Overview
Hypersensitivity to any component of the drug, pregnancy. The consequence of treatment with busulfan at the recommended dose and treatment regimen is a central suppression of bone marrow activity; a severe form of granulocytopenia, thrombocytopenia, anemia may occur; during treatment and until recovery, blood morphology should often be performed with a differential analysis of white blood cells and platelets. Consideration should be given to the use of anti-infective drugs (antibacterial, antifungal, antiviral) for the prevention and treatment of infections with neutropenia. Depending on the clinical indications, drugs can be used to increase the level of platelets and red blood cells. In adults, the total number of neutrophils 4 days after transplantation in 100% of patients was 0.5 × 109 / L and normalized 10 days procurement autologous transplantation, and 13 days after allogeneic transplantation. Thrombocytopenia occurred in 98% of patients after 5-6 days, anemia occurred in 69% of patients (hemoglobin = 3 cycles of chemotherapy or stem cell transplantation. Clinical studies have not central the occurrence of cardiac tamponade or other cardiotoxic effects associated with the use of the drug; neverthelessheart should be regularly monitored during treatment Busulfan may have toxic effects on the central system; in patients who have previously undergone radiotherapy of the mediastinum or lungs, attention should be paid to any signs of a respiratory procurement. Renal function should be monitored periodically during busulfan treatment. Patients should be informed of the increased risk of secondary malignancy. Based on human studies, bisulfan has been classified as a human carcinogen and WHO has confirmed a causal relationship another exposure to bisulfan and cancer: Numerous cytological abnormalities occurred in patients with leukemia who took busulfan ii, some developed cancer. The drug does not significantly affect the ability to drive a car and maintain mechanical equipment.
Interaction with other drugs
Itraconazole can reduce the clearance of busulfan, increasing its concentration in plasma. No interaction was found with fluconazole, as well as with antiemetic drugs from the group of 5-HT3 serotonin receptor antagonists (ondansetron, granisetron). Ketobemidone may increase serum busulfan concentrations; special care should be taken during the parallel use of these drugs. The occurrence of symptoms of poisoning may be affected by the interval between the last dose of busulfan and the first dose of cyclophosphamide; there is using this decrease in the incidence Busulfan obliterating liver diseases and other toxic symptoms in patients in whom this interval exceeded 24 hours. In children and adolescents, the use of melphalan procurement 24 hours after the last dose of busulfan is administered may procurement the onset of toxicity symptoms. Paracetamol decreases the level of glutathione in the blood and tissues; used in combination with busulfan may lead to a decrease in its clearance. Check should be exercised when using paracetamol in parallel or within 72 hours before starting treatment with busulfan.
Busulfan: side effects
Patients taking the drug in preparation for bone marrow transplantation may experience: acute inflammation of the mucous membranes, diarrhea, nausea, vomiting, and serious digestive upsets that limit the recommended dose. These symptoms occur after a dose of> 20 mg / kg body weight. Lower doses, as a rule, do not cause adverse reactions, in some cases convulsions may occur; in this regard, the use of anticonvulsants is recommended. The drug also causes a characteristic dark skin color, which disappears after a few months or throughout the year. In addition, it is believed that the use of busulfan increases the risk of liver disease, especially in combination with cyclophosphamide, as well as in combination with cyclophosphamide and whole body irradiation; this complication occurs less frequently with cyclophosphamide after more than 24 hours after the last dose of busulfan. For more information see: registered materials of the manufacturer. Very often: neutropenia, thrombocytopenia, anemia, pancytopenia, febrile neutropenia, Busulfan, pharyngitis, central reactions, anorexia, hyperglycemia, hypocalcemia, hypokalemia, hypomagnesemia, hypophosphatemia, anxiety, depression, insomnia, hypotension, headache, headache, headache, headache, headachethrombosis, vasodilation, shortness of breath, nosebleeds, cough, hiccups, stomatitis, diarrhea, abdominal pain, nausea, vomiting, dyspepsia, ascites, constipation, anal discomfort, enlarged liver, jaundice, rash, itching, alopec i, myalgia, back and / or joint pain, dysuria, oliguria, weakness, chills, fever, chest pain, edema, generalized edema, pain or inflammation at the injection site, increased activity of liver enzymes, increased bilirubin concentration, weight gain, increased creatinine. Often: hyponatremia, confusion, cardiac arrhythmias, atrial fibrillation, cardiomegaly, pericarditis, pericarditis, hyperventilation, respiratory failure, alveolar hemorrhage, asthma, atelectasis, pleurisy, bloody vomiting, intestinal obstruction, inflammation of the esophagus, liver disease and adolescents), peeling of the skin, erythema, pigmentation disorders, hematuria, moderate renal failure, increased concentration of urea in the blood, a decrease in the ejection fraction. Not very often: delirium, nervousness, hallucinations, agitation, convulsions, encephalopathy, cerebral hemorrhage, ventricular extrasystole, bradycardia, femoral artery thrombosis, capillary filtration syndrome, hypoxia, gastrointestinal bleeding. With an unknown frequency, cataracts, thinning of the cornea, premature menopause, and extinction of ovarian function occur. In case of overdose: bone marrow ablation to a large extent, pancytopenia, disorders of the central nervous system, liver, lungs and gastrointestinal tract. There is no specific antidote; hematological condition should be monitored and maintenance therapy should be used; consider using dialysis or glutathione.
Pregnancy and lactation
Category D. Animal studies have shown a negative effect on reproduction (death of the embryo and fetus, as well as malformations). The drug is contraindicated in pregnancy. Women of childbearing potential should use effective contraception during treatment and for 6 Busulfan after its completion. A drug used in myeloablative doses can cause irreversible infertility, especially if it is used after the start of hormonal activity by the genitals. Men are advised to use contraception during treatment and for 6 months after it is over, and also consider the possibility of freezing sperm. It is not known whether the drug passes into breast milk; women receiving busulfan should not breast-feed.
Busulfan: dosage
Intravenously, infusion. Conditioned treatment before classic hematopoietic stem cell transplantation in adults. 0.8 mg / kg body weight in an infusion lasting from 2 to 6 hours for 4 consecutive days (a total of 16 doses); cyclophosphamide 60 mg / kg body weight / day is then administered for 2 days; The interval between the introduction of cyclophosphamide and 16 doses of busulfan should be at least 24 hours. Preventative treatment before traditional stem cell transplantation in children and adolescents. Children weighing less than 9 kg - 1 mg / kg body weight, 9–16 kg - 1.2 mg / kg body weight, 16–23 kg - 1.1 mg / kg body weight, 23–34 kg - 0.95 mg / kg body weight, more than 34 kg - 0.8 mg / kg body weight; the drug is administered by infusion for 2 hours every 6 hours for 4 consecutive days (16 doses in total); then cyclophosphamide (4 cycles of 50 mg / kg body weight) or melphalan (one dose of 140 mg / m2) is administered with an interval of at least 24 hours after the administration of 16 doses of busulfan. All patients should receive prophylactic anticonvulsants (benzodiazepine derivatives or phenytoin) prophylactically. Before the introduction of the first dose and throughout the treatment period, antiemetic drugs should be prescribed. There is no need to change the dosage in patients with renal failure. Use with caution in patients with severe hepatic impairment. In patients with increased weight should consider changing the dosage include accordance with indicators of body weight. For detailed information on the use and modification of the dosage in certain groups of patients, see: registered materials of the manufacturer.
Notes
Store at 2–8 ° C. Do not freeze.
Busulfan has a cytostatic (inhibiting cell division) effect on myeloid cells (bone marrow cells, from which blood cells are formed - red blood cells and platelets). At relatively low doses, granulocytopoiesis (the formation of granulocytes - blood cells) selectively inhibits. In chronic granulocytic leukemia (a malignant tumor arising from hematopoietic cells and affecting bone marrow / blood cancer /), the drug reduces the total number of granulocytes, alleviates the symptoms of the disease and improves the clinical condition of the patient.
Indications for use:
Chronic granulocytic leukemia. True polyschgemia (increased red blood cell count) - to maintain prolonged remission (temporary weakening or disappearance of the manifestations of the disease), the drug is indicated in cases refractory (resistant) to radioisotope therapy in the presence of severe thrombocytosis (a sharp increase in platelet count in the blood). Certain cases of essential blood clotting (an increase in platelet count caused by unclear causes) and myelofibrosis (replacement of bone marrow cells with connective tissue).
Application Technique:
In case of chronic granulocytic leukemia during the period of induction (induction) of remission (temporary weakening or disappearance of the manifestations of the Busulfan, a daily dose of 0.06 mg / kg of body weight (maximum daily dose of 4 mg) is prescribed. The daily dose may be given once. For maintenance therapy, a dose of 0.5-2 mg / day is prescribed, but in some cases lower doses may be sufficient, while the level of leukocytes in the blood should be 10,000-15,000 in 1 mm cube. With true polythemia and essential thrombocythemia during the induction of remission, the daily dose is 4-6 mg. With myelofibrosis, the initial daily dose is 2-4 mg, while maintaining maintenance therapy, the dose is reduced.
In the course of treatment, careful monitoring of the peripheral blood picture should be carried out once a week during the period of remission induction and at least once every 4 weeks during maintenance therapy. The use of busulfan should be discontinued in cases of a decrease in the number of leukocytes to 20 000-25 000 per mm cubic meter. or lower platelet counts to 100,000 per mm3. In patients with hyperuricemia (increased uric acid in the blood) and / or hyperuricosuria (increased excretion of uric acid in the urine), correction of these disorders is required before starting treatment with busulfan.
Adverse events:
Depression (suppression of function) of the bone marrow, especially thrombocytopenia (a decrease in the number of platelets in the blood) and leukopenia (a decrease in the level of leukocytes in the blood). Cases of development of irreversible aplasia (structural damage) of the bone marrow. In patients in the period before menopause (the second phase of menopause that occurs after the last menstruation), suppression (suppression of function) of the ovaries and amenorrhea (absence of menstruation) often occurs. There are reports of the occurrence of chromosomal aberrations (changes in the structure of chromosomes - structural elements of the nucleus of the cell responsible for the transfer of hereditary information) in the cells of patients treated with busulfan, the development of azoospermia (absence of sperm in the semen) and testicular atrophy (decrease in testicular mass and volume with termination or a decrease in their function) in men. Very rarely - weakness, nausea, vomiting, diarrhea, hyperpigmentation (increased pigmentation / color / skin / mucous membranes).
Contraindications:
Pregnancy (especially the first 3 months) and the period of breastfeeding. The drug is not prescribed in the case of the development of power transformation (degeneration related pill cells from which the formed elements of the blood develop), as well as in patients who have recently received radiotherapy or other cytostatic drugs. Children are prescribed the drug in very rare cases.
