Myleranum

General characteristics. Structure:

Tablets, coated white color, round, biconvex, with the engraving "GX EF3" on one party and "M" - on another.

 1 таб.
Active ingredient: бусульфан 2 mg

Excipients: lactose anhydrous, starch prezhelatinizirovanny, magnesium stearate.

Structure of a cover: опадрай white OY-S-7322, gipromelloz, titanium dioxide, triacetin.

Release form, structure and packaging

Tablets, coated white color, round, biconvex, with the engraving "GX EF3" on one party and "M" - on another.

 1 таб.
Active ingredient: бусульфан 2 mg

Excipients: lactose anhydrous, starch prezhelatinizirovanny, magnesium stearate.

Structure of a cover: опадрай white OY-S-7322, gipromelloz, titanium dioxide, triacetin.

Pharmacological properties:

Busulfan-bifunktsionalny the alkylating drug. Believe that the mechanism of action of a busulfan is caused by linkng with DNA; diguanylic derivatives were allocated, but formation of interchained bonds was not confirmed.

The reasons of unique selection influence of a busulfan on a granulocytopoiesis are completely not established. Though drug does not allow to achieve treatment, however it considerably reduces total number of granulocytes and leads to relief of symptoms of a disease and improvement of the general condition of patients.

Therapy busulfany was more effective, than radiation of a spleen, by such criteria as survival and maintenance of level of hemoglobin; on influence on the spleen sizes efficiency of both methods did not differ.

 

Pharmacokinetics. Busulfan in doses of 2-6 mg is well soaked up; the elimination half-life makes 2.57 h.

Indicators of pharmacokinetics of a busulfan were also studied at the patients accepting high doses of drug (1 mg/kg each 6 h within 4 days). The elimination half-life made 3.4 h after reception of the first dose and 2.3 h after reception of the last dose. These data allow to assume what бусульфан can increase the speed of own metabolism at repeated use.

Stationary concentration of a busulfan in plasma vary from 0.5 to 2.0 mkg/ml (2-8 µmol). Cmax made 3.1-5.9 mkg/ml at the patient who received a total dose of 16 mg/kg, and two patients who received a total dose of 20 mg/kg have 3.8-9.7 mkg/ml.

Its metabolites were found in the patients receiving high doses of a busulfan in urine: 3 hydroxysulpholane, tetrahydrothiophene-1-oxide and sulpholane. The insignificant amount of drug (1-2%) is removed with urine in not changed look.

At appointment in high doses бусульфан gets into cerebrospinal fluid where its concentration are comparable with plasma. The ratio of concentration of a busulfan in cerebrospinal fluid and plasma averages 1.3: 1. The ratio of concentration of a busulfan in saliva and plasma makes 1.1: 1.

Extent of reversible linkng with proteins of plasma varies: from insignificant to 55%. Extent of irreversible linkng with blood cells and proteins of plasma makes 47% and 32%.

Indications to use:

— a myelosis in a chronic phase of a disease.

Busulfan causes long remission at the Osler's disease which is especially proceeding with the expressed thrombocytosis.

Busulfan can be in some cases effective at an essential trombotsitemiya and a myelofibrosis.

Route of administration and doses:

Busulfan usually appoint courses or it is constant. The dose is chosen individually for each patient depending on a clinical state and hematologic indicators. If the dose less than 2 mg / is necessary for the patient (less than one tablet), drug can be accepted not daily, and bucketed in one or more days. It is impossible to divide a tablet into parts.

Myelosis. Induction of remission at adults: treatment is usually begun right after establishment of the diagnosis.

The dose makes 0.06 mg/kg/; the maximum initial dose makes 4 mg/, it is possible to appoint it in one step.

Individual reaction on бусульфан is variable; at some patients high sensitivity of cells of marrow to drug is possible. During induction of remission it is necessary to carry out control of blood tests at least once a week.

The dose should be raised only in the absence of due effect in 3 weeks of treatment. Treatment needs to be continued until total number of leukocytes does not decrease to 15-25 x 109/l (usually within 12-20 weeks). Then treatment can be interrupted; after that within 2 more weeks there can be a further decrease in number of leukocytes. Continuation of treatment in an induction dose after this moment or after decrease in number of thrombocytes less than 100 x 109/l is followed by great risk long and, perhaps, an irreversible aplasia of marrow.

Maintenance therapy at adults:

Long remission of a leukosis can be provided without the subsequent therapy busulfany; additional courses of treatment are usually conducted at increase in number of leukocytes to 50 x 109/l or at emergence of symptoms of a disease.

Some specialists prefer to carry out a continuous maintenance therapy. Continuous treatment is more reasonable at the short duration of remissions.

The treatment purpose - to support number of leukocytes at the level of 10-15 x 109/l; the number of blood cells should be controlled at least once in 4 weeks. Usually maintenance dose makes 0.5-2 mg/, however in individual cases it can be much lower.

NOTE: бусульфан it is necessary to appoint in lower doses if it is applied in a combination with other cytotoxic means.

Children:

The myelosis occurs at children seldom.

Busulfan it is possible to apply to treatment of a leukosis with the Philadelphian chromosome (Ph-positive). The juvenile Ph-negative option busulfany answers therapy badly.

Osler's disease:

Usually the dose makes 4-6 mg/; treatment is carried out within 4-6 weeks under careful control of number of blood cells, especially thrombocytes.

At development of a recurrence course therapy can be resumed or as an alternative the maintenance therapy in the dose making about a half of an induction dose can be carried out.

If treatment of a polycythemia is generally performed by venesections, then for control of number of thrombocytes short courses can be appointed.

Myelofibrosis:

Usually initial dose makes 2-4 mg / a busulfana.

Careful control of hematologic indicators is necessary, considering very high sensitivity of cells of marrow at a myelofibrosis.

Essential trombotsitemiya:

Usually the dose makes 2-4 mg /

Treatment should be stopped if total number of leukocytes decreases less than 5 x 109/l or the number of thrombocytes makes less than 500 x 109/l.

Features of use:

Busulfan is cytotoxic means which should be used only under control of the doctors having experience of use of similar drugs.

At an intact outside cover use of tablets of a busulfan does not represent risk. Tablets should not be divided into parts. When using tablets of a busulfan it is necessary to implement recommendations about use of cytotoxic drugs.

Busulfan it is necessary to cancel at emergence of signs of toxic action on tissue of lungs.

As a rule, бусульфан do not apply in a combination with radiotheraphy or soon after carrying out a course of radiotheraphy.

Busulfan is not effective in a stage of blast transformation.

If patients with possible toxic damage of lungs need carrying out the general anesthesia, then concentration of the inhaled oxygen should be maintained at the lowest safe level; in the postoperative period it is necessary to control and support function of external respiration carefully.

At patients with a myelosis the hyperuricemia and/or a hyper uricosuria which should be eliminated before purpose of a busulfan are quite often noted. During treatment busulfany prevention of a hyperuricemia and urate nephropathy, including consumption of enough liquid and use of Allopyrinolum is necessary.

It is necessary to observe extra care at use of a busulfan for treatment of an Osler's disease and an essential trombotsitemiya, considering cancerogenic properties of drug. At the specified diseases it is not recommended to apply бусульфан at patients of young age or in the absence of symptoms. If purpose of a busulfan is necessary, then courses of therapy have to be as it is possible well.

At treatment by high doses of a busulfan patients should accept anticonvulsant drugs with the preventive purpose; it is more preferable to appoint drugs of a benzodiazepine row, than Phenytoinum.

At a concomitant use of a busulfan and an itrakonazol it is necessary to control carefully a condition of the patient for the purpose of early detection of symptoms of intoxication busulfany.

Monitoring: during treatment busulfany it is regularly necessary to carry out control of the general blood test in order to avoid the expressed miyelosupressiya and an irreversible aplasia of marrow.

Mutagen and cancerogenic properties: at the patients accepting бусульфан various aberation chromosomes were noted.

According to the conclusion of WHO, there is relationship of cause and effect between influence of a busulfan and development of cancer. At the patients accepting бусульфан for a long time revealed a widespread epithelial dysplasia; some changes were similar to precancerous. At several patients receiving бусульфан cases of development of malignant tumors are described.

Are available this, testimonial of what бусульфан, as well as other alkylating means, has leykozogenny effect. Though the acute leukosis is probably a component of the natural course of an Osler's disease, long therapy by the alkylating means can increase risk of its development.

Teratogenic properties: бусульфан had teratogenic effect in researches at animals and has potential teratogenic properties at the person. Several cases of inborn defects which were optional connected with busulfany are described; use of drug in the third trimester of pregnancy can be followed by a fruit growth disorder. At the same time many cases of the birth of healthy children after influence of a busulfan of in vivo even are known during the first trimester of pregnancy.

Fertility: at women in a premenopauza suppression of function of ovaries and an amenorrhea with menopause symptoms is often observed. Recovery of function of ovaries at treatment continuation was in rare instances noted.

Treatment by high doses of a busulfan of girls at children's and teenage age resulted in insufficiency of function of ovaries, including lack of the pubertal period.

Busulfan breaks a spermatogenesis in an experiment at animals; at men cases of sterility, an azoospermism and an atrophy of testicles are described.

Influence on ability to driving of motor transport and to control of mechanisms

There are no data on influence of a busulfan on ability to operate the vehicle and to work with the difficult equipment. Considering pharmacological properties of drug, such influence is improbable.

Side effects:

Concerning this drug there are no modern clinical data which could be used for determination of frequency of side effects. Frequency of side effects can vary depending on Busulfan's dose received by the patient, and also from other drugs used in a combination with him.

On frequency side effects were divided into the following categories: very frequent: ≥ 1:10; frequent: ≥ 1:100 and <1:10; infrequent: ≥ 1:1000 and <1:100; rare: ≥ 1:10 000 and <1:1000; very rare: <1/10 000.

From hemopoietic and lymphatic system: very frequent: the dozozavisimy oppression of marrow which is shown a leukopenia and especially thrombocytopenia; rare: aplastic anemia, usually after prolonged use of standard doses, and also when using high doses of a busulfan.

From a nervous system: rare: spasms when using high doses; very rare: heavy myasthenia.

From organs of sight: rare: changes of a crystalline lens and a cataract which can be bilateral; thinning of a cornea was observed after transplantation of marrow to which therapy by high doses of a busulfan preceded.

From heart: frequent: a cardiac tamponade at the patients with a thalassemia receiving high doses of a busulfan.

From a respiratory organs, bodies of a thorax and mediastinum: rare: intersticial pneumosclerosis. The diffusion intersticial pneumosclerosis with the progressing asthma and persistent unproductive cough arises seldom, usually after prolonged treatment within several years. Histologic signs include atypical changes of an epithelium of alveoluses and bronchioles and presence of colossal cells with large hyperchromatic kernels. In case of detection of toxic damage of lungs, the forecast, even, despite cancellation of a busulfan, adverse - in this situation of advantage of use of corticosteroids is not enough. The intersticial pneumosclerosis usually develops gradually, but can have also an acute current. This pulmonary pathology can be complicated by infections. Also ossification and dystrophic calcification of lungs are described. It is not excluded that the subsequent radiation therapy can strengthen the subclinical damage of lungs caused busulfany. Other cytotoxic drugs can cause the additive toxic damage of lungs.

From digestive tract: very frequent: nausea, vomiting, diarrhea and an ulceration of a mucous membrane of an oral cavity when using high doses of a busulfan. Possibly, symptoms can be facilitated by use of fractional doses.

Gepatobiliarny disturbances: very frequent: a hyperbilirubinemia, jaundice, occlusion of hepatic veins and centrolobular sinusoidal fibrosis with a hepatocellular atrophy and a necrosis when using high doses; rare: cholestatic jaundice and abnormal liver functions when using usual doses, centrolobular sinusoidal fibrosis.

It is considered that in usual therapeutic doses бусульфан has no significant toxic effect on a liver. At the same time, the retrospective analysis of pathoanatomical data on patients who received a low dose of a busulfan not less than two years concerning a chronic granulotsitarny leukosis revealed existence of centrolobular sinusoidal fibrosis.

The combination of a busulfan and thioguanine has strong toxic effect on a liver.

From skin and hypodermic fabrics: frequent: an alopecia at treatment by high doses, a hyperpegmentation; rare: an alopecia when using usual doses, skin reactions, including a small tortoiseshell, a mnogoformny erythema, a knotty erythema, a late skin porphyria, rash of allopurinolovy type, and also excessive dryness and fragility of skin with a full anhidrosis, dryness of mucous membranes of an oral cavity and a cheilosis, Shegren's syndrome. More expressed beam changes of skin at the patients receiving radiation therapy soon after treatment by high doses of a busulfan.

Hyperpegmentation cases, in particular at black patients are described. Often it is most expressed on a neck, an upper part of a trunk, nipples, on a stomach and in palmar folds. The hyperpegmentation can be a part of a clinical syndrome.

From kidneys and urinary tract: frequent: hemorrhagic cystitis at treatment by high doses in a combination with cyclophosphamide.

From reproductive system and mammary glands: very frequent: oppression of function of ovaries and an amenorrhea with menopause symptoms at patients in a premenopauza at treatment by high doses; heavy and resistant insufficiency of ovaries, including lack of puberty after introduction of high doses to the young girls and girls who did not reach teenage age. Sterility, an azoospermism and an atrophy of testicles at the men receiving бусульфан; infrequent: oppression of function of ovaries and an amenorrhea with menopause symptoms at patients in a premenopauza at treatment by usual doses. Recovery of function of ovaries at treatment continuation was seldom or never observed; very rare: gynecomastia.

The research of a busulfan in animal experiments revealed its toxic action on reproductive system.

Disturbances of the general character: very rare: the clinical syndrome (weakness, strong fatigue, anorexia, decrease in body weight, nausea and vomiting, a skin hyperpegmentation) reminding adrenal insufficiency (Addison's disease), but without biochemical signs of oppression of adrenal glands, a hyperpegmentation of mucous membranes and a hair loss; rare: a widespread dysplasia of an epithelium (it is observed in rare instances after long therapy busulfany). This syndrome sometimes disappears after cancellation of a busulfan.

At patients, treated busulfany, numerous histologic and cytologic changes, including a widespread dysplasia of an epithelium of a neck of uterus, bronchial tubes and an epithelium of other localization are found. In most cases such changes arise in results of long therapy, however tranzitorny anomalies of an epithelium are described also after short-term treatment by high doses.

Interaction with other medicines:

The combination of a busulfan to other pulmonotoksichny cytostatic drugs can strengthen toxic action on tissue of lungs.

Purpose of Phenytoinum to the patients accepting high doses of a busulfan can lead to decrease in effect of the last.

Simultaneous use of a busulfan and itrakonazol can reduce clearance of a busulfan.

Contraindications:

— to patients with earlier revealed resistance to a busulfan;

— to patients with hypersensitivity to any component of this drug.

 

Use of the drug MYLERANUM at pregnancy and feeding by a breast

Use of drug at pregnancy is possible only in that case when the estimated advantage for mother surpasses potential risk for a fruit.

Teratogenic properties: бусульфан had teratogenic effect in researches at animals and has potential teratogenic properties at the person. Several cases of inborn defects which were optional connected with busulfany are described; use of drug in the third trimester of pregnancy can be followed by a fruit growth disorder. At the same time many cases of the birth of healthy children after influence of a busulfan of in vivo even are known during the first trimester of pregnancy.

The women accepting this drug are not recommended to nurse the child.

 

Use for children

Treatment by high doses of a busulfan of girls at children's and teenage age resulted in insufficiency of function of ovaries, including lack of the pubertal period.

Overdose:

Symptoms: manifestation of acute dozolimitiruyushchy toxicity of a busulfan at the person is the miyelosupressiya. If бусульфан apply in a high dose in combination with transplantation of marrow, then toxic action on digestive tract with damage of mucous membranes, nausea, vomiting, diarrhea and anorexia becomes a dozolimitiruyushchy factor.

The main manifestation of chronic overdose of drug - oppression of function of marrow and a pancytopenia.

Treatment: the antidote is unknown. There are no data on possible efficiency of dialysis.

In the presence of signs of toxic action on a hemogenesis carry out the corresponding symptomatic therapy.

Storage conditions:

List A.

Drug should be stored at a temperature below 25 °C, in the place, unavailable to children.

Unused tablets should be destroyed according to rules of utilization of dangerous and toxic agents.

Period of validity 3 years. Not to use drug after the expiry date specified on packaging.

Issue conditions:

According to the recipe

Packaging:

25 - bottles of dark glass (1) - a pack cardboard.