Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland
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.
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).
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.
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.
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 (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.
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.
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 (see section 4.4).
2 Neutropenic colitis, including fatal neutropenic colitis, has been reported to occur as a complication of topotecan-induced neutropenia (see section 4.4).
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 (see section 4.4).
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 (see section 4.4).
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.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
None known.
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