatin (see section 5.1). - as monotherapy or in combination with oxaliplatin or irinotecan, with or without bevacizumab, for the treatment of patients with metastatic colorectal cancer for whom it is not possible to continue treatment with another fluoropyrimidine due to hand-foot syndrome or cardiovascular toxicity that developed in the adjuvant or metastatic setting.

HOS-095729 · has-indication-information · PDF-Seite 27

Teysuno is indicated in adults: - for the treatment of advanced gastric cancer when given in combination with cisplatin (see section 5.1). - as monotherapy or in combination with oxaliplatin or irinotecan, with or without bevacizumab, for the treatment of patients with metastatic colorectal cancer for whom it is not possible to continue treatment with another fluoropyrimidine due to hand-foot syndrome or cardiovascular toxicity that developed in the adjuvant or metastatic setting.

HOS-095726 · has-interaction-information · PDF-Seite 12

No interaction studies have been performed in adult or paediatric patients. Brivudine A clinically significant interaction between brivudine and fluoropyrimidines (e.g. capecitabine, 5- Fluorouracil, tegafur), resulting from the inhibition of dihydropyrimidine dehydrogenase by brivudine, has been described. This interaction, which leads to increased fluoropyrimidine toxicity, is potentially fatal. Therefore, brivudine must not be administered concomitantly with Teysuno (see section 4.3 and 4.4). There must be at least a 4-week waiting period between end of treatment with brivudine and start of Teysuno therapy. Treatment with brivudine can be started 24 hours after the last dose of Teysuno. Other fluoropyrimidines Co-administration of other fluoropyrimidines such as capecitabine, 5-FU, tegafur, or flucytosine can lead to additive toxicities, and is contraindicated. A minimum washout period of 7 days is recommended between administration of Teysuno and other fluoropyrimidines. The washout period described in the SmPC of other fluoropyrimidine medicinal products should be followed if Teysuno is to be administered subsequent to other fluoropyrimidine medicinal products. CYP2A6 inhibitors 12 As CYP2A6 is the major enzyme responsible for the conversion of tegafur to 5-FU, co-administration of a known CYP2A6 inhibitor and Teysuno should be avoided as effectiveness of Teysuno could be decreased (see section 5.2). Folinate/folinic acid No data are available on the concomitant use of folinic acid with Teysuno in combination with cisplatin. However, metabolites of folinate/folinic acid will form a ternary structure with thymidylate synthase and fluorodeoxyuridine monophosphate (FdUMP), potentially increasing the cytotoxicity of 5-FU. Caution is advised as folinic acid is known to enhance the activity of 5-FU. Nitroimidazoles, including metronidazole and misonidazole No data are available on the concomitant use of nitromidazoles with Teysuno in combination with cisplatin. However, nitromidazoles may reduce clearance of 5-FU and thus increase plasma levels of 5-FU. Caution is advised as co-administration may increase the toxicity of Teysuno. Methotrexate No data are available on the concomitant use of methotrexate with Teysuno in combination with cisplatin. However, polyglutamated methotrexate inhibits thymidylate synthase and dihydrofolate reductase, potentially increasing cytotoxicity of 5-FU. Caution is a

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HOS-095732 · has-interaction-information · PDF-Seite 37

No interaction studies have been performed in adult or paediatric patients. Brivudine A clinically significant interaction between brivudine and fluoropyrimidines (e.g. capecitabine, 5- Fluorouracil, tegafur), resulting from the inhibition of dihydropyrimidine dehydrogenase by brivudine, has been described. This interaction, which leads to increased fluoropyrimidine toxicity, is potentially fatal. Therefore, brivudine must not be administered concomitantly with Teysuno (see section 4.3 and 4.4). There must be at least a 4-week waiting period between end of treatment with brivudine and start of Teysuno therapy. Treatment with brivudine can be started 24 hours after the last dose of Teysuno. Other fluoropyrimidines Co-administration of other fluoropyrimidines such as capecitabine, 5-FU, tegafur, or flucytosine can lead to additive toxicities, and is contraindicated. A minimum washout period of 7 days is recommended between administration of Teysuno and other fluoropyrimidines. The washout period described in the SmPC of other fluoropyrimidine medicinal products should be followed if Teysuno is to be administered subsequent to other fluoropyrimidine medicinal products. CYP2A6 inhibitors As CYP2A6 is the major enzyme responsible for the conversion of tegafur to 5-FU, co-administration of a known CYP2A6 inhibitor and Teysuno should be avoided as effectiveness of Teysuno could be decreased (see section 5.2). Folinate/folinic acid 37 No data are available on the concomitant use of folinic acid with Teysuno in combination with cisplatin. However, metabolites of folinate/folinic acid will form a ternary structure with thymidylate synthase and fluorodeoxyuridine monophosphate (FdUMP), potentially increasing the cytotoxicity of 5-FU. Caution is advised as folinic acid is known to enhance the activity of 5-FU. Nitroimidazoles, including metronidazole and misonidazole No data are available on the concomitant use of nitromidazoles with Teysuno in combination with cisplatin. However, nitromidazoles may reduce clearance of 5-FU and thus increase plasma levels of 5-FU. Caution is advised as co-administration may increase the toxicity of Teysuno. Methotrexate No data are available on the concomitant use of methotrexate with Teysuno in combination with cisplatin. However, polyglutamated methotrexate inhibits thymidylate synthase and dihydrofolate reductase, potentially increasing cytotoxicity of 5-FU. Caution is a

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HOS-095727 · has-pregnancy-information · PDF-Seite 14

Women of childbearing potential/Contraception in males and females Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with this medicinal product. Contraceptive measures must be taken by male patients during and up to 3 months after stopping treatment with Teysuno. Contraceptive measures must be taken by female patients during and up to 6 months after stopping treatment with Teysuno. Pregnancy Teysuno is contraindicated in pregnancy (see section 4.3). There have been some case reports of foetal abnormalities. Studies in animals have shown reproductive toxicity. As with other fluoropyrimidines, Teysuno administration caused embryolethality and teratogenicity in animals (see section 5.3). If the patient becomes pregnant while receiving Teysuno, treatment should be discontinued and the potential risk to the foetus must be explained. Genetic counseling should be considered. Breast-feeding Teysuno is contraindicated during breast-feeding (see section 4.3). It is not known whether Teysuno or its metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of Teysuno or its metabolites in milk (for details see section 5.3). A risk to newborns/infants cannot be excluded. Breast-feeding must be discontinued while receiving treatment with Teysuno. Fertility No data are available on the effect of Teysuno in combination with cisplatin on human fertility. Non- clinical studies demonstrated that Teysuno did not appear to affect male or female fertility in the rat (see section 5.3). Refer to the cisplatin SmPC for the effects of cisplatin on fertility, pregnancy and lactation.

HOS-095733 · has-pregnancy-information · PDF-Seite 38

Women of childbearing potential/Contraception in males and females 38 Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with this medicinal product. Contraceptive measures must be taken by male patients during and up to 3 months after stopping treatment with Teysuno. Contraceptive measures must be taken by female patients during and up to 6 months after stopping treatment with Teysuno. Pregnancy Teysuno is contraindicated in pregnancy (see section 4.3). There have been some case reports of foetal abnormalities. Studies in animals have shown reproductive toxicity. As with other fluoropyrimidines, Teysuno administration caused embryolethality and teratogenicity in animals (see section 5.3). If the patient becomes pregnant while receiving Teysuno, treatment should be discontinued and the potential risk to the foetus must be explained. Genetic counseling should be considered. Breast-feeding Teysuno is contraindicated during breast-feeding (see section 4.3). It is not known whether Teysuno or its metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of Teysuno or its metabolites in milk (for details see section 5.3). A risk to newborns/infants cannot be excluded. Breast-feeding must be discontinued while receiving treatment with Teysuno. Fertility No data are available on the effect of Teysuno in combination with cisplatin on human fertility. Non-clinical studies demonstrated that Teysuno did not appear to affect male or female fertility in the rat (see section 5.3). Refer to the cisplatin SmPC for the effects of cisplatin on fertility, pregnancy and lactation.

HOS-095725 · has-warning-information · PDF-Seite 9

Dose limiting toxicities include diarrhoea and dehydration. Most adverse reactions are reversible and can be managed by symptomatic therapy, dose interruptions and dose reductions. Bone marrow suppression Treatment-related bone marrow suppression, including neutropaenia, leukopaenia, thrombocytopaenia, anaemia, and pancytopaenia, has been reported among patients treated with Teysuno in combination with cisplatin. Patients with low white blood cell counts should be monitored carefully for infection and risk of other complications of neutropaenia and treated as medically indicated (e.g., with antibiotics, granulocyte-colony stimulating factor [G-CSF]). Patients with low platelet counts are at increased risk for bleeding and should be monitored carefully. The dose should be modified as recommended in section 4.2. Hepatitis B reactivation Administration of Teysuno in hepatitis B virus carriers, HBc antigen negative and HBc antibody positive patients, or HBs antigen negative and HBs antibody positive patients may result in reactivation of hepatitis B. Patients should be tested for HBV infection before initiating treatment with Teysuno. Experts in liver disease and in the treatment of hepatitis B should be consulted before treatment is initiated in patients with positive hepatitis B serology (including those with active disease) and for patients who test positive for HBV infection during treatment. Carriers of HBV who require treatment with Teysuno should be closely monitored for signs and symptoms of active HBV infection throughout therapy, and follow-up monitoring for hepatic function tests or viral markers are recommended. Diarrhoea Patients with diarrhoea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated. Prophylactic treatment for diarrhoea should be administered as indicated. Standard anti-diarrhoeal therapy (e.g., loperamide) and intravenous fluids/electrolytes should be initiated early when diarrhoea develops. Dose suspension/adjustment should be implemented with the occurrence of Grade 2 or higher diarrhoea if symptoms persist despite adequate treatment. Dehydration Dehydration and any associated electrolyte disturbances should be prevented or corrected at onset. Patients with anorexia, asthenia, nausea, vomiting, diarrhoea, stomatitis, and gastrointestinal obstruction should be monitored closely for signs of dehydration. Dehydration should be managed aggressively with rehydration and other appr

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HOS-095731 · has-warning-information · PDF-Seite 33

Dose limiting toxicities include diarrhoea and dehydration. Most adverse reactions are reversible and can be managed by symptomatic therapy, dose interruptions and dose reductions. 33 Bone marrow suppression Treatment-related bone marrow suppression, including neutropaenia, leukopaenia, thrombocytopaenia, anaemia, and pancytopaenia, has been reported among patients treated with Teysuno in combination with cisplatin. Patients with low white blood cell counts should be monitored carefully for infection and risk of other complications of neutropaenia and treated as medically indicated (e.g., with antibiotics, granulocyte-colony stimulating factor [G-CSF]). Patients with low platelet counts are at increased risk for bleeding and should be monitored carefully. The dose should be modified as recommended in section 4.2. Hepatitis B reactivation Administration of Teysuno in hepatitis B virus carriers, HBc antigen negative and HBc antibody positive patients, or HBs antigen negative and HBs antibody positive patients may result in reactivation of hepatitis B. Patients should be tested for HBV infection before initiating treatment with Teysuno. Experts in liver disease and in the treatment of hepatitis B should be consulted before treatment is initiated in patients with positive hepatitis B serology (including those with active disease) and for patients who test positive for HBV infection during treatment. Carriers of HBV who require treatment with Teysuno should be closely monitored for signs and symptoms of active HBV infection throughout therapy, and follow-up monitoring for hepatic function tests or viral markers are recommended. Diarrhoea Patients with diarrhoea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated. Prophylactic treatment for diarrhoea should be administered as indicated. Standard anti-diarrhoeal therapy (e.g., loperamide) and intravenous fluids/electrolytes should be initiated early when diarrhoea develops. Dose suspension/adjustment should be implemented with the occurrence of Grade 2 or higher diarrhoea if symptoms persist despite adequate treatment. Dehydration Dehydration and any associated electrolyte disturbances should be prevented or corrected at onset. Patients with anorexia, asthenia, nausea, vomiting, diarrhoea, stomatitis, and gastrointestinal obstruction should be monitored closely for signs of dehydration. Dehydration should b

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