Mitoksantron

General characteristics. Structure:

Active ingredient: 2 mg of a mitoksantron in 1 ml of solution.

Drug with an antineoplastic and immunodepressive effect.

Pharmacological properties:

Pharmacodynamics. It is built in between couples of bases of DNA, breaks its structure and function, inhibits synthesis of RNA and a mitosis (it is preferential in a late stage of a S-phase). Affects both on proliferating, and not proliferating cells. Quickly gets into fabrics, slightly more slowly into a head and spinal cord, eyes.

The highest concentration are created in a thyroid gland, lungs, a liver, heart and erythrocytes. Dozozavisimo it is also irreversible (at long treatment) oppresses functions of gonads, causing an amenorrhea or an azoospermism. Prolonged use can promote development of secondary malignant tumors (the remote effect).

Has mutagen effect in bacterial systems, causes aberation chromosomes in animals, damage of DNA and exchange of sister chromatids to in vitro experiments. In experiences on rabbits increases the frequency of premature births, on rats — slows down formation of kidneys and causes decrease in body weight of posterity. Thus, at appointment it is necessary to consider possible mutagen, teratogenic and cancerogenic action.

Pharmacokinetics. Contacts proteins of plasma for 78%. It is removed slowly: T1/2 in plasma — 2,3–13 days. The stable volume of distribution is 1000 l/sq.m. In a liver is oxidized and forms derivatives mono - and dicarboxylic acids. It is excreted through gepatobiliarny system (25% of a dose are found in Calais in 5 days later in/in introductions) and kidneys. The abnormal liver function of average degree (concentration of bilirubin of 13-34 mg/l) is not followed by change of pharmacokinetic properties, more expressed change (concentration of bilirubin more than 34 mg/l) leads to decrease in plasma clearance and increase in AUC (correction of the mode of dosing is necessary).

Removal by kidneys is limited: only 6–11% of a dose appear in urine in 5 days of reception (65% — not changed drug, 35% — 2 inactive acid metabolites and their glucuronides). The most part of a dose actively communicates in fabrics and is released gradually, causing a tendency to cumulation. Practically is not removed at a hemodialysis or peritoneal dialysis.

Indications to use:

Breast cancer (with the regional or remote metastasises); cancer of a liver, ovaries, a prostate (including gormonalnoustoychivy the IV stages with a pain syndrome); nekhodzhkinsky lymphoma; acute miyeloblastny, promiyelotsitarny, monoblast leukosis; an erythremic myelosis at adults (at inefficiency of traditional means), cancer ascites.

Route of administration and doses:

In/in, in / and, intraperitoneally. The mode of dosing is set individually. The adult at leukoses for remission induction — in/in infusionally in a dose of 12 mg/sq.m/days from 1 to 3 day in a combination with Cytarabinum — 100 mg/sq.m/days in the form of long 24-hour infusion from 1 to 7 day.

At insufficient effect carrying out a repeated induction course is possible: митоксантрон it is entered in the 1 and 2 day and Cytarabinum from 1 to 5 day in the same doses.

For remission maintenance — 12 mg/sq.m/days in the 1 and 2 day in a combination of 100 mg/sq.m  of Cytarabinum a day entered in/in during 24 h from 1 to 5 day approximately in 6 weeks after the termination of an induction course (the second supporting year is conducted in 4 weeks after the first). At a prostate cancer — 12–14 mg/sq.m of 1 times in 3 weeks (in a combination with corticosteroids).

At a breast cancer, a liver and nekhodzhkinsky lymphoma — 14 mg/sq.m/days each 3 weeks. At a combination therapy the initial dose is lowered on 2–4 mg / м2по to comparison with a dose at monotherapy.

Features of use:

Use is possible only under observation of the doctor having experience of chemotherapy. Prior to the beginning of and during treatment (with small intervals) constant control of cellular composition of peripheral blood, definition of hemoglobin or a hematocrit, number of leukocytes (the general, differential), thrombocytes, definition of concentration of uric acid, carrying out functional researches of heart, lungs is necessary, for a liver, kidneys.

The expressed leukopenia is observed within 10 days (the number of leukocytes is recovered for 3 weeks), the inflammation of mucous membranes is shown during 1 week after an initiation of treatment. At emergence of the following symptoms: a pancytopenia, a fever, fever, cough or hoarseness, lower back pain or a side, the painful or complicated urination, bleedings or hemorrhages, a black chair, blood in urine or Calais it is necessary to consult immediately with the doctor.

Development of a neutropenia causes need of careful observation for the purpose of early detection of symptoms of an infection. It is necessary to delay the schedule of vaccination (it is possible not earlier than in 3 months and till 1 year after end of a last year of chemotherapy), to exclude contact with infectious patients or to use nonspecific actions for prevention (a protective mask, etc.).

Other family members living with the patient should refuse immunization by a peroral vaccine against poliomyelitis. When developing thrombocytopenia extreme care at implementation of invasive procedures, regular survey of places in/in introductions, skin and mucous membranes (for identification of signs of bleeding), control of content of blood in urine, emetic masses is recommended, to Calais.

Such patients need to have a shave, do manicure with care, to brush teeth, to use dental flosses and toothpicks, it is necessary to avoid falling and other damages, alcohol intake and acetylsalicylic acid increasing risk of gastrointestinal bleedings. The additional course of treatment is possible after disappearance of gematotoksichny effects.

At cumulative doses it is higher than 140 mg/sq.m  or 100 mg/sq.m  at patients with risk factors (radiation of a mediastinum, a heart disease in the anamnesis, the previous treatment by anthracyclines) the risk of cardiotoxic action increases. Development of the nephropathy caused by the increased formation of uric acid can be prevented by adequate consumption of liquid, use of Allopyrinolum or alkalifying of urine.

Safety and efficiency of use for children are not established therefore it is necessary to refrain from appointment at children's age. During treatment it is necessary to use adequate measures of contraception. It is necessary to warn the patient about possible danger to a fruit if during treatment there is pregnancy.

In case of contact of drug with skin or mucous membranes careful washing by water (mucous membranes) or water with soap is necessary (skin). At emergence of extravasate in time in/in an injection or infusion introduction should be stopped and resumed in other vein.

Special instructions. In 1–2 days perhaps blue-green coloring of urine, in rare instances — reversible blue coloring of scleras, veins and paravenous fabrics, nails (amotio of nail plates is probable). For in/in introductions the concentrate of a mitoksantron of a hydrochloride should be diluted previously with 0,9% solution of sodium of chloride or 5% dextrose solution. Dissolution, cultivation and administration of drug is carried out by the trained medical personnel with observance of protective measures (gloves, masks, clothes, etc.).

Use at pregnancy and feeding by a breast. Contraindicated at pregnancy. Category of action on a fruit on FDA — D. For the period of treatment it is necessary to stop breastfeeding.

Side effects:

From a nervous system and sense bodys: headache (10%), spasms (4%), weakness, fatigue.

From cardiovascular system and blood (a hemopoiesis, a hemostasis): heart failure (5%), arrhythmia (3%), tachycardia, thorax pain, passing changes on an ECG, reduction of fraction of emission of a left ventricle, a myocardial infarction, hypotension, phlebitis, bleedings, a leukopenia, thrombocytopenia, an erythrocytopenia.

From bodies of a GIT: appetite loss, nausea and vomiting (72%), diarrhea (47%), stomatitis (29%), gastrointestinal bleedings (16%), an abdominal pain (15%), jaundice (3%), ulcers in an oral cavity and on lips, abnormal liver functions (increase in level of bilirubin, change of activity of nuclear heating plant, ALT), a lock.

From integuments: alopecia (37%), fungal infections of skin (15%), petechias / экхимозные rashes (7%), rash, urticaria, itch.

From respiratory system: grippopodobny syndrome (78%), asthma (18%), cough (13%).

From urinogenital system: hyperuricemia, renal failure, amenorrhea, azoospermism.

Others: development of infections — 66% (including sepsis — 34%, fungal infections — 15%, pneumonia — 9%, upper respiratory tract infections — 7%), fervescence, allergic reactions (an anaphylaxis, etc.), conjunctivitis (5%), irritation in an injection site, a necrosis of a hypodermic fatty tissue (at hit under skin and in okolososudisty space).

Interaction with other medicines:

Toxicity is increased by other antineoplastic and myelotoxic drugs, пробенецид, Sulfinpyrazonum, radiation therapy.

Daunorubitsin, doxorubicine, radiation of area of a mediastinum increase risk of cardiotoxic action.

The probability of a nephropathy is increased by uricosuric antigouty drugs (correction of doses at treatment of a hyperuricemia and gout is necessary).

NPVS exponentiate side effects from blood (risk of bleedings).

Weakens efficiency of immunization by the inactivated vaccines; when using the vaccines containing live viruses strengthens replication of a virus and side effects of vaccination (immunodepressive effect).

Pharmaceutical it is incompatible with thiamin (causes its destruction), heparin and with other medicines in infusion solution or in one syringe.

Contraindications:

Hypersensitivity, intrathecal introduction, pregnancy, feeding by a breast.

Restrictions to use. Ratio assessment risk advantage is necessary in the following cases: a leukopenia, a pancytopenia, hard proceeding associated diseases, an abnormal liver function and/or kidneys, gout, chicken pox, the surrounding herpes, the previous cytotoxic or radiation therapy, advanced or children's age.

Overdose:

Symptoms: the expressed depression of marrow (lasting up to 3 weeks), an agranulocytosis, necrotic quinsy, infectious damages of a GIT, diarrhea, bleedings, cardiotoxicity manifestations.

Treatment: hospitalization, monitoring of the vital functions; reduction of a dose or drug withdrawal; symptomatic therapy; if necessary — transfusion of components of blood, platelet and leukocytic concentrate, prescription of antibiotics of a broad spectrum of activity.

Issue conditions:

According to the recipe

Packaging:

Concentrate for preparation of solution for infusions of 2 mg/ml, on 5 ml or on 10 ml in each bottle. On 1 bottle, together with the application instruction in cardboard packaging.