GIKAMTIN
Active material: Topotecan
When ATH: L01XX17
CCF: Anticancer drug
ICD-10 codes (testimony): C34, C53, C56
When CSF: 22.03.01.02
Manufacturer: GlaxoSmithKline Trading Company (Russia)
PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING
Valium for solution for infusion in the form of a porous mass of light yellow to greenish-yellow in color.
| 1 fl. | |
| topotecan (the hydrochloride) | 4 mg |
Excipients: tartaric acid, mannitol, hydrochloric acid, Sodium hydroxide.
Bottles glass volume 17 ml (1) – packs cardboard.
Bottles glass volume 17 ml (5) – trays, plastic (1) – packs cardboard.
Pharmacological action
Anticancer drug, topoisomerase I inhibitor. topoisomerase I – enzyme, directly involved in DNA replication. Topotecan stabilizes the covalent complex of enzyme and DNA spiral rasschepennoy, which is an intermediate of the catalytic mechanism.
Inhibition of topoisomerase I leads to rupture of single-stranded DNA and stop DNA replication.
Pharmacokinetics
Distribution
The on / in adults topotecan administered at doses 0.5-1.5 mg / m2 as a 30-minute infusion daily for 5 Days AUC increased proportionally to the dose.
Binding to plasma proteins pentahydrate – 35%. Distribution between blood cells and plasma uniform. Vd is about 132 l.
Metabolism
It is metabolized in the liver. The main route of metabolism pentahydrate is pH-dependent hydrolysis of the lactone ring, wherein the phenol is formed with an open ring.
Topotecan does not inhibit CYP1A2 isoenzymes, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A, CYP4A, and did not inhibit cytosolic enzymes or xanthine oxidase digidropirimidinoksidazu.
Deduction
The on / in adults topotecan administered at doses 0.5-1.5 mg / m2 as a 30-minute infusion daily for 5 days of clearance of topotecan – 64 l /, that is approximately 2/3 hepatic blood flow. T1/2 is 2-3 no. 20-60% dose was excreted in the urine in unchanged form and as metabolites.
Pharmacokinetics in special clinical situations
In patients with renal insufficiency (CC 41-60 ml / min) plasma clearance is reduced by 67%. Vd somewhat reduced and, thus, T1/2 increases only 14%. In patients with moderate renal impairment topotecan plasma clearance is reduced to 34%. Vd reduced by about 25%, which leads to the increase of the average T1/2 from 1.9 h to 4.9 no.
In patients with hepatic impairment the plasma clearance of topotecan lactone is reduced to 67%, and the total plasma clearance – on 10% compared with the control group. T1/2 topotecan increases by approximately 30%, wherein significant changes Vd not observed.
In appointing Gikamtina® in combination with tsisplatinom (Cisplatin in 1 day, topotecan in the 1 st and 5 th day) topotecan clearance is decreased on the 5th day compared to first day (19.1 l / h / m2 compared with 21.3 l / h / m2).
Testimony
- small cell lung cancer;
- ovarian cancer;
- recurrent or persistent cervical cancer, is not amenable to surgery and / or radiation therapy (Stage IV B), in a combination therapy with cisplatin.
Dosage regimen
Gikamtin® administered as a 30 minute i / v infusion.
Adults and elderly patients
Before the appointment of the first course of therapy Gikamtinom® neutrophil count should be >1500/l, Platelet >100 000/l, hemoglobin level >9 g / dl.
At small cell lung cancer and ovarian cancer appoint 1.5 mg / m2 body surface area daily for 5 consecutive days at intervals of 3 of the week.
it is recommended to spend at least to achieve the effect 4 therapy course (median time of onset of effect in patients with ovarian cancer is 8-11.7 of the week, in patients with small cell lung cancer – 6.1 of the week. Approximately 18% patients with ovarian cancer effect was achieved after 5 or more courses of therapy).
Repeated courses of therapy Gikamtinom® It can be carried out only under the following terms: Neutrophils >1000/l, platelets >100 000/l, hemoglobin > 9 g / dl (incl. after blood transfusion, if necessary).
In severe neutropenia (the number of neutrophils <500/l) during 7 days or more, or febrile neutropenia, or in the case of treatment delay because of neutropenia, should reduce the dose of the drug to 1.25 mg / m2/day or as necessary to 1 mg / m2/day or the following courses are held with the purpose of prophylactic administration of granulocyte colony-stimulating factor (G-CSF), starting from the 6th day of treatment (no earlier than 24 hours after treatment topotecan). If neutropenia on the background of G-CSF is stored, the dose should be reduced.
By reducing platelet count during the previous course of chemotherapy <25 000/l dose should be reduced in a similar manner.
If required dose reduction below in connection with the side effects 1 mg / m2, topotecan therapy should be discontinued.
At cervical cancer recommended dose Gikamtina® is 0.75 mg / m2 in 1-St, 2-Her and her 3-days. In the 1 st day of therapy prior to administration Gikamtina® infusion is carried cisplatin 50 mg / m2. This pattern is repeated every 21 day, Total 6 rates. If signs of disease progression Gikamtin® should be abolished.
Repeated courses of therapy Gikamtinom® It can be carried out only under the following terms: Neutrophils >1000/l, platelets >100 000/l, hemoglobin >9 g / dl (incl. after blood transfusion, if necessary).
If febrile neutropenia (increase in body temperature to 38 ° C and above in an amount of neutrophils <1000/l) for subsequent courses is recommended to reduce the dose Gikamtina® on 20% to 0.6 mg / m2.
By reducing the number of platelets <10 000/l dose should be reduced in a similar manner.
Alternatively, the dose reduction with febrile neutropenia, patients are advised administration of granulocyte colony stimulating factor (G-CSF) at the end of each subsequent year (before resorting to dose reduction), starting from the 4th day of treatment (no earlier than 24 hours after treatment Gikamtinom®). If febrile neutropenia in the background of G-CSF is stored, the dose for subsequent courses should be reduced by 20% to 0.45 mg / m2.
At monotherapy to Patients with CC > 40 ml / min correction dosing regime is not required. The recommended dose for of patients with CC 20 to 39 ml / min is 0.75 mg / m2/d. Recommendations on dosing regime at patients with a reduction in QC < 20 ml / min no.
At combination therapy Gikamtinom® with cisplatin for treatment of cervical cancer to begin therapy is only recommended for patients, whose creatinine concentration in plasma does not exceed 1.5 mg / dL. If during treatment with the creatinine level in plasma exceeds 1.5 mg / dL, should implement the recommendations on the use of cisplatin instructions on how to decrease the dose / cancellation. In the event of cancellation of cisplatin have sufficient data, concerning the continuation Gikamtinom monotherapy® in patients with cervical cancer.
To patients with impaired liver function (bilirubin from 1.5 to 10 mg / dL) dose adjustment is required.
Using Gikamtina® treatment children not recommended, tk. existing experience with the drug in this category of patients is not enough.
Terms of preparation of the solution
The contents of the bottle should dissolve in 4 ml of sterile water for injection to a concentration of 1 mg / ml. The resulting solution must be diluted 0.9% solution of sodium chloride or 5% dextrose to a concentration of 25-50 ug / ml.
Side effect
Long-term use did not cause an increase in toxicity of the drug. Serious manifestations of cardiotoxicity, neurotoxicity, organ toxicity was observed.
The incidence of adverse events was classified as follows:: Often (≥1/10), often (≥1/100, <1/10), sometimes (≥1/1000, <1/100), rarely (≥1/10 000, <1/1000), rarely (<1/10 000, including individual cases).
From the hematopoietic system: Often – neutropenia, febrile neutropenia, leukopenia, thrombocytopenia, anemia; often – pancytopenia; rarely – expressed bleeding, due to thrombocytopenia.
From the digestive system: Often – diarrhea, nausea, vomiting (incl. severe), pain in the abdominal area, constipation, stomatitis, anorexia (including severe); often – giperʙiliruʙinemija.
Dermatological reactions: Often – alopecia.
Other: Often – fever, fatigue, asthenia, the accession of secondary infections; often – weakness, sepsis; rarely – ecchymosis, hemorrhage (mild and did not require specific treatment).
Contraindications
- pronounced suppression of bone marrow function (neutrophil count less than 1,500 / mm, Platelet - less 100 000/l);
- Pregnancy;
- Lactation (breast-feeding);
- Children's age (lack of experience);
- hypersensitivity to topotecan or other components, part of the drug.
Pregnancy and lactation
The drug is contraindicated during pregnancy and lactation (breast-feeding).
Women of childbearing age and men while taking Gikamtina® must use reliable methods of contraception.
Cautions
topotecan treatment should be supervised by a specialist, with experience in anti-cancer drugs.
Not recommended for topotecan monotherapy as a first-line therapy.
Hematological toxicity of topotecan depends on the dose, you should regularly conduct detailed analyzes of blood from the hemoglobin level, gematokrita, counting the number of leukocytes, neutrophils and platelets.
With the combination of topotecan with other cytotoxic drugs need to adjust the dose.
If severe neutropenia should be carefully monitored for timely diagnosis of infectious complications.
In the event of severe thrombocytopenia should be very careful when performing invasive procedures, Regular inspection of the skin and mucous membranes, as well as the discharge (for signs of bleeding).
When working with the preparation necessary to comply with the general rules for handling cytotoxic drugs. In case of accidental contact with the drug on the skin or eyes should be washed with plenty of water.
Effects on ability to drive vehicles and management mechanisms
Some of the undesirable effects of the drug, such as fatigue and weakness, may adversely affect the ability to concentration of attention and quickness of psychomotor reactions.
It should take into account the overall clinical condition of the patient and the possible development of adverse events when assessing the ability to control the car and work with mechanisms, requiring responsiveness.
Overdose
Symptoms: suppression of bone marrow function, stomatitis.
Treatment: antidote topotecan unknown. Spend cimptomaticheskuyu therapy.
Drug Interactions
With simultaneous application Gikamtina® with other cytotoxic agents (eg, paklitakselom or эtopozidom) may increase myelosuppression (Dosage adjustment of topotecan).
Character pentahydrate interaction with platinum drugs depends on platinum destination sequence, namely, designate whether platinum drugs in the 1st or the 5th day of administration of topotecan. If platinum drugs administered in 1 day, It should be used lower doses of each drug compared with doses in the appointment of platinum drugs in the 5 th day.
Below dose and regimen of topotecan and platinum drugs:
- Cisplatin in 1-day dose 50 mg / m2 and topotecan in doze 0.75 mg / m2 from 1 st to 5 th day.
- cisplatin and 5-day dose 50 mg / m2 and topotecan in doze 1.25 mg / m2 from 1 st to 5 th day.
- carboplatin in 1 day: AUC 5 (Calvert formula); topotecan in doze 0.5 mg / m2 from 1 st to 5 th day.
- carboplatin in 5th day: AUC 5 (clearance 51Cr-EDTA); topotecan in doze 1.0 mg / m2 from 1 st to 5 th day.
Gikamtin® does not inhibit cytochrome P450 isozymes. The combined use of ondansetron, granisetronom, morphine or corticosteroids did not significantly influence the pharmacokinetic parameters of topotecan.
Conditions of supply of pharmacies
The drug is released under the prescription.
Conditions and terms
A List. The drug should be stored out of reach of children, dark place at temperatures not above 30 ° C. Shelf life – 3 year.
The prepared solution should be stored at temperatures from 5 ° to 30 ° C is not more 24 no.
