Topotecan

Topotecan has the same mechanism of action as irinotecan and is believed to exert its cytotoxic effects during the S-phase of DNA synthesis. Topoisomerase I relieves torsional strain in DNA by inducing reversible single strand breaks. Topotecan binds to the topoisomerase I-DNA complex and prevents religation of these single strand breaks. This ternary complex interferes with the moving replication fork, which leads to the induction of replication arrest and lethal double-stranded breaks in DNA. As mammalian cells cannot efficiently repair these double strand breaks, the formation of this ternary complex eventually leads to apoptosis (programmed cell death).

Topotecan mimics a DNA base pair and binds at the site of DNA cleavage by intercalating between the upstream (-1) and downstream (+1) base pairs. Intercalation displaces the downstream DNA, thus preventing religation of the cleaved strand. By specifically binding to the enzyme–substrate complex, Topotecan acts as an uncompetitive inhibitor.

Verify dose using body surface area prior to dispensing. Recommended dosage should generally not exceed 4 mg intravenously 

Ovarian Cancer: The recommended dose of Topotecan is 1.5 mg/m² by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on Day 1 of a 21-day course.

Small Cell Lung Cancer: The recommended dose of Topotecan is 1.5 mg/m² by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on Day 1 of a 21-day course.

Cervical Cancer: The recommended dose of Topotecan is 0.75 mg/m² by intravenous infusion over 30 minutes daily on Days 1, 2, and 3 in combination with cisplatin 50 mg/m² on Day 1, repeated every 21 days.

Increased clearance with phenytoin. G-CGF to be given 24 hr after completion of treatment with topotecan as concurrent admin may prolong duration of neutropenia. Increased bone marrow supression with other cytotoxic drugs (e.g. cisplatin) so dose reduction may be needed.

Severe bone marrow depression (e.g. baseline neutrophil count of <1500 cells/mm³ and platelet count <100,000/mm³). Pregnancy, lactation, severe renal or hepatic impairment.

Neutropenia (nadir of white cell count occurs about 9-12 days after admin), thrombocytopenia and anaemia. GI upset, total alopecia, headache, dyspnoea. Fatigue, weakness, malaise, pruritus and hyperbilirubinaemia.

Pregnancy category D. There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Preexisting bone marrow depression. Frequent monitoring of peripheral blood cell counts during treatment. Do not continue subsequent courses until neutrophils recover to >1000 cells/mm³, platelets recover to >100,000 cells/mm³ and haemoglobin levels recover to 9.0 g/dl (with transfusion if needed). May impair ability to drive or operate machinery.

Renal Impairment:

• Ovarian carcinoma, Small cell lung cancer: CrCl 20-30: Initial dose 0.75 mg/m².
• Cervical cancer: Treatment to be initiated only if serum creatinine ≤1.5 mg/dl.

Hepatic Impairment: Avoid

Symptoms: Bone marrow supression.

Cytotoxic Chemotherapy

Add 4 ml of sterile water for inj to the vial containing 4 mg of topotecan in order to obtain a solution with 1 mg/ml of topotecan. The required daily dose is further diluted in a suitable volume (e.g. 50-250 ml) of 5% dextrose or 0.9% sodium chloride inj and infused IV over a period of 30 min. Solution should be prepared immediately before use.

Unopened vial: Store at 20-25°C; protect from light. Reconstituted solution: Stable for 24 hr at 20-25°C in ambient light.