MILERAN

Active material: Busulfan
When ATH: L01AB01
CCF: Anticancer drug. Alkilirutee connection
ICD-10 codes (testimony): Q92.1, D45, D 47.1, (D) 47.3, Z 32.0, Z94
When CSF: 22.01.05
Manufacturer: GlaxoSmithKline Trading Company (Russia)

Pharmaceutical form, composition and packaging

Pills, coated white, round, lenticular, Engraved “GX EF3” on one side and “M” – another.

Excipients: lactose bezvodnaya, pre-gelatinized starch, magnesium stearate.

The composition of the shell: White opadraj OY-S-7322, gipromelloza, Titanium dioxide, triacetine.

25 PC. – vials of dark glass (1) – packs cardboard.

Pharmacological action

Anticancer drug, bifunkcional'noe alkilirutee connection. It is believed, that its mechanism of action is due to binding to DNA; were allocated diguanilovye derivatives, but education mezhcepochechnyh links has not been finally confirmed.

Causes of unique selective influence on busulfan granoulozitopoez has not been fully established. Although the drug is not allows to achieve cure, but significantly reduces the total number of granulocytes, leads to relieve symptoms and improve the general condition of patients.

Mileran causes long-term remission if true polycytemia, especially flowing with a pronounced trombozitozom. Can be effective in some cases essencialna trombozitemii and mielofibrosa.

Drug therapy is more effective, than irradiation of spleen, According to the following criteria:, as the survival and maintenance of hemoglobin. On the influence of spleen size efficiency of both methods is the same.

Pharmacokinetics

Absorption.In adults the bioavailability of oral busulfan is characterized by pronounced differences in the same patient, in the range of 47% to 103% (medium- 68%). Area under the curve "concentration in plasma-time» (AUC) and maximum concentrations (Smaks) busulfan in plasma is linearly dependent on the dose. After a single oral administration 2 mg of busulfan AUCi Smaks amounted 125 ± 17 NG x h/ml 28 ± 5 ng/ml, respectively. Noted the appearance lag busulfan in plasma 2 hours after his admission.

Indicators of pharmacokinetics of busulfan also studied in patients, taking high doses of the drug (1 mg / kg every 6 h for 4 days). AUCi Smaks in adults vary greatly and in determining the method of HPLC amounted, respectively, 8260 NG x h/ml (range from 2484 to 21090) and 1047 ng / ml (range from 295 to 2558), and in determining the chromatographic method- 6135 NG x h/ml (range from 3978 to 12304) and 1980 ng / ml (range from 894 to 3800).

Distribution.In adults, the volume of distribution is busulfan 0.64 ± 0.12 l/kg.. When assigning busulfan in high doses, it falls into the cerebrospinal fluid (CSF) at concentrations, comparable with plasma, the average ratio of concentrations in the CSF : plasma equals 1.3 : 1. Distribution of busulfan in saliva : plasma is 1.1 : 1. Reversible busulfan binding to plasma proteins varies from small to 55%. Irreversible binding of the drug to the blood cells and plasma proteins is, respectively, 47% and 32%.

Metabolism. Metabolism includes busulfan reaction with gljutationom, which occurs in the liver under the influence of glutathione-S-transferase.

Patients, treated with high-dose busulfan, in the urine were found its metabolites: 3-gidroksisul'folan, tetragidrotiofen-1-oxide and sulfolane.

Deduction. The average elimination half-life is between busulfan 2.3 to 2.8 o'clock. In adult patients clearance busulfan equals 2.4 – 2.6 ml / min / kg. The readmission half-life busulfan decreases, that suggests, that busulfan, perhaps, speeds up your own metabolism. A very small amount of the drug (1-2%) excreted in the urine as unchanged.

Special groups of patients

Children.Busulfan oral bioavailability is highly variable ranging from 22% to 120% (average, 80%). In appointing the drug dose 1 mg / kg every 6 hours during 4 days plasma clearance in children 2 – 4 above the fold itself in adults. When dispensing medication depending on the body surface area AUCi Smaks in children the same, in adults. Area under the curve in children under 15 years is half, and children under 3 years-a quarter of the rate in adults. The volume of distribution of busulfan in children is equal to 1.15 ± 0.52 l/kg.. In appointing the drug dose 1 mg / kg every 6 hours during 4 days the ratio of its concentrations in the CSF : plasma equals 1.02 : 1. But, When appointing the dose 37.5 mg / m² every 6 hours during 4 days this ratio equals 1.39 : 1.

Patients with obesity.Obesity increases the clearance of busulfan. In obese patients dosage is calculated based on the body surface or adjusted ideal body weight.

Testimony

— air-conditioning modes before transplantation of hemopoietic progenitor cells in those case, When the best option for conditioning the individual patient is a combination of high-dose busulfan and cyclophosphamide;

is palliative treatment chronic myeloid leukemia in chronic phase of the disease;

is Polycythemia vera, especially leaky with pronounced trombozitozom(to achieve long-term remission);

— essencialnaya trombozitemia and Myelofibrosis (in some cases).

Dosage regimen

The drug is usually prescribed courses or continuously. Dose picked individually for each patient depending on the clinical and haematological status indicators. If the patient requires a daily dose is less than the, that corresponds to an existing dosage form, the drug can be taken daily, (a) at intervals of one or more days. Divide the pill into parts cannot be.

In patients with obesity dose is calculated on the basis of body surface area or ideal body weight.

IN modes of air-conditioning before transplantation of hematopoietic progenitor cells adult the recommended dose busulfan is 1 mg / kg of body weight every 6 h for 4 days, starting over 7 days until transplant. Usually through 24 h after the last reception of busulfan appoint cyclophosphamide dose 60 mg / kg / day for 2 days.

Children under 18 years cumulative dose busulfan recommended ranges from 480 to 600 mg / m². Doses of ziklofosfamida same, in adults.

At chronic myeloid leukemia to remission induction in Adult treatment is usually started immediately after diagnosis. The dose is 0.06 mg / kg / day; maximum initial dose – 4 mg / day, You can assign in one step. Private reaction to very different busulfan; some patients possible high sensitivity of bone marrow to the drug. During remission induction, there is a need to control the number of loose blood at least once a week.

The dose should be increased only if there are no expected effect through 3 of the week. Treatment should continue until the, While the total number of cells has been reduced to a 15 000-25000/MKL (usually within 12-20 weeks). Then you can stop treatment; After that for another 2 weeks can be further reduction in the number of cells. Continued treatment induction dose after this moment or after the decrease in the number of platelets less 100 000/MCL is accompanied by significant risk of a long and, perhaps, irreversible aplazii bone marrow.

When carrying out maintenance therapy in adults long remission of leukemia can be maintained without further busul'fanom therapy; additional courses of treatment usually spend while increasing the number of cells to 50 000×10⁹/l or reset symptoms.

Some clinicians prefer to spend a continuous supportive therapy. Permanent cure is more appropriate at short duration of remission. The goal of treatment – support the number of cells at the level of 10 000-15 000/l; the number of blood cells should be monitored at least once a 4 of the week. Usually supporting dose is 0.5-2 mg / day, However, in individual cases, it may be considerably lower.

In combination with other cytotoxic funds busulfan should designate smaller doses.

Chronic myelogenous leukemia in children rare. Busulfan can be used for the treatment of leukemia with the Philadelphia chromosome (Ph'-positive). Juvenile Ph'-negative variant on therapy busul'fanom meets bad.

At polycythemia vera The recommended dose is 4-6 mg / day; treatment is carried out within 4-6 weeks under the close supervision of a number of blood cells, especially platelets.

With the development of relapses, conduct refresher courses of treatment. Alternatively, you can carry out supportive therapy at a dose, of approximately half of the induction dose.

If the treatment is done by mostly polycytemia venesekcij, to control the number of platelets can be assigned to short courses of busulfan.

At mielofiʙroze the recommended starting dose busulfan is 2-4 mg / day. Requires careful monitoring blood indicators, given the very high sensitivity of bone marrow cells in mielofibroze.

At essential trombozitemii The recommended dose is 2-4 mg / day. Treatment should be discontinued, If the total number of cells decreases less than 5000/µl or the number of platelets less than 50 0000/l.

Side effect

Against this drug no modern clinical data, that could be used to determine the frequency of side effects. The frequency of side effects can vary depending on the dose busulfan, as well as being used in combination with other drugs.

On the frequency of side effects are classified by frequency of occurrence using the following graduation: Often – ≥0.1; often – ≥ 0.01 and <0.1; sometimes – ≥ 0.001 and <0.01; rarely – ≥ 0.0001 and <0.001; rarely – <0.00001.

Benign, malignant tumors and tumors with an unspecified degree of malignancy (including cysts and polyps): often-secondary acute leukemia.

From the hematopoietic system: Often – dose-dependent inhibition of bone marrow, reflected lakopenia and thrombocytopenia in particular; rarely – aplasticheskaya anemia, usually after a long use of the standard dose and using high-dose busulfan.

From the central and peripheral nervous system: rarely – seizures using high doses; very rarely-myasthenia gravis.

On the part of the organ of vision: rarely – change the lens and cataract, which may be bilateral; thinning of the cornea after bone marrow transplantation, preceded by high-dose busulfan therapy.

Cardio-vascular system:often– Cardiac tamponade in patients with Thalassemia, receiving high-dose busulfan.

The respiratory system: very often, the syndrome of idiopathic pneumonia amid high-dose therapy; often – Interstitial Pulmonary Fibrosis with long-term use of standard doses of. Pulmonary toxicity when using busulfan in high or standard doses usually shown nonspecific unproductive cough, shortness of breath and hypoxia symptoms of respiratory dysfunction. Other cytotoxic drugs can cause additive toxic lung damage. Maybe, subclinical lesion of lungs, caused by busul'fanom, can be aggravated by work carried out in the subsequent radiation therapy. In the presence of pulmonary toxicity prediction is considered unsatisfactory, Despite the abolition of busulfan; the efficacy of corticosteroids in this situation a little obvious. Idiopathic pneumonia syndrome – This they diffuse pneumonia, that may occur within three months after the application of busulfan conditioning regime before allogeneic or autologous cells. Diffuse alveolar hemorrhage can also be detected in some cases of bronchial lavage. Using chest x-ray and CT SCAN detected diffuse or nonspecific local infiltrates, and if the biopsy detected interstitial Pneumonitis and diffuse alveolar lesion and sometimes fibrosis. Intersticialnaya pneumonia can develop when using standard doses and lead to pulmonary fibrosis, usually after many years of therapy. The beginning of the gradual complications, but there may be a sharp. Histological signs include atypical epithelial changes alveoli and Bronchioles and the presence of giant cells with large nuclei with lots of chromatin. This pulmonary pathology may be complicated by infections. Also describes the ossification and dystrophic calcification of lungs.

From the digestive system: Often – nausea, vomiting, diarrhea and Ulcerative Stomatitis in vysokodoznom mode of therapy, giperʙiliruʙinemija, jaundice, occlusion of hepatic veins and centrolobuljarnyj sinusoidal fibrosis with Hepatocellular necrosis and atrophy using high doses; rarely - nausea, vomiting, Ulcerative Stomatitis and diarrhea when using standard doses, and these symptoms are reduced by a fractional appointment preparation, Cholestatic jaundice and violations of functional liver samples when used in normal doses, centrolobuljarnyj sinusoidal fibrosis. It is believed, that the normal therapeutic dose busulfan has no meaningful hepatotoxic action. At the same time, retrospective analysis of autopsy data of patients, who were receiving low dose busulfan for at least two years over chronic granulocytic leukemia, revealed centrolobuljarnogo sinusoidal fibrosis.

Dermatological reactions: often – alopecia in the therapy mode vysokodoznom, giperpigmentatsiya; rarely – alopecia when used in normal doses, skin reactions, including urticaria, multiformnuu Erythema, uzlovatuju Erythema, Late each Porphyry, rash allopurinolovogo type, as well as excessive dryness and brittleness of the skin with full angidrozom, dry mucous membranes of the oral cavity and Cheilitis, Sjogren syndrome. More radiant skin changes in patients, receiving radiation therapy shortly after applying vysokodoznogo therapy busul'fanom. Describes cases of hyperpigmentation, in particular, dark-skinned patients. It is most often expressed in the neck, upper torso, nipple, on the abdomen and ladonnyh folds. Hyperpigmentation could be part of a clinical syndrome.

From the urinary system: often – hemorrhagic cystitis when treating high doses in combination with cyclophosphamide.

On the part of the reproductive system: ochen'chasto – inhibition of ovarian function and amenorrhea with menopausal symptoms in patients, the age of menopause (When treating high doses); severe and resistant ovarian failure, including lack of puberty after high doses to young girls and girls, the age of adolescence. Sterility, azoospermia and testicular atrophy in patients, male, receiving busulfan; sometimes – inhibition of ovarian function and amenorrhea with menopausal symptoms in patients, the age of menopause, When conventional treatment doses, in very rare cases, there has been a restoration of ovarian function for continuing treatment; rarely – gynecomastia. (Busulfan animals provided a toxic effect on the reproductive system.)

From the body as a whole: in some cases – clinical syndrome (weakness, severe fatigue, anorexia, weight loss, nausea and vomiting, dermatomelasma), resembling adrenal insufficiency (Addison's disease), but without biochemical signs of oppression napochechnikov, hyperpigmentation of the mucous membranes and hair loss; rarely – common epithelial dysplasia (observed in rare cases after long-term therapy busul'fanom). This syndrome sometimes disappears after canceling busulfan. Patients, treated busul'fanom, discovered numerous histological and cytological changes, including common cervical epithelium dysplasia, the bronchi and the epithelium of the different localization. In most cases, such changes occur as a result of long-term therapy, However, transient epithelial abnormalities are described and after short-term treatment with high doses of.

Contraindications

— previously identified resistance to busul'fanu;

- Hypersensitivity to any component of the drug.

Pregnancy and lactation

If possible, avoid busulfan assignment during pregnancy, especially in the I trimester. In each case it is necessary to assess the potential risk to the fetus and the expected benefit to the mother.

Unknown, whether allocated busulfan with breast milk. Women, host busulfan, We recommend that you stop breastfeeding.

As with any treatment zitotoksicskimi drugs, When taking any of busulfan partners need to take measures to prevent pregnancy.

Busulfan provided teratogenic effects in animal studies, and has the potential teratogenic properties in humans. Describes several cases of birth defects, which were not necessarily related to busul'fanom; use of the drug in the third trimester of pregnancy may be accompanied by violation of the fetal growth. At the same time, there are many cases of birth healthy babies after applying busulfan, even during the 1st trimester of pregnancy.

Women, the age of menopause, often observed inhibition of ovarian function and amenorrhea with symptoms of menopause. In rare cases, noted restoration of ovarian function for continuing treatment.

Treatment of busul'fanom in high doses of girls in childhood and adolescence resulted in failure of ovarian function, including lack of puberty.

Busulfan violates spermatogenesis in experiment animals; men are the cases of sterility, azoospermia and testicular atrophy.

Cautions

Busulfan is cytotoxic means, that should only be used under medical supervision, with experience of therapy similar drugs.

When using an external envelope intact tablets Busulfan does not represent risk. Tablets should not be divided into parts. If you are using tablets Busulfan should comply with recommendations on the use of cytotoxic drugs.

Busulfan should be abolished when the signs of toxic effects on the lungs.

Usually, busulfan (myleran ®) do not apply in combination with radiation therapy or shortly thereafter.

Busulfan is inefficient in blastnoj stage of transformation (blastic crisis).

If patients with possible toxic lesions of lungs need general anesthesia, the inhaled oxygen concentration should be maintained at the lowest safe level; in the postoperative period, you must carefully monitor and maintain external respiratory function.

Immunization of live vakcinymi immunokomprometirovannyh patients is not recommended.

In patients with chronic myelogenous leukemia is often marked by elevated levels of uric acid in the blood and/or urine, that should be addressed before the appointment of busulfan. During treatment busul'fanom necessary prevention of gieperriquemii and mochekisloy nephropathy, including drinking enough fluids and the use of allopurinol.

Be cautious when applying busulfan treatment for true and essential polycytemia trombozitemii, in view of the carcinogenic properties of the drug. When these diseases is not recommended busulfan in patients of young age or, in the absence of symptoms. If the appointment is necessary busulfan, courses of therapy should be as short as possible.

While receiving a standard dose busulfan and itraconazole or metronidazole should carefully observe the patient for timely detection of signs of toxicity of busulfan. Simultaneous reception of metronidazole and busulfan in high doses not recommended. The appointment of high doses of busulfan simultaneously with itrakonazolom is left to the discretion of the attending physician and must be based on an assessment of the balance of risks and benefits.

When applying busulfan in the mode of high-dose therapy patients should take prophylactic anticonvulsants; It is preferable to designate drugs benzodiazepinovogo stimulants, rather than phenytoin.

Patients, taking busulfan, There were a variety of chromosomal aberrations. On the conclusion of the who, There is a causal link between application of busulfan and cancer development. Patients, long took busulfan, identify common epithelial dysplasia, some changes were similar with precancerous. Several patients, received busulfan, Describes cases of malignant tumors.

Accumulate data on, that Busulfan, like other alkylating means, provides lejkozogennoe effect. Although acute leukemia, probably, is a component of the natural history of true polycytemia, prolonged therapy an alkylating tool may increase the risk of its development.

Monitoring of laboratory parameters

During treatment busul'fanom you must regularly determine the number of loose blood to avoid pronounced mielosupression and irreversible aplazii bone marrow.

Overdose

Symptoms: manifestation of acute dozolimitirujushhej toxicity of busulfan in human is mielosuprescia. The main manifestation of chronic drug overdose – oppression kostnomozgovy blood and pancytopenia.

Treatment: the antidote is unknown. Perhaps dialysis (There is one report of successful breeding busulfan by dialysis). If there are signs of gematotoksicheskogo actions carry out appropriate supportive therapy.

Drug Interactions

Combination with other cytotoxic drugs busulfan, providing toxic effects on the lungs, can have an additive toxic effect on lung tissue.

Appointment of fenitoina patients, host busulfan in high doses, mielosupressivnogo may decrease the effect of the last.

Simultaneous application of busulfan and itraconazole may reduce the ground clearance by about busulfan 20%, with a corresponding increase in concentrations of busulfan in plasma. Metronidazole increases the minimum concentration of approximately busulfan 80%. Fluconazole did not affect clearance busulfan. For this reason, high-dose busul'fanom therapy in combination with itrakonazolom or metronidazole is accompanied by increased risk of toxicity of busulfan.

Patients, receiving high-dose busul'fanom therapy in combination with cyclophosphamide, WENO frequency-okkljuzivnoj liver disease and other signs of toxicity of this regime is reduced, If the appointment of the first dose of ziklofosfamida lay up, than 24 h after the last reception of busulfan.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug should be stored out of reach of children at or above 25 ° C. Shelf life – 3 year. Do not use the drug after expiry date, on the package.

Unused tablets should be destroy in accordance with the rules of hazardous and noxious substances.