Chemical formula: C₂₃H₂₃N₃O₅ Molecular mass: 421.446 g/mol PubChem compound: 60700
Topotecan interacts in the following cases:
Monotherapy (ovarian and small cell lung carcinoma): There is insufficient experience with the use of topotecan in patients with severely impaired renal function (creatinine clearance <20 ml/min). Use of topotecan in this group of patients is not recommended.
Limited data indicate that the dose should be reduced in patients with moderate renal impairment. The recommended monotherapy dose of topotecan in patients with ovarian or small cell lung carcinoma and a creatinine clearance between 20 and 39 ml/min is 0.75 mg/m²/day for five consecutive days.
There is insufficient experience with the use of topotecan in patients with severely impaired hepatic function (serum bilirubin ≥10 mg/dl) due to cirrhosis. Topotecan is not recommended to be used in this patient group.
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.
No effects on male or female fertility have been observed in reproductive toxicity studies in rats. However, as with other cytotoxic medicinal products, topotecan is genotoxic and effects on fertility, including male fertility, cannot be excluded.
Topotecan monotherapy and topotecan in combination with cisplatin are commonly associated with clinically relevant thrombocytopenia. This should be taken into account when prescribing topotecan, e.g. if patients at increased risk of tumour bleeds are considered for therapy.
Topotecan has been associated with reports of interstitial lung disease (ILD), some of which have been fatal. 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.
Haematological toxicity is dose-related and full blood count including platelets should be determined regularly.
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. 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.
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.
Topotecan is contraindicated during breast-feeding. Although it is not known whether topotecan is excreted in human breast milk, breast-feeding should be discontinued at the start of therapy.
Topotecan has been shown to cause embryo-foetal lethality and malformations in preclinical studies. 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.
No effects on male or female fertility have been observed in reproductive toxicity studies in rats. However, as with other cytotoxic medicinal products, topotecan is genotoxic and effects on fertility, including male fertility, cannot be excluded.
No studies of the effects on the ability to drive and use machines have been performed. However, caution should be observed when driving or operating machines if fatigue and asthenia persist.
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.
Very common: Infection
Common: Sepsis1
Very common: Febrile neutropenia, neutropenia (see “Gastrointestinal disorders”), thrombocytopenia, anaemia, leucopenia
Common: Pancytopenia
Not known: Severe bleeding (associated with thrombocytopenia)
Common: Hypersensitivity reaction including rash
Rare: Anaphylactic reaction, angioedema, urticaria
Very common: Anorexia (which may be severe)
Rare: Interstitial lung disease (some cases have been fatal)
Very common: Nausea, vomiting and diarrhoea (all of which may be severe), constipation, abdominal pain2, mucositis
Not known: Gastrointestinal perforation
Common: Hyperbilirubinaemia
Very common: Alopecia
Common: Pruritus
Very common: Pyrexia, asthenia, fatigue
Common: Malaise
Very rare: Extravasation3
Not known: Mucosal inflammation
1 Fatalities due to sepsis have been reported in patients treated with topotecan.
2 Neutropenic colitis, including fatal neutropenic colitis, has been reported to occur as a complication of topotecan-induced neutropenia.
3 Reactions have been mild and have not generally required specific therapy.
The adverse events listed above have the potential to occur with a higher frequency in patients who have a poor performance status.
The frequencies associated with the haematological and non-haematological adverse events listed below represent the adverse event reports considered to be related/possibly related to topotecan therapy.
Severe (neutrophil count <0.5 × 109/l) during course 1 in 55% of patients, with duration seven days in 20%, and overall in 77% of patients (39% of courses). In association with severe neutropenia, fever or infection occurred in 16% of patients during course 1 and overall in 23% of patients (6% of courses). Median time to onset of severe neutropenia was nine days and the median duration was seven days. Severe neutropenia lasted beyond seven days in 11% of courses overall. Among all patients treated in clinical studies (including both those with severe neutropenia and those who did not develop severe neutropenia), 11% (4% of courses) developed fever and 26% (9% of courses) developed infection. In addition, 5% of all patients treated (1% of courses) developed sepsis.
Severe (platelets <25 × 109/l) in 25% of patients (8% of courses); moderate (platelets between 25.0 and 50.0 × 109/l) in 25% of patients (15% of courses). Median time to onset of severe thrombocytopenia was day 15 and the median duration was five days. Platelet transfusions were given in 4% of courses. Reports of significant sequelae associated with thrombocytopenia, including fatalities due to tumour bleeds, have been infrequent.
Moderate to severe (Hb ≤8.0 g/dl) in 37% of patients (14% of courses). Red cell transfusions were given in 52% of patients (21% of courses).
Frequently reported non-haematological effects were gastrointestinal, such as nausea (52%), vomiting (32%), diarrhoea (18%), constipation (9%) and mucositis (14%). The incidence of severe (Grade 3 or 4) nausea, vomiting, diarrhoea and mucositis was 4, 3, 2 and 1%, respectively.
Mild abdominal pain was reported in 4% of patients.
Fatigue was observed in approximately 25% and asthenia in 16% of patients receiving topotecan. Severe (Grade 3 or 4) fatigue and asthenia both occurred with an incidence of 3%.
Total or pronounced alopecia was observed in 30% of patients and partial alopecia in 15% of patients.
Other severe events that were recorded as related or possibly related to topotecan treatment were anorexia (12%), malaise (3%) and hyperbilirubinaemia (1%).
Hypersensitivity reactions including rash, urticaria, angioedema and anaphylactic reactions have been reported rarely. In clinical studies, rash was reported in 4% of patients and pruritus in 1.5% of patients.
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.
Very common: Infection
Common: Sepsis1
Very common: Febrile neutropenia, neutropenia (see “Gastrointestinal disorders”), thrombocytopenia, anaemia, leucopenia
Common: Pancytopenia
Not known: Severe bleeding (associated with thrombocytopenia)
Common: Hypersensitivity reaction including rash
Rare: Anaphylactic reaction, angioedema, urticaria
Very common: Anorexia (which may be severe)
Rare: Interstitial lung disease (some cases have been fatal)
Very common: Nausea, vomiting and diarrhoea (all of which may be severe), which may lead to dehydration
Common: Abdominal pain2, constipation, mucositis, dyspepsia
Not known: Gastrointestinal perforation
Common: Hyperbilirubinaemia
Very common: Alopecia
Common: Pruritus
Very common: Fatigue
Common: Asthenia, pyrexia, malaise
Not known: Mucosal inflammation
1 Fatalities due to sepsis have been reported in patients treated with topotecan.
2 Neutropenic colitis, including fatal neutropenic colitis, has been reported to occur as a complication of topotecan-induced neutropenia
The adverse events listed above have the potential to occur with a higher frequency in patients who have a poor performance status.
Safety data are presented based on an integrated data set of 682 patients with relapsed lung cancer administered 2,536 courses of oral topotecan monotherapy (275 patients with relapsed SCLC and 407 with relapsed non-SCLC).
Severe neutropenia (Grade 4 – neutrophil count <0.5 × 109/l) occurred in 32% of patients in 13% of courses. Median time to onset of severe neutropenia was day 12 with a median duration of 7 days. In 34% of courses with severe neutropenia, the duration was >7 days. In course 1 the incidence was 20%, by course 4 the incidence was 8%. Infection, sepsis and febrile neutropenia occurred in 17%, 2%, and 4% of patients, respectively. Death due to sepsis occurred in 1% of patients. Pancytopenia has been reported. Growth factors were administered to 19% of patients in 8% of courses.
Severe thrombocytopenia (Grade 4 – platelets <10 × 109/l) occurred in 6% of patients in 2% of courses. Median time to onset of severe thrombocytopenia was day 15 with a median duration of 2.5 days. In 18% of courses with severe thrombocytopenia the duration was >7 days. Moderate thrombocytopenia (Grade 3 – platelets between 10.0 and 50.0 × 109/l) occurred in 29% of patients in 14% of courses. Platelet transfusions were given to 10% of patients in 4% of courses. Reports of significant sequelae associated with thrombocytopenia including fatalities due to tumour bleeds have been infrequent.
Moderate to severe anaemia (Grade 3 and 4 – Hb 8.0 g/dl) occurred in 25% of patients (12% of courses). Median time to onset of moderate to severe anaemia was day 12 with a median duration of 7 days. In 46% of courses with moderate to severe anaemia, the duration was >7 days. Red blood cell transfusions were given in 30% of patients (13% of courses). Erythropoietin was administered to 10% of patients in 8% of courses.
The most frequently reported non-haematological effects were nausea (37%), diarrhoea (29%), fatigue (26%), vomiting (24%), alopecia (21%) and anorexia (18%). All cases were irrespective of associated causality. For severe cases (CTC Grade ¾) reported as related/possibly related to topotecan administration the incidence was diarrhoea 5%, fatigue 4%, vomiting 3%, nausea 3% and anorexia 2%.
The overall incidence of drug-related diarrhoea was 22%, including 4% with Grade 3 and 0.4% with Grade 4. Drug-related diarrhoea was more frequent in patients 65 years of age (28%) compared to those less than 65 years of age (19%).
Complete alopecia related/possibly related to topotecan administration was observed in 9% of patients and partial alopecia related/possibly related to topotecan administration in 11% of patients.
Therapeutic interventions associated with non-haematological effects included anti-emetic agents, given to 47% of patients in 38% of courses and anti-diarrhoeal agents, given to 15% of patients in 6% of courses. A 5-HT3 antagonist was administered to 30% of patients in 24% of courses. Loperamide was administered to 13% of patients in 5% of courses. The median time to onset of Grade 2 or worse diarrhoea was 9 days.
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