Verotecan (Verotekan)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceTopotecanTopotecan
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  • Verotecan
    lyophilizate d / infusion 
    VEROPHARM SA     Russia
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    lyophilizate d / infusion 
    VEROPHARM SA     Russia
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    lyophilizate d / infusion 
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  • Topotecan-Aktavis
    lyophilizate d / infusion 
    Actavis PTS ehf Group     Iceland
    • Dosage form: & nbsplyophilizate for solution for infusion
    Composition:

    1 bottle contains:

    active substance: topotecan hydrochloride in terms of topotecan -1 mg; Excipients: tartaric acid 5.0 mg, mannitol (mannitol) 48.0 mg,

    * sodium hydroxide 0.1 M or 1 M solution or * hydrochloric acid 0.1 M or

    1 M solution.

    * If necessary, to adjust the pH of the drug solution in the process.

    Description:The porous mass is from light yellow to greenish-yellow.
    Pharmacotherapeutic group:Antitumor agent - alkaloid
    ATX: & nbsp

    L.01.X.X   Other antineoplastic agents

    L.01.X.X.17   Topotecan

    Pharmacodynamics:
    The antitumor effect of topotecan is due to the inhibition of topoisomerase I, an enzyme that directly participates in DNA replication. Topotecan stabilizes the covalent complex of the enzyme and spiral-cleaved DNA, which is an intermediate link of the catalytic mechanism. Inhibition of topoisomerase I results in the rupture of single-stranded DNA and the stopping of DNA replication.
    Pharmacokinetics:

    With intravenous administration of topotecan to adults at a dose of 0.5-1.5 mg / m2 in the form of a 30-minute daily infusion over 5 days, the area under the concentration-time curve (AUC) increases in proportion to the increase in dose. Binding to plasma proteins is 35%. Volume of distribution (Vd) is about 132 liters.

    Metabolised in the liver. The main way of topotecan metabolism is the pH-dependent hydrolysis of the lactone ring, in which a carbolic acid with an open ring is formed. Topotecan does not inhibit isoenzymes CYP1A2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A or CYP4A, included in the cytochrome system R450, as well as cytosolic enzymes dihydropyrimidine oxidase or xanthine oxidase. Plasma clearance - 64 l / h. Half-life (T1/2) 2-3 hours 20-60% of the administered dose is excreted by the kidneys in unchanged form or in the form of metabolites.

    Topotecan plasma clearance in patients with renal insufficiency (creatinine clearance (CK) 41-60 ml / min) decreases by approximately 67%. Vd also decreases somewhat and, thus, T1/2 increases by only 14%. In patients with moderate renal failure, plasma clearance of topotecan is reduced by 34%. Vd decreases by 25%, which leads to an increase in T1/2 from 1.9 hours to 4.9 hours. Plasma topotecan clearance in patients with hepatic insufficiency decreases to 67%, T1/2 increases by about 30%, with significant changes in the Vd not visible.

    When administering topotecan in combination with cisplatin (cisplatin in the first day, topotecan in the 1st and 5th day) the clearance of topotecan decreases on the 5th day in comparison with the 1st day (19.1 L / h / m2 compared with 21.3 l / h / m2).

    Indications:
    - Small cell lung cancer.
    - Cancer of the ovary.
    - 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.
    Contraindications:
    - Hypersensitivity to topotecan or components of the drug.
    - The expressed inhibition of bone marrow function (the number of neutrophils is less than 1500 / μl, platelets - less than 100,000 / μl).
    - Anemia (hemoglobin below 9 g / dL).
    - Pregnancy and lactation.
    - Childhood (lack of sufficient experience).
    Pregnancy and lactation:Verotecan is contraindicated in pregnancy and during breastfeeding. During the period of treatment it is recommended to stop breastfeeding.
    Dosing and Administration:

    Intravenously in the form of a 30-minute infusion.

    Before the first course of topotecan therapy, the number of neutrophils should be≥1500 / mkl, platelets - ≥100000 / mkl, and hemoglobin - ≥9 g / dl.

    Small cell lung cancer. Ovarian cancer.

    At 1.5 mg / m2 daily for 5 consecutive days with an interval of 3 weeks. To achieve the effect, it is recommended to conduct a minimum of 4 courses of therapy (the average time of onset of the effect in patients with ovarian cancer is 8-11.7 weeks, in patients with small cell lung cancer, -6.1 weeks.) Approximately in 18% of patients with ovarian cancer the effect is achieved after 5 and more courses of therapy).

    Repeated courses of topotecan therapy can be carried out only with the following indices: the number of neutrophils ≥1000 / μL, platelets - ≥100000 / mkl, and hemoglobin - ≥9 g / dl (including after a blood transfusion, if necessary). For severe neutropenia (neutrophil count less than 500 / μl) for 7 days or more, or febrile neutropenia, or in the event of delayed treatment due to neutropenia, it should be:

    - reduce the dose of the drug to 1.25 mg / m2 per day or, if necessary, up to 1.0 mg / m2 in a day.

    or

    - subsequent courses should be conducted with the appointment of preventive introduction of granulocyte colony-stimulating factor (G-CSF) starting from the 6th day of treatment (not earlier than 24 hours after the end of topotecan therapy).If neutropenia against the background of G-CSF persists, the dose of topotecan should be reduced.

    If the number of platelets decreases with the previous course of chemotherapy less than 25,000 / μl, the dose of topotecan should be reduced in a similar way.

    If, in connection with side effects, a dose reduction of the drug is required below 1.0 mg / m2, topotecan therapy should be discontinued.

    Cervical cancer

    The recommended dose of topotecan is 0.75 mg / m in the 1 st, 2 nd and 3 rd days. On the first day of therapy, before administration of topotecan, an infusion of cisplatin in a dose of 50 mg / m2. This scheme is repeated every 21 days, only 6 courses. When there are signs of disease progression topotecan should be canceled.

    Repeated courses of topotecan therapy can be carried out only with the following indices: the number of neutrophils >1500 / mkl, platelets - ≥100,000 / μL ,. and hemoglobin -≥9 g / dl (including after a blood transfusion, if necessary). For febrile neutropenia (increase in body temperature to 38 ° C and higher with neutrophil counts less than 1000 / μl), it is recommended to lower the dose of topotecan by 20% to 0.6 mg / m for subsequent courses2.

    If the number of platelets is less than 10,000 / μl, the dose of topotecan should be reduced in a similar way.

    As an alternative to decreasing the dose of topotecan in febrile neutropenia, the administration of G-CSF at the end of each subsequent course (before resorting to a decrease in the dose of topotecan) is recommended starting from the 4th day of treatment (no earlier than 24 hours after the end of topotecan therapy). If febrile neutropenia against G-CSF persists, the dose of topotecan for subsequent courses should be reduced by 20% to 0.45 mg / m2.

    Doses in patients with impaired renal function

    Monotherapy

    For patients with QC ≥40 ml / min correction, dosing regimen is not required.

    The recommended dose for patients with SC from 20 to 39 ml / min is 0.75 mg / m2 in a day. Recommendations on the dosing regimen in patients with a decrease in CK less than 20 ml / min absent.

    Combination Therapy

    Topotecan therapy in combination with cisplatin for the treatment of cervical cancer is recommended only for patients with a plasma creatinine concentration of less than 1.5 mg / dl. If during treatment, the creatine concentration in the plasma of the blood exceeded 1.5 mg / dL, the recommendations of the instruction on the use of cisplatin to reduce its dose / withdrawal should be followed.In the case of cisplatin abolition, there is insufficient data on the continuation of topotecan therapy in the form of monotherapy in patients with cervical cancer.

    Doses in patients with impaired liver function

    For patients with a violation of liver function (bilirubin concentration from 1.5 to 10 mg / dl), dose adjustment is not required.

    Rules for the preparation of an infusion solution

    The contents of the vial are dissolved in 1 ml of sterile water for injections to a concentration of 1 mg / ml.

    The resulting solution must be diluted with 0.9% sodium chloride solution or 5% dextrose solution to a concentration of 25-50 μg / ml.

    Side effects:

    Long-term use does not cause an increase in the toxic effect of topotecan. Serious manifestations of cardiotoxicity, neurotoxicity, organ toxicity were not observed.

    The incidence of adverse events is classified as follows: very often (≥1/10), often (≥1/100, <1/10), sometimes (≥1/1000, <1/100), rarely (≥1/10000, <1/1000), very rarely (<1/10000, including individual cases).

    On the part of the hematopoiesis system: very often - neutropenia, febrile neutropenia, leukopenia, thrombocytopenia, anemia; often - pancytopenia; rare - severe bleeding due to thrombocytopenia; very rarely - ecchymosis, hemorrhage (poorly expressed and not requiring specific treatment).

    From the respiratory system: rarely - interstitial lung disease.

    From the immune system: often - hypersensitivity reactions, skin rashes, anaphylactoid reactions, angioedema.

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

    From the skin and skin appendages: very often, alopecia.

    Etcclear: very often - increased body temperature, increased fatigue, asthenia, attachment of a secondary infection; often - weakness, sepsis.

    Overdose:

    Symptoms: increasing bone marrow depression, stomatitis.

    Treatment: symptomatic, specific antidote is unknown.

    Interaction:

    Enhancement of myelosuppression is possible with the combined use of topotecan with other cytostatic drugs, which requires appropriate dose adjustment topotecan.

    The nature of the interaction of topotecan with platinum drugs depends on the sequence of their appointment, namely, whether the drugs are prescribed platinum in 1st or 5th day of application of topotecan.If platinum drugs are prescribed on day 1, then reduced doses of each drug should be used as compared with doses at the appointment of platinum drugs on the 5th day. Below are the doses and patterns of application topotecan and platinum preparations:

    - cisplatin in the first day at a dose of 50 mg / m2 and topotecan in a dose of 0.75 mg / m2 from the 1st to the 5th day;

    - cisplatin in the 5th day in a dose of 50 mg / m2 and topotecan in a dose of 1.25 mg / m2 from the 1st to the 5th day;

    - carboplatin on day 1: AUC 5 (the Calvert formula), topotecan in a dose of 0.5 mg / m2 from the 1st to the 5th day;

    - carboplatin on the 5th day: AUC 5 (the Calvert formula), topotecan in a dose of 1.0 mg / m2 from the 1st to the 5th day;

    Topotecan does not inhibit cytochrome P isoenzymes450. Joint use with granisetron, ondansetron, morphine, glucocorticosteroids does not significantly affect the pharmacokinetic parameters of topotecan.

    Special instructions:
    Topotecan treatment should be performed under the supervision of a specialist with experience in working with antitumor drugs.
    Topotecan monotherapy is not recommended as the first line of therapy.
    Hematologic toxicity of topotecan depends on its dose, it is necessary to conduct regular blood tests with determination of the level of hemoglobin, hematocrit, the number of leukocytes, neutrophils and platelets.
    When topotecan is combined with other cytostatic drugs, it is necessary to adjust its dose.
    With the development of severe neutropenia, careful monitoring is necessary to timely diagnose infectious complications. Neutropenia, induced by topotecan, may be the cause of the development of neutropenic colitis. Patients should be monitored for symptoms of interstitial lung disease (IBL) (eg, cough, fever, dyspnoea and / or hypoxia). When confirming a newly diagnosed IBL, topotecan therapy should be discontinued. When there is severe thrombocytopenia, extreme caution is required when performing invasive procedures, regular examination of the skin and mucous membranes, as well as discharge (to identify signs of bleeding). Women of reproductive age and men during topotecan therapy should use reliable methods of contraception.

    When working with the drug must comply with the generally accepted rules for the treatment of cytotoxic drugs. In case of accidental contact with the skin or eyes, rinse with plenty of water.

    Effect on the ability to drive transp. cf. and fur:Some undesirable effects of the drug, such as increased fatigue and weakness can adversely affect the ability to concentrate and the speed of psychomotor reactions. It is necessary to take into account the general clinical condition and the possibility of development of undesirable phenomena in assessing the ability to drive and work with mechanisms that require an increased concentration of attention and speed of psychomotor reactions.
    Form release / dosage:
    Lyophilizate for the preparation of a solution for infusions of 1 mg in a vial of colorless glass.
    Packaging:
    One bottle together with the instruction for use is placed in a pack of cardboard.
    5 bottles together with the instruction for use are placed in a bundle with partitions or special cardboard sockets.
    25, 40 or 75 bottles with an equal number of instructions for use are placed in a cardboard box (for hospitals).
    Storage conditions:In the dark place at a temperature of no higher than 30 ° C. Keep out of the reach of children.
    Shelf life:3 years. Do not use after the expiry date printed on the package.
    Terms of leave from pharmacies:On prescription
    Registration number:LP-001537
    Date of registration:27.02.2012 / 12.08.2016
    Expiration Date:27.02.2017
    The owner of the registration certificate:VEROPHARM SA VEROPHARM SA Russia
    Manufacturer: & nbsp
    Information update date: & nbsp05.02.2017
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