Tepadina · 4.3 Contraindications · 1

HOS-154522 · has-adverse-reaction-information · PDF-Seite 26

Summary of the safety profile The safety of thiotepa has been examined through a review of adverse events reported in published data from clinical trials. In these studies, a total of 6 588 adult patients and 902 paediatric patients received thiotepa for conditioning treatment prior to haematopoietic progenitor cell transplantation. Serious toxicities involving the haematologic, hepatic and respiratory systems were considered as expected consequences of the conditioning regimen and transplant process. These include infection and Graft-versus host disease (GvHD) which, although not directly related, were the major causes of morbidity and mortality, especially in allogeneic HPCT. The most frequently adverse reactions reported in the different conditioning treatments including thiotepa are: infections, cytopenia, acute GvHD and chronic GvHD, gastrointestinal disorders, haemorrhagic cystitis and mucosal inflammation. Leukoencephalopathy Cases of leukoencephalopathy have been observed following treatment with thiotepa in adult and paediatric patients with multiple previous chemotherapies, including methotrexate and radiotherapy. Some cases had a fatal outcome. Tabulated list of adverse reactions Adults The adverse reactions considered at least possibly related to conditioning treatment including thiotepa, reported in adult patients as more than an isolated case, are listed below by system organ class and by frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as: 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), not known (cannot be estimated from the available data). System organ Not known Very common Common Uncommon class Infections and Infection Toxic shock infestations susceptibility syndrome increased Sepsis Neoplasms Treatment related benign, second malignant and malignancy unspecified (incl cysts and polyps) Blood and Leukopenia lymphatic Thrombocytopeni system a disorders Febrile neutropenia

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HOS-154516 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile The safety of thiotepa has been examined through a review of adverse events reported in published data from clinical trials. In these studies, a total of 6 588 adult patients and 902 paediatric patients received thiotepa for conditioning treatment prior to haematopoietic progenitor cell transplantation. Serious toxicities involving the haematologic, hepatic and respiratory systems were considered as expected consequences of the conditioning regimen and transplant process. These include infection and Graft-versus host disease (GvHD) which, although not directly related, were the major causes of morbidity and mortality, especially in allogeneic HPCT. The most frequently adverse reactions reported in the different conditioning treatments including thiotepa are: infections, cytopenia, acute GvHD and chronic GvHD, gastrointestinal disorders, haemorrhagic cystitis and mucosal inflammation. Leukoencephalopathy Cases of leukoencephalopathy have been observed following treatment with thiotepa in adult and paediatric patients with multiple previous chemotherapies, including methotrexate and radiotherapy. Some cases had a fatal outcome. 8 Tabulated list of adverse reactions Adults The adverse reactions considered at least possibly related to conditioning treatment including thiotepa, reported in adult patients as more than an isolated case, are listed below by system organ class and by frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as: 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), not known (cannot be estimated from the available data). System organ Not known Very common Common Uncommon class Infections and Infection Toxic shock infestations susceptibility syndrome increased Sepsis Neoplasms Treatment related benign, second malignant and malignancy unspecified (incl cysts and polyps) Blood and Leukopenia lymphatic Thrombocytopeni system a disorders Febrile

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HOS-154512 · has-contraindication-information · PDF-Seite 5

Hypersensitivity to the active substance. 5 Pregnancy and lactation (see section 4.6). Concomitant use with yellow fever vaccine and with live virus and bacterial vaccines (see section 4.5).

HOS-154518 · has-contraindication-information · PDF-Seite 23

Hypersensitivity to the active substance. Pregnancy and lactation (see section 4.6). Concomitant use with yellow fever vaccine and with live virus and bacterial vaccines (see section 4.5).

HOS-154511 · has-indication-information · PDF-Seite 2

TEPADINA is indicated, in combination with other chemotherapy medicinal products: • with or without total body irradiation (TBI), as conditioning treatment prior to allogeneic or autologous haematopoietic progenitor cell transplantation (HPCT) in haematological diseases in adult and paediatric patients; • when high dose chemotherapy with HPCT support is appropriate for the treatment of solid tumours in adult and paediatric patients.

HOS-154517 · has-indication-information · PDF-Seite 19

TEPADINA is indicated, in combination with other chemotherapy medicinal products: • with or without total body irradiation (TBI), as conditioning treatment prior to allogeneic or autologous haematopoietic progenitor cell transplantation (HPCT) in haematological diseases in adult and paediatric patients; • when high dose chemotherapy with HPCT support is appropriate for the treatment of solid tumours in adult and paediatric patients.

HOS-154514 · has-interaction-information · PDF-Seite 7

Specific interactions with thiotepa Live virus and bacterial vaccines must not be administered to a patient receiving an immunosuppressive chemotherapeutic agent and at least three months must elapse between discontinuation of therapy and vaccination. Thiotepa appears to be metabolised via CYP2B6 and CYP3A4. Co-administration with inhibitors of CYP2B6 (for example clopidogrel and ticlopidine) or CYP3A4 (for example azole antifungals, macrolides like erythromycin, clarithromycin, telithromycin, and protease inhibitors) may increase the plasma concentrations of thiotepa and potentially decrease the concentrations of the active metabolite TEPA. Co-administration of inducers of cytochrome P450 (such as rifampicin, carbamazepine, phenobarbital) may increase the metabolism of thiotepa leading to increased plasma concentrations of the active metabolite. Therefore, during the concomitant use of thiotepa and these medicinal products, patients should be carefully monitored clinically. Thiotepa is a weak inhibitor for CYP2B6, and may thereby potentially increase plasma concentrations of substances metabolised via CYP2B6, such as ifosfamide, tamoxifen, bupropion, efavirenz and cyclophosphamide. CYP2B6 catalyzes the metabolic conversion of cyclophosphamide to its active form 4-hydroxycyclophosphamide (4-OHCP) and co-administration of thiotepa may therefore lead to decreased concentrations of the active 4-OHCP. Therefore, a clinical monitoring should be exercised during the concomitant use of thiotepa and these medicinal products. Contraindications of concomitant use Yellow fever vaccine: risk of fatal generalized vaccine-induced disease. More generally, live virus and bacterial vaccines must not be administered to a patient receiving an immunosuppressive chemotherapeutic agent and at least three months must elapse between discontinuation of therapy and vaccination. Concomitant use not recommended Live attenuated vaccines (except yellow fever): risk of systemic, possibly fatal disease. This risk is increased in subjects who are already immunosuppressed by their underlying disease. An inactivated virus vaccine should be used instead, whenever possible (poliomyelitis). Phenytoin: risk of exacerbation of convulsions resulting from the decrease of phenytoin digestive absorption by cytotoxic medicinal product or risk of toxicity enhancement and loss of efficacy of the cytotoxic medicinal product due to increased hepatic metabolism by phenytoin. Concomitant use to tak

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HOS-154520 · has-interaction-information · PDF-Seite 24

Specific interactions with thiotepa Live virus and bacterial vaccines must not be administered to a patient receiving an immunosuppressive chemotherapeutic agent and at least three months must elapse between discontinuation of therapy and vaccination. Thiotepa appears to be metabolised via CYP2B6 and CYP3A4. Co-administration with inhibitors of CYP2B6 (for example clopidogrel and ticlopidine) or CYP3A4 (for example azole antifungals, macrolides like erythromycin, clarithromycin, telithromycin, and protease inhibitors) may increase the plasma concentrations of thiotepa and potentially decrease the concentrations of the active metabolite TEPA. Co-administration of inducers of cytochrome P450 (such as rifampicin, carbamazepine, phenobarbital) may increase the metabolism of thiotepa leading to increased plasma concentrations of the active metabolite. Therefore, during the concomitant use of thiotepa and these medicinal products, patients should be carefully monitored clinically. Thiotepa is a weak inhibitor for CYP2B6, and may thereby potentially increase plasma concentrations of substances metabolised via CYP2B6, such as ifosfamide, tamoxifen, bupropion, efavirenz and cyclophosphamide. CYP2B6 catalyzes the metabolic conversion of cyclophosphamide to its active form 4-hydroxycyclophosphamide (4-OHCP) and co-administration of thiotepa may therefore lead to decreased concentrations of the active 4-OHCP. Therefore, a clinical monitoring should be exercised during the concomitant use of thiotepa and these medicinal products. Contraindications of concomitant use Yellow fever vaccine: risk of fatal generalized vaccine-induced disease. More generally, live virus and bacterial vaccines must not be administered to a patient receiving an immunosuppressive chemotherapeutic agent and at least three months must elapse between discontinuation of therapy and vaccination. Concomitant use not recommended 24 Live attenuated vaccines (except yellow fever): risk of systemic, possibly fatal disease. This risk is increased in subjects who are already immunosuppressed by their underlying disease. An inactivated virus vaccine should be used instead, whenever possible (poliomyelitis). Phenytoin: risk of exacerbation of convulsions resulting from the decrease of phenytoin digestive absorption by cytotoxic medicinal product or risk of toxicity enhancement and loss of efficacy of the cytotoxic medicinal product due to increased

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HOS-154515 · has-pregnancy-information · PDF-Seite 8

Women of childbearing potential/Contraception in males and females Women of childbearing potential have to use effective contraception during treatment and for at least 6 months after cessation of treatment. A pregnancy test should be performed before treatment is started. Male patients should not father a child while treated and for at least 3 months after cessation of treatment (see section 5.3). Pregnancy There are no data on the use of thiotepa during pregnancy. In pre-clinical studies thiotepa, as most alkylating agents, has been shown to cause embryofoetal lethality and teratogenicity (see section 5.3). Therefore, thiotepa is contraindicated during pregnancy. Breast-feeding It is unknown whether thiotepa is excreted in human milk. Due to its pharmacological properties and its potential toxicity for breast-fed newborns/infants, breast-feeding is contraindicated during treatment with thiotepa. Fertility As most alkylating agents, thiotepa might impair male and female fertility. Male patients should seek for sperm cryopreservation before therapy is started (see section 5.3).

HOS-154521 · has-pregnancy-information · PDF-Seite 25

Women of childbearing potential/Contraception in males and females Women of childbearing potential have to use effective contraception during treatment and for at least 6 months after cessation of treatment. A pregnancy test should be performed before treatment is started. Male patients should not father a child while treated and for at least 3 months after cessation of treatment (see section 5.3). Pregnancy There are no data on the use of thiotepa during pregnancy. In pre-clinical studies thiotepa, as most alkylating agents, has been shown to cause embryofoetal lethality and teratogenicity (see section 5.3). Therefore, thiotepa is contraindicated during pregnancy. Breast-feeding It is unknown whether thiotepa is excreted in human milk. Due to its pharmacological properties and its potential toxicity for breast-fed newborns/infants, breast-feeding is contraindicated during treatment with thiotepa. Fertility As most alkylating agents, thiotepa might impair male and female fertility. Male patients should seek for sperm cryopreservation before therapy is started (see section 5.3).

HOS-154513 · has-warning-information · PDF-Seite 6

The consequence of treatment with thiotepa at the recommended dose and schedule is profound myelosuppression, occurring in all patients. Severe granulocytopenia, thrombocytopenia, anaemia or any combination thereof may develop. Frequent complete blood counts, including differential white blood cell counts, and platelet counts need to be performed during the treatment and until recovery is achieved. Platelet and red blood cell support, as well as the use of growth factors such as Granulocyte- colony stimulating factor (G-CSF), should be employed as medically indicated. Daily white blood cell counts and platelet counts are recommended during therapy with thiotepa and after transplant for at least 30 days. Prophylactic or empiric use of anti-infectives (bacterial, fungal, viral) should be considered for the prevention and management of infections during the neutropenic period. Thiotepa has not been studied in patients with hepatic impairment. Since thiotepa is mainly metabolized through the liver, caution needs to be observed when thiotepa is used in patients with pre- existing impairment of liver function, especially in those with severe hepatic impairment. When treating such patients it is recommended that serum transaminase, alkaline phosphatase and bilirubin are monitored regularly following transplant, for early detection of hepatotoxicity. Patients who have received prior radiation therapy, greater than or equal to three cycles of chemotherapy, or prior progenitor cell transplant may be at an increased risk of hepatic veno-occlusive disease (see section 4.8). Caution must be used in patients with history of cardiac diseases, and cardiac function must be monitored regularly in patients receiving thiotepa. Caution must be used in patients with history of renal diseases and periodic monitoring of renal function should be considered during therapy with thiotepa. Thiotepa might induce pulmonary toxicity that may be additive to the effects produced by other cytotoxic agents (busulfan, fludarabine and cyclophosphamide) (see section 4.8). Previous brain irradiation or craniospinal irradiation may contribute to severe toxic reactions (e.g. encephalopathy). The increased risk of a secondary malignancy with thiotepa, a known carcinogen in humans, must be explained to the patient. Concomitant use with live attenuated vaccines (except yellow fever vaccines), phenytoin and fosphenytoin is not recommended (see section 4.5). Thiotepa must not be concurrently

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HOS-154519 · has-warning-information · PDF-Seite 23

The consequence of treatment with thiotepa at the recommended dose and schedule is profound myelosuppression, occurring in all patients. Severe granulocytopenia, thrombocytopenia, anaemia or any combination thereof may develop. Frequent complete blood counts, including differential white blood cell counts, and platelet counts need to be performed during the treatment and until recovery is achieved. Platelet and red blood cell support, as well as the use of growth factors such as Granulocyte- colony stimulating factor (G-CSF), should be employed as medically indicated. Daily white blood cell counts and platelet counts are recommended during therapy with thiotepa and after transplant for at least 30 days. Prophylactic or empiric use of anti-infectives (bacterial, fungal, viral) should be considered for the prevention and management of infections during the neutropenic period. Thiotepa has not been studied in patients with hepatic impairment. Since thiotepa is mainly metabolized through the liver, caution needs to be observed when thiotepa is used in patients with pre- existing impairment of liver function, especially in those with severe hepatic impairment. When treating such patients it is recommended that serum transaminase, alkaline phosphatase and bilirubin are monitored regularly following transplant, for early detection of hepatotoxicity. Patients who have received prior radiation therapy, greater than or equal to three cycles of chemotherapy, or prior progenitor cell transplant may be at an increased risk of hepatic veno-occlusive disease (see section 4.8). Caution must be used in patients with history of cardiac diseases, and cardiac function must be monitored regularly in patients receiving thiotepa. Caution must be used in patients with history of renal diseases and periodic monitoring of renal function should be considered during therapy with thiotepa. Thiotepa might induce pulmonary toxicity that may be additive to the effects produced by other cytotoxic agents (busulfan, fludarabine and cyclophosphamide) (see section 4.8). 23 Previous brain irradiation or craniospinal irradiation may contribute to severe toxic reactions (e.g. encephalopathy). The increased risk of a secondary malignancy with thiotepa, a known carcinogen in humans, must be explained to the patient. Concomitant use with live attenuated vaccines (except yellow fever vaccines), phenytoin and fosphenytoin is not recommende

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