MITOXANTRON (Mitoxantron)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceMitoxantroneMitoxantrone
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    • Dosage form: & nbspconcentrate for solution for intravenous and intrapleural administration
    Composition:

    In 1 ml of the concentrate contains:

    active substance: mitoxantrone dihydrochloride - 2.33 mg (in terms of mitoxantrone - 2 mg);

    Excipients: acetic acid 0.46 mg, sodium acetate trihydrate 0.05 mg, sodium chloride 8 mg, water for injection up to 1 ml.

    Description:The liquid is dark blue.
    Pharmacotherapeutic group:Antitumour agent, antimetabolite
    ATX: & nbsp

    L.01.D.B.07   Mitoxantrone

    L.01.D.B   Anthracyclines and related drugs

    Pharmacodynamics:

    MITOXANTRON is a cytostatic drug, a synthetic derivative of anthracenedione. It is embedded in DNA through hydrogen bonds, causing cross-linking and breaking of chains. MITOXANTRON also interacts with RNA and is a potent inhibitor of topoisomerase II (an enzyme responsible for the despiralization and repair of damaged DNA). Has a cytotoxic effect on both dividing and non-dividing cells (lack of phase-specificity).

    In vitro inhibits the proliferation of B- and T-lymphocytes and macrophages, disrupts the recognition of antigens, the secretion of interferon gamma, tumor necrosis factor alpha and interleukin-2.

    Pharmacokinetics:

    After intravenous administration mitoxantrone quickly penetrates and is distributed in tissues, from which then its gradual release occurs. It is found in high concentrations in the liver, lungs and in descending order: in the bone marrow, heart, thyroid gland, spleen, pancreas, in the adrenal gland and kidney.

    The volume of distribution reaches 1000 l / m 2. It does not penetrate the blood-brain barrier.

    Connection with blood plasma proteins - 90%.

    The pharmacokinetics of mitoxantrone after single-valued intravenous administration can be characterized as a three-phase model: the average half-life of alpha is 6-12 minutes, the average half-life of beta is 1.1-3.1 hours, the average half-life of gamma is 23-215 hours 75 h).

    Metabolised in the liver. Within 5 days of excretion from the bile is derived from 13,6% to 24,8% and in the urine from 5,2% to 7,9% mitoxantrone.

    In patients with impaired liver function, there was a decrease in the rate of elimination of mitoxantrone.

    Indications:

    - Acute non-lymphoblastic leukemia in adults;

    - mammary cancer;

    - malignant non-Hodgkin's lymphomas;

    - primary hepatocellular carcinoma;

    ovarian cancer;

    - hormone-resistant prostate cancer with pain syndrome.

    Contraindications:

    - Hypersensitivity to mitoxantrone or other components of the drug;

    - the neutrophil count is less than 1500 / μl (excluding the treatment of non-lymphoblastic leukemia);

    - pregnancy and the period of breastfeeding;

    - age to 18 years.

    Carefully:Use with caution MITOXANTRON in patients with heart disease (including acute period of myocardial infarction, decompensated CHF, tachysystolic forms of arrhythmia, severe angina), with previous mediastinal irradiation, with oppression of hematopoiesis, with marked violations of the liver or kidney function, with bronchial asthma, with acute infectious diseases of the viral (including chicken pox, shingles), fungal or bacterial nature (risk of severe complications and generalization of the process), with diseases in which there is an increased enny risk of hyperuricemia (gout or urate nephrolithiasis) and in patients previously treated with anthracyclines.
    Dosing and Administration:

    A drug MITOXANTRON is included in many chemotherapy regimens, therefore, when choosing the route of administration, regimen and dosage in each individual case, reference should be made to the literature.

    The drug is administered intravenously slowly, for at least 5 minutes or intravenously drip for 15-30 minutes. Preferably enter MITOXANTRON into the tube of the infusion system slowly against a background of rapid infusion with 0.9% sodium chloride solution or 5% dextrose solution. The drug can be administered intrapleurally.

    Intrathecal, intraarterial, intramuscular, subcutaneous injection of the drug is prohibited!

    The maximum total dose of the drug MITOXANTRON - 200 mg / m2 surface of the body.

    In breast cancer, non-Hodgkin's lymphoma, primary hepatic-cell carcinoma and ovarian cancer in the monotherapy of the drug MITOXANTRON used in a dose of 14 mg / m2 1 time in 3 weeks. In patients who received chemotherapy earlier, and also when combined with other antitumour agents, the dose of the drug is reduced to 10-12 mg / m2. With repeated courses of dose of the drug MITOXANTRON are selected taking into account the degree of severity and duration of oppression of bone marrow hematopoiesis.

    In case of a decrease in the number of neutrophils at previous courses <1500 and / or platelets <50,000 cells / μl of blood, the dose of the drug MITOXANTRON decreases by 2 mg / m2, with a decrease in the number of neutrophils <1000 and / or platelets <25,000 cells / μl of blood subsequent doses of the drug MITOXANTRON decrease by 4 mg / m2.

    In the treatment acute non-lymphoblastic leukemia in adults for remission induction remedy MITOXANTRON prescribe in a dose of 10-12 mg / m2 daily for 5 days to a total dose of 50-60 mg / m2. It is possible to administer high doses of the drug MITOXANTRON - 14 mg / m2 and more daily for 3 days.

    For treatment hormone-resistant prostate cancer with pain syndrome a drug MITOXANTRON prescribe in a dose of 12-14 mg / m2 1 every 21 days in combination with daily intake of low doses of glucocorticosteroids (prednisolone 10 mg / day or hydrocortisone 40 mg / day).

    When intrapleural instillation with metastases in the pleura (with breast cancer and non-Hodgkin's lymphomas), the recommended single dose is 20-30 mg. For intrapleural instillation, the drug MITOXANTRON dilute in 50 ml of 0.9% solution of sodium chloride. Before the beginning of therapy evacuate, whenever possible, pleural exudate. A drug MITOXANTRON, diluted in 50 ml of 0.9% sodium chloride solution, warmed to body temperature and injected slowly for 5-10 minutes. Exposure period of the preparation MITOXANTRON in the pleural cavity is 48 hours. During this period, patients should move to ensure optimal intrapleural distribution of the drug. After the end of this time (48 hours), the pleural cavity is re-drained. If the amount of effusion is less than 200 ml, the first treatment cycle is stopped. If the amount of effusion is greater than 200 ml, a repeated instillation of 30 mg of the drug MITOXANTRON. Before carrying out the repeated instillation of the drug, hematological parameters should be monitored. The second dose of MITOXANTRON may remain in the pleural cavity. The maximum dose for one treatment cycle is 60 mg. If the number of neutrophils and platelets is within normal limits, intrapleural instillation can be repeated after 4 weeks.

    For 4 weeks before and 4 weeks after intrapleural administration of the drug MITOXANTRON should avoid systemic cytotoxic therapy.

    Side effects:

    On the part of the hematopoiesis system: leukopenia (usually on day 6-15, recovery on day 21), neutropenia, thrombocytopenia, erythrocytopenia, anemia.

    From the digestive system: nausea, vomiting, anorexia, decreased appetite, diarrhea, abdominal pain, constipation, gastrointestinal bleeding, stomatitis, increased activity of "liver" transaminases, impaired liver function.

    From the cardiovascular system: changes in ECG, tachycardia, arrhythmia, myocardial ischemia, lowering of the left ventricular ejection fraction, chronic heart failure. Toxic myocardial damage, in particular chronic heart failure (CHF), can develop both during treatment with mitoxantrone, and in months and years after the end of therapy. The risk of a cardiotoxic effect increases when the total dose is 140 mg / m2.

    On the part of the respiratory system: cases of interstitial pneumonitis are described. Allergic reactions: pruritus, rash, hives, lowering of blood pressure, dyspnea, anaphylactic reactions (including anaphylactic shock).

    Local reactions: phlebitis; when extravasation - erythema, swelling, pain, burning, necrosis of surrounding tissues.Cases of intense blue staining of veins, into which the preparation was administered and surrounding tissues, are described.

    Other: alopecia, fatigue, general weakness, fever, nonspecific neurological symptoms, back pain, headache, menstrual irregularity, amenorrhea, blue skin and nail staining, dystrophy, nails and reversible blue staining sclera, secondary infections, hyperuricemia, hypercreatinemia .

    Overdose:In case of an overdose, it is possible to intensify, primarily, myelotoxicity and the above-mentioned dose-dependent side effects, the occurrence of dyspnea, an increase in the concentration of urea in the blood. The use of dialysis is not effective. In case of an overdose, careful monitoring of the patient should be made and, if necessary, symptomatic therapy should be performed. The specific antidote for mitoxantrone is not known.
    Interaction:

    - Pharmaceutical: do not mix the drug with other agents (with the exception of 0.9% solution of sodium chloride or 5% solution of dextrose) with intravenous administration (precipitation may occur)

    - pharmacodynamic: a drug MITOXANTRON potentiates the effects of many cytotoxic drugs, such as cytarabine, cisplatin, cyclophosphamide, fluorouracil, methotrexate, vincristine, dacarbazine

    - with simultaneous application of the drug MITOXANTRON with other antitumour agents or irradiation of the mediastinal region, it is possible to increase its cardio- and myelotoxicity

    - concomitant use of drugs that block tubular secretion (including uricosuric antipodal agents sulfinpyrazone), may increase the risk of developing nephropathy

    - Due to the immunosuppressive effect of the drug and the possibility of developing severe infections, it is not recommended to apply live attenuated vaccines during chemotherapy

    - pharmacokinetic: no dangerous interactions were found with other drugs.

    Special instructions:

    Treatment with mitoxantrone should be performed under the supervision of a doctor who has experience with antitumor drugs.

    In the process of treatment, a systematic control of the peripheral blood picture is necessary, (before each introduction, a complete blood test, including platelet counting), laboratory liver function tests,as well as cardiac activity (ECG, echocardiography with determination of the left ventricular ejection fraction (LVEF)). After reaching the total dose of mitoxantrone in 100 mg / m2 determination of LVEF values ​​should be made before each next injection.

    Cardiovascular disease in the active or inactive phase, radiation therapy to the mediastinum / pericardial area, held previously or carried out simultaneously with the treatment of mitoxantrone prior treatment with other - with anthracyclines or anthracenediones, as well as concomitant treatment with other cardiotoxic drugs may increase the risk of toxic damage to the heart.

    The risk of cardiotoxicity increases when the total dose of mitoxantrone exceeds 140 mg / m2, however, toxic heart damage can develop at lower total doses of the drug.

    In the treatment of leukemia, hyperuricemia may occur as a result of rapid disintegration of tumor cells. If necessary, hypouricemic drugs should be prescribed.

    In the case of extravasation, it is necessary to stop the administration of the drug and, if necessary, continue the infusion into another vein.

    The use of topoisomerase II inhibitors, including mitoxantrone, in combination with other antitumor drugs and / or radiotherapy, can lead to the development of acute myeloblastic leukemia (AML) or myelodysplastic syndrome (MDS). Women and men during treatment with mitoxantrone, and also within 6 months after its withdrawal should use reliable methods of contraception.

    Avoid contact with the skin or mucous membranes, peak. possibly the emergence of tissue necrosis. The skin, in case of contact with the drug, must be thoroughly rinsed with warm water.

    The drug reduces the effectiveness of vaccination. Vaccination should be carried out 3 months after the completion of therapy.

    Effect on the ability to drive transp. cf. and fur:During the treatment period, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.
    Form release / dosage:Concentrate for the preparation of a solution for intravenous and intrapleural administration of 10 mg / 5 ml, 20 mg / 10 ml, 30 mg / 15 ml (2 mg / ml).
    Packaging:

    Producer of PJSC "PHARMSTANDART-BIOLEC".

    5 ml in bottles of a glass tube or 5 ml, 10 ml, 15 ml in bottles of glass, sealed with rubber plugs with aluminum caps or with caps combined of aluminum and plastic.

    For 10 bottles of 5 ml, 10 ml or 1 bottle of 5 ml, 10 ml or 15 ml, along with instructions for use in a pack of cardboard.

    It is allowed to pack in a film of 10 packs of 1 bottle of 5 ml or 10 ml.

    Manufacturer of ONKO JENERICS.

    5 ml or 10 ml in bottles of glass, sealed with rubber stoppers with aluminum caps or with caps combined of aluminum and plastic.

    For 1 bottle of 5 ml or 10 ml, along with instructions for use in a pack of cardboard.

    For 10 packs of 1 vial of 5 ml or 10 ml packed in a film.

    Storage conditions:

    In a dry, protected from light place at a temperature of no higher than 25 ° C. Freezing is not allowed!

    Keep out of the reach of children.

    Shelf life:

    2.5 years.

    Do not use after the expiry date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:PL-000296
    Date of registration:17.02.2011 / 11.12.2013
    Expiration Date:17.02.2016
    The owner of the registration certificate:FARM STANDART, OJSC FARM STANDART, OJSC Russia
    Manufacturer: & nbsp
    Information update date: & nbsp09.06.2018
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