Temodal · 4.4 Special warnings and precautions for use · 1

HOS-083890 · has-adverse-reaction-information · PDF-Seite 27

Summary of the safety profile Clinical trial experience with hard capsules In patients treated with TMZ in clinical trials, the most common adverse reactions were nausea, vomiting, constipation, anorexia, headache, fatigue, convulsions, and rash. Most haematologic adverse reactions were reported commonly; the frequency of Grade 3-4 laboratory findings is presented after Table 4. For patients with recurrent or progressive glioma, nausea (43 %) and vomiting (36 %) were usually Grade 1 or 2 (0 – 5 episodes of vomiting in 24 hours) and were either self-limiting or readily controlled with standard anti-emetic therapy. The incidence of severe nausea and vomiting was 4 %. Tabulated list of adverse reactions Adverse reactions observed in clinical studies and reported from post-marketing use of TMZ are listed in Table 4. These reactions are classified according to System Organ Class and frequency. Frequency groupings are defined according to 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); Not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Table 4. Adverse reactions in patients treated with temozolomide Infections and infestations Common: Infections, herpes zoster, pharyngitisa, candidiasis oral Uncommon: Opportunistic infection (including PCP), sepsis†, meningoencephalitis herpetic†, CMV infection, CMV reactivation, hepatitis B virus†, herpes simplex, infection reactivation, wound infection, gastroenteritisb Neoplasm benign, malignant, and unspecified Uncommon: Myelodysplastic syndrome (MDS), secondary malignancies, including myeloid leukaemia Blood and lymphatic system disorders Common: Febrile neutropenia, neutropenia, thrombocytopenia, lymphopenia, leukopenia, anaemia Uncommon: Prolonged pancytopenia, aplastic anaemia†, pancytopenia, petechiae Immune system disorders Common: Allergic reaction

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HOS-083884 · has-adverse-reaction-information · PDF-Seite 9

Summary of the safety profile Clinical trial experience In patients treated with TMZ in clinical trials, the most common adverse reactions were nausea, vomiting, constipation, anorexia, headache, fatigue, convulsions, and rash. Most haematologic adverse reactions were reported commonly; the frequency of Grade 3-4 laboratory findings is presented after Table 4. For patients with recurrent or progressive glioma, nausea (43 %) and vomiting (36 %) were usually Grade 1 or 2 (0 – 5 episodes of vomiting in 24 hours) and were either self-limiting or readily controlled with standard anti-emetic therapy. The incidence of severe nausea and vomiting was 4 %. Tabulated list of adverse reactions Adverse reactions observed in clinical studies and reported from post-marketing use of TMZ are listed in Table 4. These reactions are classified according to System Organ Class and frequency. Frequency groupings are defined according to 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); Not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Table 4. Adverse reactions in patients treated with temozolomide Infections and infestations Common: Infections, herpes zoster, pharyngitisa, candidiasis oral Uncommon: Opportunistic infection (including PCP), sepsis†, meningoencephalitis herpetic†, CMV infection, CMV reactivation, hepatitis B virus†, herpes simplex, infection reactivation, wound infection, gastroenteritisb Neoplasm benign, malignant, and unspecified Uncommon: Myelodysplastic syndrome (MDS), secondary malignancies, including myeloid leukaemia Blood and lymphatic system disorders Common: Febrile neutropenia, neutropenia, thrombocytopenia, lymphopenia, leukopenia, anaemia Uncommon: Prolonged pancytopenia, aplastic anaemia†, pancytopenia, petechiae Immune system disorders Common: Allergic reaction

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HOS-083886 · has-contraindication-information · PDF-Seite 23

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Hypersensitivity to dacarbazine (DTIC). Severe myelosuppression (see section 4.4). 23

HOS-083880 · has-contraindication-information · PDF-Seite 6

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Hypersensitivity to dacarbazine (DTIC). Severe myelosuppression (see section 4.4).

HOS-083879 · has-indication-information · PDF-Seite 3

Temodal is indicated for the treatment of: - adult patients with newly-diagnosed glioblastoma multiforme concomitantly with radiotherapy (RT) and subsequently as monotherapy treatment. - children from the age of three years, adolescents and adult patients with malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression after standard therapy.

HOS-083885 · has-indication-information · PDF-Seite 21

Temodal is indicated for the treatment of: - adult patients with newly-diagnosed glioblastoma multiforme concomitantly with radiotherapy (RT) and subsequently as monotherapy treatment. - children from the age of three years, adolescents and adult patients with malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression after standard therapy.

HOS-083882 · has-interaction-information · PDF-Seite 8

In a separate phase I study, administration of TMZ with ranitidine did not result in alterations in the extent of absorption of temozolomide or the exposure to its active metabolite monomethyl triazenoimidazole carboxamide (MTIC). Administration of TMZ with food resulted in a 33 % decrease in Cmax and a 9 % decrease in area under the curve (AUC). As it cannot be excluded that the change in Cmax is clinically significant, Temodal should be administered without food. Based on an analysis of population pharmacokinetics in phase II trials, co-administration of dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2 receptor antagonists, or phenobarbital did not alter the clearance of TMZ. Co-administration with valproic acid was associated with a small but statistically significant decrease in clearance of TMZ. No studies have been conducted to determine the effect of TMZ on the metabolism or elimination of other medicinal products. However, since TMZ does not undergo hepatic metabolism and exhibits low protein binding, it is unlikely that it would affect the pharmacokinetics of other medicinal products (see section 5.2). Use of TMZ in combination with other myelosuppressive agents may increase the likelihood of myelosuppression. Paediatric population Interaction studies have only been performed in adults.

HOS-083888 · has-interaction-information · PDF-Seite 26

In a separate phase I study, administration of TMZ with ranitidine did not result in alterations in the extent of absorption of temozolomide or the exposure to its active metabolite monomethyl triazenoimidazole carboxamide (MTIC). Based on an analysis of population pharmacokinetics in phase II trials, co-administration of dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2 receptor antagonists, or phenobarbital did not alter the clearance of TMZ. Co-administration with valproic acid was associated with a small but statistically significant decrease in clearance of TMZ. No studies have been conducted to determine the effect of TMZ on the metabolism or elimination of other medicinal products. However, since TMZ does not undergo hepatic metabolism and exhibits low protein binding, it is unlikely that it would affect the pharmacokinetics of other medicinal products (see section 5.2). Use of TMZ in combination with other myelosuppressive agents may increase the likelihood of myelosuppression. Paediatric population Interaction studies have only been performed in adults.

HOS-083883 · has-pregnancy-information · PDF-Seite 8

Pregnancy There are no data in pregnant women. In preclinical studies in rats and rabbits receiving 150 mg/m2 TMZ, teratogenicity and/or foetal toxicity were demonstrated (see section 5.3). Temodal should not be administered to pregnant women. If use during pregnancy must be considered, the patient should be apprised of the potential risk to the foetus. Breast-feeding It is not known whether TMZ is excreted in human milk; thus, breast-feeding should be discontinued while receiving treatment with TMZ. Women of childbearing potential Women of childbearing potential have to use effective contraception to avoid pregnancy while they are receiving TMZ, and for at least 6 months following completion of treatment. 8 Male fertility TMZ can have genotoxic effects. Therefore, men being treated with it should use effective contraceptive measures and be advised not to father a child for at least 3 months after receiving the last dose and to seek advice on cryoconservation of sperm prior to treatment, because of the possibility of irreversible infertility due to therapy with TMZ.

HOS-083889 · has-pregnancy-information · PDF-Seite 26

Pregnancy There are no data in pregnant women. In preclinical studies in rats and rabbits receiving 150 mg/m2 TMZ, teratogenicity and/or foetal toxicity were demonstrated (see section 5.3). Temodal should not be administered to pregnant women. If use during pregnancy must be considered, the patient should be apprised of the potential risk to the foetus. Breast-feeding It is not known whether TMZ is excreted in human milk; thus, breast-feeding should be discontinued while receiving treatment with TMZ. Women of childbearing potential Women of childbearing potential have to use effective contraception to avoid pregnancy while they are receiving TMZ, and for at least 6 months following completion of treatment. Male fertility TMZ can have genotoxic effects. Therefore, men being treated with it should use effective contraceptive measures and be advised not to father a child for at least 3 months after receiving the last dose and to seek advice on cryoconservation of sperm prior to treatment, because of the possibility of irreversible infertility due to therapy with TMZ. 26

HOS-083881 · has-warning-information · PDF-Seite 6

Opportunistic infections and reactivation of infections Opportunistic infections (such as Pneumocystis jirovecii pneumonia) and reactivation of infections (such as HBV, CMV) have been observed during the treatment with TMZ (see section 4.8). Meningoencephalitis herpetic In post marketing cases, meningoencephalitis herpetic (including fatal cases) has been observed in patients receiving TMZ in combination with radiotherapy, including cases of concomitant steroids administration. Pneumocystis jirovecii pneumonia Patients who received concomitant TMZ and RT in a pilot trial for the prolonged 42-day schedule were shown to be at particular risk for developing Pneumocystis jirovecii pneumonia (PCP). Thus, prophylaxis against PCP is required for all patients receiving concomitant TMZ and RT for the 42-day regimen (with a maximum of 49 days) regardless of lymphocyte count. If lymphopenia occurs, they are to continue the prophylaxis until recovery of lymphopenia to grade ≤ 1. There may be a higher occurrence of PCP when TMZ is administered during a longer dosing regimen. However, all patients receiving TMZ, particularly patients receiving steroids, should be observed closely for the development of PCP, regardless of the regimen. Cases of fatal respiratory failure have been reported in patients using TMZ, in particular in combination with dexamethasone or other steroids. HBV Hepatitis due to hepatitis B virus (HBV) reactivation, in some cases resulting in death, has been reported. Experts in liver disease should be consulted before treatment is initiated in patients with positive hepatitis B serology (including those with active disease). During treatment patients should be monitored and managed appropriately. Hepatotoxicity Hepatic injury, including fatal hepatic failure, has been reported in patients treated with TMZ (see section 4.8). Baseline liver function tests should be performed prior to treatment initiation. If abnormal, physicians should assess the benefit/risk prior to initiating temozolomide including the potential for fatal hepatic failure. For patients on a 42 day treatment cycle liver function tests should be repeated midway during this cycle. For all patients, liver function tests should be checked after each treatment cycle. For patients with significant liver function abnormalities, physicians should assess the benefit/risk of continuing treatment. Liver toxicity may occur several weeks or more after the last treatment with temozolomide.

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HOS-083887 · has-warning-information · PDF-Seite 24

Opportunistic infections and reactivation of infections Opportunistic infections (such as Pneumocystis jirovecii pneumonia) and reactivation of infections (such as HBV, CMV) have been observed during the treatment with TMZ (see section 4.8). Meningoencephalitis herpetic In post marketing cases, meningoencephalitis herpetic (including fatal cases) has been observed in patients receiving TMZ in combination with radiotherapy, including cases of concomitant steroids administration. Pneumocystis jirovecii pneumonia Patients who received concomitant TMZ and RT in a pilot trial for the prolonged 42-day schedule were shown to be at particular risk for developing Pneumocystis jirovecii pneumonia (PCP). Thus, prophylaxis against PCP is required for all patients receiving concomitant TMZ and RT for the 42-day regimen (with a maximum of 49 days) regardless of lymphocyte count. If lymphopenia occurs, they are to continue the prophylaxis until recovery of lymphopenia to grade ≤ 1. There may be a higher occurrence of PCP when TMZ is administered during a longer dosing regimen. However, all patients receiving TMZ, particularly patients receiving steroids, should be observed closely for the development of PCP, regardless of the regimen. Cases of fatal respiratory failure have been reported in patients using TMZ, in particular in combination with dexamethasone or other steroids. HBV Hepatitis due to hepatitis B virus (HBV) reactivation, in some cases resulting in death, has been reported. Experts in liver disease should be consulted before treatment is initiated in patients with positive hepatitis B serology (including those with active disease). During treatment patients should be monitored and managed appropriately. Hepatotoxicity Hepatic injury, including fatal hepatic failure, has been reported in patients treated with TMZ (see section 4.8). Baseline liver function tests should be performed prior to treatment initiation. If abnormal, physicians should assess the benefit/risk prior to initiating temozolomide including the potential for fatal hepatic failure. For patients on a 42 day treatment cycle liver function tests should be repeated midway during this cycle. For all patients, liver function tests should be checked after each treatment cycle. For patients with significant liver function abnormalities, physicians should assess the benefit/risk of continuing treatment. Liver toxicity may occur several weeks or more after the last treatment with temozolomide.

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