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10 X 0.25 mg
10 X 1 mg
Method of administration: HYCAMTIN capsules should only be prescribed and therapy supervised by a physician experienced in the use of chemotherapeutic agents.
Initial dose: The recommended dose of HYCAMTIN capsules is 2.3 mg/m² body surface area/day administered for five consecutive days with a three week interval between the start of each course. If well tolerated, treatment may continue until disease progression.
The capsule(s) must be swallowed whole, and must not be chewed crushed or divided. Hycamtin capsules may be taken with or without food.
Prior to administration of the first course of topotecan, patients must have a baseline neutrophil count of ≥ 1.5 x 109/l, a platelet count of ≥ 100 x 109/l and a haemoglobin level of ≥ 9 g/dl (after transfusion if necessary).
Subsequent doses: Topotecan should not be re-administered unless the neutrophil count is ≥ 1 x 109/l, the platelet count is ≥ 100 x 109/l, and the haemoglobin level is ≥ 9 g/dl (after transfusion if necessary). Standard oncology practice for the management of neutropenia is either to administer topotecan with other medications (e.g. G-CSF) or to dose reduce to maintain neutrophil counts. If dose reduction is chosen for patients who experience severe neutropenia (neutrophil count < 0.5 x 109/l) for seven days or more, or severe neutropenia associated with fever or infection, or who have had treatment delayed due to neutropenia, the dose should be reduced by 0.4 mg/m²/day to 1.9 mg/m²/day (or subsequently down to 1.5 mg/m²/day if necessary). Doses should be similarly reduced if the platelet count falls below 25 x 109/l. In clinical trials, topotecan was discontinued if the dose needed to be reduced below 1.5 mg/m². For patients who experience Grade 3 or 4 diarrhoea, the dose should be reduced by 0.4 mg/m²/day for subsequent courses. Patients with Grade 2 diarrhoea may need to follow the same dose modification guidelines. Proactive management of diarrhoea with anti-diarrhoeal agents is important. Severe cases of diarrhoea may require administration of oral or intravenous electrolytes and fluids, and interruption of topotecan therapy.
Dosage in renally impaired patients: The recommended monotherapy dose of oral topotecan in patients with small cell lung carcinoma with a creatinine clearance between 30 and 49 ml/min is 1.9 mg/m²/day for five consecutive days. If well tolerated, the dose may be increased to 2.3 mg/m²/day in subsequent cycles. Limited data in Korean patients with creatinine clearance less than 50 ml/min suggest a further lowering of dose may be required. Insufficient data are available to make a recommendation for patients with a creatinine clearance < 30 ml/min.
Dosage in hepatically impaired patients: Pharmacokinetics capsules have not been specifically studied in patients with impaired hepatic function. There are insufficient data available with HYCAMTIN capsules to make a dose recommendation for this patient group.
Paediatric population: The experience in children is limited, therefore no recommendation for treatment of paediatric patients with HYCAMTIN can be given.
Older people: No overall differences in effectiveness were observed between patients over 65 years and younger adult patients. However in the two studies administering both oral and intravenous topotecan, patients older than 65 years old receiving oral topotecan experienced an increase in drug related diarrhoea compared to those younger than 65 years of age.
For full details see prescribing information.
Treatment of patients with relapsed small cell lung cancer (SCLC) for whom re-treatment with the first-line regimen is not considered appropriate.
History of severe hypersensitivity reactions to topotecan and excipients. Pregnancy and lactation. Severe bone marrow depression prior to starting first course, as evidenced by baseline neutrophils less than 1.5 x 109/L, and/or platelet count of less than 100 x 109/L.
Haematological toxicity is dose-related and full blood count including platelets should be monitored 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 trials 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. Underlying risk factors include history of ILD, pulmonary fibrosis, lung cancer, thoracic exposure to radiation and use of pneumotoxic drugs 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. in case patients at increased risk of tumour bleeds are considered for therapy. As 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. Accurate assessment of performance status at the time therapy is given is important, to ensure that patients have not deteriorated to performance status 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. Topotecan is not recommended to be used in these patients.
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 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). Topotecan is not recommended to be used in these patients.
Diarrhoea, including severe diarrhoea requiring hospitalization, 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 includes 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 hospitalization. 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. For full details see prescribing information.
Very common: Infection, anemia, febrile neutropenia, leucopenia, neutropenia, thrombocytopenia, anorexia (may be severe), diarrhea, nausea and vomiting (may be severe), alopecia, fatigue.
Common: Sepsis, pancytopenia, hypersensitivity, including rash, abdominal pain, constipation, stomatitis, asthenia, pyrexia, malaise.
For full details see prescribing information.
No in vivo human pharmacokinetic interaction studies have been performed.
Topotecan does not inhibit human P450 enzymes. In an intravenous population study, 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 drug known to inhibit ABCB1 or ABCG2. In combining topotecan with other chemotherapy agents, reduction of the doses of each medicinal product may be required to improve tolerability. However, in 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 was generally unchanged when coadministered with ranitidine.
For full details see prescribing information.
Pregnancy and Lactation
Women of childbearing potential and Pregnancy: 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 and to inform the treating physician immediately should this occur.
Breastfeeding: Topotecan is contra-indicated 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.
There is no known antidote for topotecan overdose. Overdoses have been reported in patients being treated with topotecan capsules (up to 5 fold of the recommended dose) and intravenous topotecan (up to 10 fold of the recommended dose). The observed signs and symptoms for overdose were consistent with the known undesirable events associated with topotecan. The primary complications of overdose are anticipated to be bone marrow suppression and mucositis. In addition, elevated hepatic enzymes have been reported with intravenous topotecan overdose.
Storage: Store in a refrigerator (2ºC – 8ºC). Keep the blister card in the outer carton in order to protect from light. Do not freeze.