Hycamtin · 4.8 Undesirable effects · 2

HOS-083263 · has-adverse-reaction-information · PDF-Seite 6

In dose-finding studies involving 523 patients with relapsed ovarian cancer and 631 patients with relapsed small cell lung cancer, the dose-limiting toxicity of topotecan monotherapy was found to be haematological. Toxicity was predictable and reversible. There were no signs of cumulative haematological or non-haematological toxicity. The safety profile of topotecan when given in combination with cisplatin in the cervical cancer clinical studies is consistent with that seen with topotecan monotherapy. The overall haematological toxicity is lower in patients treated with topotecan in combination with cisplatin compared to topotecan monotherapy, but higher than with cisplatin alone. Additional adverse events were seen when topotecan was given in combination with cisplatin; however, these events were seen with cisplatin monotherapy and were not attributable to topotecan. The prescribing information for cisplatin should be consulted for a full list of adverse events associated with cisplatin use. The integrated safety data for topotecan monotherapy are presented below. Adverse reactions are listed below, by system organ class and absolute frequency (all reported events). 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) and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Infections and infestations Very common Infection Common Sepsis1 Blood and lymphatic system disorders Very common Febrile neutropenia, neutropenia (see “Gastrointestinal disorders”), thrombocytopenia, anaemia, leucopenia Common Pancytopenia Not known Severe bleeding (associated with thrombocytopenia) 6  Immune system disorders Common Hypersensitivity reaction including rash Rare Anaphylactic reaction, angioedema, urticaria Metabolism and nutrition disorders Very common Anorexia (which may be severe) Respiratory, thoracic and mediastinal disorders Rare Interstitial lung disease (some cases have been fatal) Gastrointestinal disorders Very common Nausea, vomiting and diarrhoea (all of which may be severe), constipation, abdominal pain2, mucositi

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HOS-083269 · has-adverse-reaction-information · PDF-Seite 20

In clinical studies involving patients with relapsed small cell lung cancer, the dose-limiting toxicity of oral topotecan monotherapy was found to be haematological. Toxicity was predictable and reversible. There were no signs of cumulative haematological or non-haematological toxicity. The frequencies associated with the haematological and non-haematological adverse events presented are for adverse events considered to be related/possibly related to oral topotecan therapy. Adverse reactions are listed below, by system organ class and absolute frequency (all reported events). 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) and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Infections and infestations Very common Infection Common Sepsis1 Blood and lymphatic system disorders Very common Febrile neutropenia, neutropenia (see “Gastrointestinal disorders”), thrombocytopenia, anaemia, leucopenia Common Pancytopenia Not known Severe bleeding (associated with thrombocytopenia) Immune system disorders Common Hypersensitivity reaction including rash Rare Anaphylactic reaction, angioedema, urticaria Metabolism and nutrition disorders Very common Anorexia (which may be severe) Respiratory, thoracic and mediastinal disorders Rare Interstitial lung disease (some cases have been fatal) Gastrointestinal disorders Very common Nausea, vomiting and diarrhoea (all of which may be severe), which may lead to dehydration (see sections 4.2 and 4.4) Common Abdominal pain2, constipation, mucositis, dyspepsia Not known Gastrointestinal perforation Hepatobiliary disorders Common Hyperbilirubinaemia Skin and subcutaneous tissue disorders Very common Alopecia Common Pruritus General disorders and administration site conditions Very common Fatigue Common Asthenia, pyrexia, malaise 20  Not known Mucosal inflammation 1 Fatalities due to sepsis have been reported in patients treated with topotecan (see section 4.4). 2 Neutropenic colitis, including fata

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HOS-083265 · has-contraindication-information · PDF-Seite 17

− Severe hypersensitivity to the active substance or to any of the excipients. − Breast-feeding (see section 4.6). − Severe bone marrow depression prior to starting first course, as evidenced by baseline 17  neutrophils <1.5 x 109/l and/or a platelet count of 100 x 109/l.

HOS-083259 · has-contraindication-information · PDF-Seite 4

− Severe hypersensitivity to the active substance or to any of the excipients. − Breast-feeding (see section 4.6). − Severe bone marrow depression prior to starting first course, as evidenced by baseline neutrophils <1.5 x 109/l and/or a platelet count of 100 x 109/l.

HOS-083258 · has-indication-information · PDF-Seite 2

Topotecan monotherapy is indicated for the treatment of: • patients with metastatic carcinoma of the ovary after failure of first-line or subsequent therapy. • patients with relapsed small cell lung cancer (SCLC) for whom re-treatment with the first-line regimen is not considered appropriate (see section 5.1). Topotecan in combination with cisplatin is indicated for patients with carcinoma of the cervix recurrent after radiotherapy and for patients with Stage IVB disease. Patients with prior exposure to cisplatin require a sustained treatment-free interval to justify treatment with the combination (see section 5.1).

HOS-083264 · has-indication-information · PDF-Seite 16

HYCAMTIN capsules are indicated as monotherapy for the treatment of adult patients with relapsed small cell lung cancer (SCLC) for whom re-treatment with the first-line regimen is not considered appropriate (see section 5.1).

HOS-083267 · has-interaction-information · PDF-Seite 19

No in vivo human pharmacokinetic interaction studies have been performed. Topotecan does not inhibit human P450 enzymes (see section 5.2). In a population study using the intravenous route, the co-administration of granisetron, ondansetron, morphine or corticosteroids did not appear to have a significant effect on the pharmacokinetics of total topotecan (active and inactive form). Topotecan is a substrate for both ABCB1 (P-glycoprotein) and ABCG2 (BCRP). Inhibitors of ABCB1 and ABCG2 administered with oral topotecan have been shown to increase topotecan exposure. Cyclosporin A (an inhibitor of ABCB1, ABCC1 [MRP-1], and CYP3A4) administered with oral topotecan increased topotecan AUC to approximately 2-2.5-fold of control. Patients should be carefully monitored for adverse reactions when oral topotecan is administered with a substance known to inhibit ABCB1 or ABCG2 (see section 5.2). When combining topotecan with other chemotherapy agents, reduction of the doses of each medicinal product may be required to improve tolerability. However, when combining with platinum agents, there is a distinct sequence-dependent interaction depending on whether the platinum agent is given on day 1 or 5 of the topotecan dosing. If either cisplatin or carboplatin is given on day 1 of the topotecan dosing, a lower dose of each agent must be given to improve tolerability compared to the dose of each agent which can be given if the platinum agent is given on day 5 of the topotecan dosing. Currently there is only limited experience in combining oral topotecan with other chemotherapy agents. The pharmacokinetics of topotecan were generally unchanged when co-administered with ranitidine.

HOS-083261 · has-interaction-information · PDF-Seite 5

No in vivo human pharmacokinetic interaction studies have been performed. Topotecan does not inhibit human P450 enzymes (see section 5.2). In a population study using the intravenous route, the co-administration of granisetron, ondansetron, morphine or corticosteroids did not appear to have a significant effect on the pharmacokinetics of total topotecan (active and inactive form). When combining topotecan with other chemotherapy agents, reduction of the doses of each medicinal product may be required to improve tolerability. However, when combining with platinum agents, there is a distinct sequence-dependent interaction depending on whether the platinum agent is given on day 1 or 5 of the topotecan dosing. If either cisplatin or carboplatin is given on day 1 of the topotecan dosing, a lower dose of each agent must be given to improve tolerability compared to the dose of each agent which can be given if the platinum agent is given on day 5 of the topotecan dosing. When topotecan (0.75 mg/m2/day for 5 consecutive days) and cisplatin (60 mg/m2/day on day 1) were administered in 13 patients with ovarian cancer, a slight increase in AUC (12%, n = 9) and Cmax (23%, n = 11) was noted on day 5. This increase is considered unlikely to be of clinical relevance.

HOS-083262 · has-pregnancy-information · PDF-Seite 5

Women of childbearing potential / Contraception in males and females Topotecan has been shown to cause embryo-foetal lethality and malformations in preclinical studies (see section 5.3). As with other cytotoxic medicinal products, topotecan may cause foetal harm and therefore women of childbearing potential should be advised to avoid becoming pregnant during therapy with topotecan. As with all cytotoxic chemotherapy, patients being treated with topotecan must be advised that they or their partner must use an effective method of contraception. Women of childbearing potential should use effective contraceptive measures while being treated with topotecan and for 6 months following completion of treatment. Men are recommended to use effective contraceptive measures and to not father a child while receiving topotecan and for 3 months following completion of treatment. 5 Pregnancy If topotecan is used during pregnancy, or if the patient becomes pregnant during therapy with topotecan, the patient must be warned of the potential hazards to the foetus. Breast-feeding Topotecan is contraindicated during breast-feeding (see section 4.3). Although it is not known whether topotecan is excreted in human breast milk, breast-feeding should be discontinued at the start of therapy. Fertility No effects on male or female fertility have been observed in reproductive toxicity studies in rats (see section 5.3). However, as with other cytotoxic medicinal products, topotecan is genotoxic and effects on fertility, including male fertility, cannot be excluded.

HOS-083268 · has-pregnancy-information · PDF-Seite 19

Women of childbearing potential / Contraception in males and females Topotecan has been shown to cause embryo-foetal lethality and malformations in preclinical studies (see section 5.3). As with other cytotoxic medicinal products, topotecan may cause foetal harm and therefore women of childbearing potential should be advised to avoid becoming pregnant during therapy with topotecan. As with all cytotoxic chemotherapy, patients being treated with topotecan must be advised that they or their partner must use an effective method of contraception. Women of childbearing potential should use effective contraceptive measures while being treated with topotecan and for 6 months following completion of treatment. Men are recommended to use effective contraceptive measures and to not father a child while receiving topotecan and for 3 months following completion of treatment. Pregnancy If topotecan is used during pregnancy, or if the patient becomes pregnant during therapy with topotecan, the patient must be warned of the potential hazards to the foetus. Breast-feeding Topotecan is contraindicated during breast-feeding (see section 4.3). Although it is not known whether topotecan is excreted in human breast milk, breast-feeding should be discontinued at the start of therapy. 19 Fertility No effects on male or female fertility have been observed in reproductive toxicity studies in rats (see section 5.3). However, as with other cytotoxic medicinal products, topotecan is genotoxic and effects on fertility, including male fertility, cannot be excluded.

HOS-083266 · has-warning-information · PDF-Seite 18

Haematological toxicity is dose-related and full blood count including platelets should be determined regularly (see section 4.2). As with other cytotoxic medicinal products, topotecan can cause severe myelosuppression. Myelosuppression leading to sepsis and fatalities due to sepsis have been reported in patients treated with topotecan (see section 4.8). Topotecan-induced neutropenia can cause neutropenic colitis. Fatalities due to neutropenic colitis have been reported in clinical studies with topotecan. In patients presenting with fever, neutropenia and a compatible pattern of abdominal pain, the possibility of neutropenic colitis should be considered. Topotecan has been associated with reports of interstitial lung disease (ILD), some of which have been fatal (see section 4.8). Underlying risk factors include history of ILD, pulmonary fibrosis, lung cancer, thoracic exposure to radiation and use of pneumotoxic substances and/or colony stimulating factors. Patients should be monitored for pulmonary symptoms indicative of ILD (e.g. cough, fever, dyspnoea and/or hypoxia), and topotecan should be discontinued if a new diagnosis of ILD is confirmed. Topotecan monotherapy and topotecan in combination with cisplatin are commonly associated with clinically relevant thrombocytopenia. This should be taken into account when prescribing HYCAMTIN, e.g. if patients at increased risk of tumour bleeds are considered for therapy. As would be expected, patients with poor performance status (PS >1) have a lower response rate and an increased incidence of complications such as fever, infection and sepsis (see section 4.8). Accurate assessment of performance status at the time therapy is given is important, to ensure that patients have not deteriorated to PS 3. Topotecan is partly eliminated via renal excretion and renal impairment might lead to increased exposure to topotecan. Dosing recommendations for patients receiving oral topotecan with creatinine clearance less than 30 ml/min have not been established. Use of topotecan in these patients is not recommended (see section 4.2). A small number of hepatically impaired patients (serum bilirubin between 1.5 and 10 mg/dl) were given intravenous topotecan at 1.5 mg/m2/day for five days every three weeks. A reduction in topotecan clearance was observed. However, there are insufficient data available to make a dose recommendation for this patient group. There is insufficient experience of the use of topotecan in patients w

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HOS-083260 · has-warning-information · PDF-Seite 4

Haematological toxicity is dose-related and full blood count including platelets should be determined regularly (see section 4.2). As with other cytotoxic medicinal products, topotecan can cause severe myelosuppression. Myelosuppression leading to sepsis and fatalities due to sepsis have been reported in patients treated with topotecan (see section 4.8). Topotecan-induced neutropenia can cause neutropenic colitis. Fatalities due to neutropenic colitis have been reported in clinical studies with topotecan. In patients presenting with fever, neutropenia and a compatible pattern of abdominal pain, the possibility of neutropenic colitis should be considered. Topotecan has been associated with reports of interstitial lung disease (ILD), some of which have been fatal (see section 4.8). Underlying risk factors include history of ILD, pulmonary fibrosis, lung cancer, thoracic exposure to radiation and use of pneumotoxic substances and/or colony stimulating factors. Patients should be monitored for pulmonary symptoms indicative of ILD (e.g. cough, fever, dyspnoea and/or hypoxia), and topotecan should be discontinued if a new diagnosis of ILD is confirmed. Topotecan monotherapy and topotecan in combination with cisplatin are commonly associated with clinically relevant thrombocytopenia. This should be taken into account when prescribing HYCAMTIN, e.g. if patients at increased risk of tumour bleeds are considered for therapy. 4 As would be expected, patients with poor performance status (PS >1) have a lower response rate and an increased incidence of complications such as fever, infection and sepsis (see section 4.8). Accurate assessment of performance status at the time therapy is given is important, to ensure that patients have not deteriorated to PS 3. There is insufficient experience of the use of topotecan in patients with severely impaired renal function (creatinine clearance <20 ml/min) or severely impaired hepatic function (serum bilirubin 10 mg/dl) due to cirrhosis. Use of topotecan in these patient groups is not recommended (see section 4.2). A small number of hepatically impaired patients (serum bilirubin between 1.5 and 10 mg/dl) were given intravenous topotecan at 1.5 mg/m2/day for five days every three weeks. A reduction in topotecan clearance was observed. However, there are insufficient data available to make a dose recommendation for this patient group (see section 4.2). Hycamtin contains

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