Topotecan - instructions for use, doses, side effects, contraindications

It inhibits topoisomerase I (an enzyme that reversibly breaks the primary structure of DNA during its replication and is vital for cell growth and proliferation), which leads to disruption in the restoration of the primary DNA structure and cell death. It has a suppressive effect not only on tumoral, but also on other quickly dividing cells.

Pharmacokinetics:

The binding of topotecan with plasma proteins is 35%. Metabolised in the liver. Half-life is 2-3 hours. 20-60% of the dose is excreted in the urine in unchanged form and in the form of metabolites.

Indications:

Small cell lung cancer;
Ovarian cancer;
Recurrent or persistent cervical cancer that does not respond to surgical treatment and / or radiotherapy (stage IVB), as part of a combination therapy with cisplatin.

ICD-10

XXI.Z80-Z99.Z85.1 In a personal history, a malignant neoplasm of the trachea, bronchi, and lung

II.C51-C58.C53 Malignant neoplasm of cervix

II.C51-C58.C56 Malignant neoplasm of ovary

Contraindications:

Neutropenia (less than 1.5 × 109 / L at the beginning of treatment or less than 1 × 109 / L during therapy).

Thrombocytopenia (less than 100 × 109 / l).

Anemia (hemoglobin concentration during treatment is less than 90 g / l).

Severe renal insufficiency (SC less than 20 ml / min).

Pregnancy, breast-feeding.

Carefully:

Hypersensitivity to topotecan, chicken pox or herpes zoster, bacterial and fungal infections, renal dysfunction with creatinine clearance 20-39 ml / min, cytotoxic or radiation therapy in history, oppression of bone marrow hematopoiesis.

Pregnancy and lactation:

In the presence of indications, it is necessary to relate the risk and benefit and take into account the mutagenic and carcinogenic potential of these agents. In view of the potential threat to the fetus for women of childbearing age, topotecan is recommended to use contraceptives. There is no information on the penetration into breast milk. Due to the excretion of other antitumor drugs with milk and the potential risk of unwanted effects on the child (side effects,carcinogenicity, mutagenicity) during topotecan treatment, breast-feeding is recommended to be discontinued.

Recommendations for FDA - category D.

Dosing and Administration:

Topotecan is administered as a 30-minute intravenous infusion.

Side effects:

From the side hematopoiesis system: very often - neutropenia, febrile neutropenia, leukopenia, thrombocytopenia, anemia; often - pancytopenia; rare - severe bleeding due to thrombocytopenia.

From the side respiratory system: rarely - interstitial lung disease.

From the side digestive system: very often - diarrhea, nausea, vomiting (including severe), abdominal pain, constipation, stomatitis, anorexia (including severe); often - hyperbilirubinemia.

From the side skin and skin appendages: very often - alopecia.

Allergic reactions: often - hypersensitivity reactions, including skin rash (including erythematous, maculopapular rash, dermatitis, bullous erythema); rarely - anaphylactoid reactions, angioedema, hives.

Other: very often - an increase in body temperature, increased fatigue, asthenia,joining of secondary infections; often - weakness, sepsis; very rarely - ecchymosis, hemorrhage (poorly expressed and not requiring specific treatment). In very rare cases, extravasation was reported. In the case of extravasation, there may be a hematoma or skin hyperemia at the injection site.

Overdose:

Myelosuppression, including anemia, leukopenia or neutropenia (including febrile neutropenia), thrombocytopenia.

Treatment symptomatic: with severe myelosuppression - blood transfusion, colony-stimulating factors, with febrile neutropenia - empirical antibiotic therapy with a wide spectrum of action followed by correction based on the results of the study of blood cultures, monitoring of vital functions.

Interaction:

Cisplatinum - Increased incidence of unpredictable severe myelosuppression and non-hematological toxicity of III-IV degree (diarrhea, nausea, vomiting, inhibition) with parallel application without increasing the effectiveness of treatment. The safety and efficacy of the combination of cisplatin and topotecan have not been determined.

Filgrastim - it is possible to use to reduce the duration and severity of topotecan-induced neutropenia, but due to the possibility of prolonging the neutropenia period, it should be started with filgrastim treatment no earlier than 24 hours after the last injection of topotecan.

Other immunosuppressants (azathioprine, glucocorticoids, mercaptopurine, muromonab-cD3, tacrolimus, chlorambucil, cyclophosphamide, ciclosporin) - it is possible to increase the risk of infections in parallel application.

Tubular secretion blockers - reduction of renal clearance of topotecan by 50%.

NSAIDs - increased risk of bleeding.

When mixed with ticarcillin or sodium clavulanate - loss of 12.3% activity within 4 hours.

Chemically incompatible with dexamethasone and fluorouracil.

When mixed with mitomycin - Change in color of the solution and loss of 15-20% activity for 4 hours or more (pH of the solution is 3.3-3.5).

Special instructions:

Topotecan is administered only intravenously drip.

To prepare a solution for intravenous administration, 4 ml of sterile water for injection is added to the contents of the vial. The resulting solution has a yellow or yellow-green color and an active substance concentration of 1 mg / ml.The required amount of the drug is diluted in 50-100 ml of a 5% dextrose solution or 0.9% sodium chloride solution to a final concentration of 20-200 μg / ml.

With the development of myelosuppression during treatment with topotecan, the next administration should be postponed until the hemoglobin concentration is restored at least 90 g / l, the amount of neutrophils is more than 1 × 109 / l and the platelet count is more than 100 × 109 / l.

In the development of severe neutropenia (less than 0.5 × 109 / L), which lasts more than 7 days, it is necessary to reduce the dose of topotecan in the subsequent treatment cycle by 0.25 mg / m2 or provide hematological support to colony-stimulating factors (for example, filgrastim, starting after 24 h and more after the last administration of topotecan).

Modification of topotecan dose depending on the severity of renal failure. With moderate insufficiency (CK 40-60 ml / min), a decrease in the dose of topotecan is usually not required (or 1.0 mg / m2 for six or more cycles of myelosuppressive therapy, multiple platelet transfusions in a history or low self-service ability). At CC 20-39 ml / min - 0.75 mg / m2 (or 0.5 mg / m2 for six or more cycles of myelosuppressive therapy, multiple transfusions of platelets in history, or low self-service ability).

Instructions

Topotecan (Topotecanum)