Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland
Topotecan monotherapy is indicated for the treatment of:
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).
The use of topotecan should be confined to units specialised in the administration of cytotoxic chemotherapy. Topotecan should only be administered under the supervision of a physician experienced in the use of chemotherapy (see section 6.6).
When topotecan is used in combination with cisplatin, the full prescribing information for cisplatin should be consulted.
Prior to administration of the first course of topotecan, patients must have a baseline neutrophil count of ≥1.5 × 109/l, a platelet count of ≥100 × 109/l and a haemoglobin level of ≥9 g/dl (after transfusion if necessary).
The recommended dose of topotecan is 1.5 mg/m² body surface area per day administered by intravenous infusion over 30 minutes daily for five consecutive days with a three-week interval between the start of each course. If well tolerated, treatment may continue until disease progression (see sections 4.8 and 5.1).
Topotecan should not be re-administered unless the neutrophil count is ≥1 × 109/l, the platelet count is ≥100 × 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 medicinal products (e.g. G-CSF) or to reduce the dose to maintain neutrophil counts.
If dose reduction is chosen for patients who experience severe neutropenia (neutrophil count <0.5 × 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 0.25 mg/m²/day to 1.25 mg/m²/day (or subsequently down to 1.0 mg/m²/day if necessary).
Doses should be similarly reduced if the platelet count falls below 25 × 109/l. In clinical studies, topotecan was discontinued if the dose had been reduced to 1.0 mg/m²/day and a further dose reduction was required to manage adverse effects.
The recommended dose of topotecan is 0.75 mg/m²/day administered as a 30-minute intravenous infusion on days 1, 2 and 3. Cisplatin is administered as an intravenous infusion on day 1 at a dose of 50 mg/m²/day and following the topotecan dose. This treatment schedule is repeated every 21 days for six courses or until progressive disease.
Topotecan should not be re-administered unless the neutrophil count is ≥1.5 × 109/l, the platelet count is ≥100 × 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 medicinal products (e.g. G-CSF) or to reduce the dose to maintain neutrophil counts.
If dose reduction is chosen for patients who experience severe neutropenia (neutrophil count <0.5 × 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 20% to 0.60 mg/m² /day for subsequent courses (or subsequently down to 0.45 mg/m²/day if necessary).
Doses should be similarly reduced if the platelet count falls below 25 × 109/l.
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 (see section 4.4).
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.
Combination therapy (cervical carcinoma): In clinical studies with topotecan in combination with cisplatin for the treatment of cervical cancer, therapy was only initiated in patients with serum creatinine less than or equal to 1.5 mg/dl. If, during topotecan/cisplatin combination therapy, serum creatinine exceeds 1.5 mg/dl, it is recommended that the full prescribing information be consulted for any advice on cisplatin dose reduction/continuation. If cisplatin is discontinued, there are insufficient data regarding continuing monotherapy with topotecan in patients with cervical cancer.
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 4.4).
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 (see section 4.4).
Currently available data are described in sections 5.1 and 5.2 but no recommendation on a posology can be made.
Topotecan must be reconstituted and further diluted before use (see section 6.6).
Overdoses have been reported in patients being treated with intravenous topotecan (up to 10 fold of the recommended dose) and topotecan capsules (up to 5 fold of the recommended dose). The signs and symptoms observed following overdose were consistent with the known undesirable events associated with topotecan (see section 4.8). The primary complications of overdose are bone marrow suppression and mucositis. In addition, elevated hepatic enzymes have been reported with intravenous topotecan overdose.
There is no known antidote for topotecan overdose. Further management should be as clinically indicated or as recommended by the national poisons centre, where available.
Vials: 3 years.
Reconstituted and diluted solutions: The product should be used immediately after reconstitution as it contains no antibacterial preservative. If reconstitution and dilution is performed under strict aseptic conditions (e.g. an LAF bench) the product should be used (infusion completed) within 12 hours at room temperature or 24 hours if stored at 2-8°C after the first puncture of the vial.
Keep the vial in the outer carton in order to protect from light.
For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.
HYCAMTIN 1 mg powder for concentrate for solution for infusion:
Type I flint glass vial with grey butyl rubber stopper and aluminium seal with plastic flip-off cap containing 1 mg of topotecan.
HYCAMTIN 1 mg is available in packs containing 1 vial and 5 vials.
HYCAMTIN 4 mg powder for concentrate for solution for infusion:
Type I flint glass vial, with grey butyl rubber stopper and aluminium seal with plastic flip-off cap containing 4 mg of topotecan.
HYCAMTIN 4 mg is available in packs containing 1 vial and 5 vials.
Not all pack sizes may be marketed.
The contents of HYCAMTIN 1 mg vials must be reconstituted with 1.1 ml water for injections. Since the vial contains a 10% overage, the clear, reconstituted solution is yellow to yellow-green in colour and provides 1 mg of topotecan per ml. Further dilution of the appropriate volume of the reconstituted solution with either sodium chloride 9 mg/ml (0.9%) or 5% w/v glucose is required to give a final concentration of between 25 and 50 microgram/ml.
The contents of HYCAMTIN 4 mg vials must be reconstituted with 4 ml water for injections. The clear, reconstituted solution is yellow to yellow-green in colour and provides 1 mg of topotecan per ml. Further dilution of the appropriate volume of the reconstituted solution with either sodium chloride 9 mg/ml (0.9%) or 5% w/v glucose is required to a final concentration of between 25 and 50 microgram/ml.
The normal procedures for proper handling and disposal of anticancer medicinal products should be adopted, namely:
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