HYCAMTIN IV 4MG INJECTION

Indications

• Relapsed small-cell lung cancer
• Metastatic ovarian cancer
• Recurrent cervical cancer after radiotherapy

Dosage

Children: Refer to the BNF for Children for specific dosing guidelines in pediatric patients, as dosing may vary based on age, weight, and specific indications.

Adults: The typical dosing for adults involves intravenous infusion of Topotecan, often starting at 1.5 mg/m²/day for 5 consecutive days, repeated every 21 days, depending on the treatment protocol and clinical scenario.

Mechanism of action

Topotecan exerts its cytotoxic effects during the S-phase of DNA synthesis by binding to the topoisomerase I-DNA complex and preventing the religation of reversible single-strand breaks. This leads to replication arrest and the formation of lethal double-stranded breaks in DNA, which are not efficiently repaired by mammalian cells, ultimately resulting in apoptosis.

Pharmacodynamics

Topotecan is an anti-tumor drug with topoisomerase I-inhibitory activity. It disrupts the normal functioning of DNA topoisomerases, which are critical for DNA replication and repair. By creating a ternary complex with topoisomerase I and DNA, Topotecan inhibits the re-ligation of DNA strands, thereby interfering with cell replication and leading to cell death, particularly in rapidly dividing cancer cells.

Pharmacokinetics

Topotecan is administered intravenously or orally, with bioavailability affected by the route of administration. It exhibits linear pharmacokinetics, with plasma protein binding primarily to albumin. The drug is metabolized in the liver, and its elimination half-life is approximately 3 hours. Excretion occurs primarily through the urine, with a fraction of the drug appearing as metabolites.

Contra-indications

• Hypersensitivity to topotecan or any component of the formulation
• Severe bone marrow depression

Adverse effects

• Alopecia
• Anaemia
• Appetite loss
• Asthenia
• Colitis
• Constipation
• Diarrhoea
• Febrile neutropenia
• Gastrointestinal discomfort
• Hyperbilirubinaemia
• Leucopenia
• Malaise
• Mucositis
• Nausea
• Neutropenia
• Pancytopenia
• Sepsis
• Skin reactions
• Thrombocytopenia
• Angioedema
• Interstitial lung disease

Interactions

• Darolutamide (severe - increases exposure)
• Voxilaprevir (severe - increases concentration)
• Berotralstat (moderate - increases concentration)
• Eliglustat (moderate - increases exposure)
• Roxadustat (moderate - increases exposure)
• Sotorasib (moderate - increases exposure)
• Tucatinib (moderate - increases exposure)
• Isavuconazole (unknown - increases exposure)
• Verapamil (unknown - increases exposure)
• Ceritinib (unknown - increases exposure)

Precautions

• Monitor blood counts regularly due to risk of bone marrow suppression
• Use caution in patients with impaired liver function
• Avoid in pregnancy unless the benefits outweigh the risks
• Patients should be advised of potential side effects including gastrointestinal effects

Pregnancy

Topotecan is not recommended during pregnancy due to potential harm to the fetus. Use only if the benefit justifies the risk.

Breast-feeding

It is not known whether topotecan is excreted in human milk. Caution is advised; breastfeeding should be discontinued during treatment.

Storage

Store in a refrigerator (2-8°C). Protect from light. Do not freeze.

Formulations

• Topotecan (as Topotecan hydrochloride) 1 mg powder for concentrate for solution for infusion vials

Mechanism of action

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. 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. The cytotoxicity of topotecan is thought to be due to double-strand DNA damage produced during DNA synthesis, when replication enzymes interact with the ternary complex formed by topotecan, topoisomerase I, and DNA. Mammalian cells cannot efficiently repair these double strand breaks.

Pharmacodynamics

Topotecan, a semi-synthetic derivative of camptothecin (a plant alkaloid obtained from the <i>Camptotheca acuminata</i> tree), is an anti-tumor drug with topoisomerase I-inhibitory activity similar to irinotecan. DNA topoisomerases are enzymes in the cell nucleus that regulate DNA topology (3-dimensional conformation) and facilitate nuclear processes such as DNA replication, recombination, and repair. During these processes, DNA topoisomerase I creates reversible single-stranded breaks in double-stranded DNA, allowing intact single DNA strands to pass through the break and relieve the topologic constraints inherent in supercoiled DNA. The 3'-DNA terminus of the broken DNA strand binds covalently with the topoisomerase enzyme to form a catalytic intermediate called a cleavable complex. After DNA is sufficiently relaxed and the strand passage reaction is complete, DNA topoisomerase reattaches the broken DNA strands to form the unaltered topoisomers that allow transcription to proceed. Topotecan interferes with the growth of cancer cells, which are eventually destroyed. Since the growth of normal cells can be affected by the medicine, other effects may also occur. Unlike irinotecan, topotecan is found predominantly in the inactive carboxylate form at neutral pH and it is not a prodrug.