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.
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 with severely impaired hepatic function (serum bilirubin 10 mg/dl). Use of topotecan in these patients is not recommended (see section 4.2).
Diarrhoea, including severe diarrhoea requiring hospitalisation, has been reported during treatment with oral topotecan. Diarrhoea related to oral topotecan can occur at the same time as drug-related neutropenia and its sequelae. Communication with patients prior to drug administration regarding these side effects and proactive management of early and all signs and symptoms of diarrhoea is important. Cancer treatment-induced diarrhoea (CTID) is associated with significant morbidity and may be life-threatening. Should diarrhoea occur during treatment with oral topotecan, physicians are advised to aggressively manage diarrhoea. Clinical guidelines describing the aggressive management of CTID include specific recommendations on patient communication and awareness, recognition of early warning signs, use of anti-diarrhoeals and antibiotics, changes in fluid intake and diet, and need for hospitalisation (see sections 4.2 and 4.8).
Intravenous topotecan should be considered in the following clinical situations: uncontrolled emesis, swallowing disorders, uncontrolled diarrhoea, clinical conditions and medication that may alter gastrointestinal motility and drug absorption.
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.
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 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 (see sections 4.2 and 4.4)
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 (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)
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).
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% (see section 4.4), 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.
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.
Not applicable.
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