Myleran pills 2mg, 25pcs

Composition

Active ingredient: busulfan 2.0 mg.

Excipients: lactose anhydrous, pregelatinized starch, magnesium stearate.

Tablet shell: opadray white OY-S-7322, hypromellose, titanium dioxide, triacetin.

Pharmacological action

Pharmacological action Busulfan is a bifunctional alkylating drug. It is believed that the mechanism of action of busulfan is due to binding to DNA; diguanyl derivatives have been isolated, but the formation of inter-chain bonds has not been confirmed.

The reasons for the unique selective effect of busulfan on granulocytopoiesis are not fully established. Although the drug does not allow for a cure, it significantly reduces the total number of granulocytes and leads to relief of symptoms of the disease and improvement of the general condition of patients.

Busulfan therapy was more effective than spleen irradiation in terms of survival and maintenance of hemoglobin levels; the effectiveness of both methods did not differ in terms of the effect on the size of the spleen.

Pharmacokinetics Basulfan in doses of 2-6 mg is well absorbed; the half-life is 2.57 hours.

The pharmacokinetics of busulfan were also studied in patients taking high doses of the drug (1 mg / kg every 6 hours for 4 days). The elimination half-life was 3.4 hours after the first dose and 2.3 hours after the last dose. These data suggest that busulfan may increase the rate of its own metabolism with repeated use.

Steady – state plasma concentrations of busulfan vary from 0.5 to 2.0 µg / ml (2-8 µmol). Cmax was 3.1-5.9 mcg / ml in a patient who received a total dose of 16 mg / kg, and 3.8-9.7 mcg / ml in two patients who received a total dose of 20 mg/kg.

In patients who received high doses of busulfan, its metabolites were detected in the urine: 3-hydroxysulfolan, tetrahydrothiophene-1-oxide and sulfolane. A small amount of the drug (1-2%) is excreted unchanged in the urine.

When administered in high doses, busulfan penetrates into the cerebrospinal fluid, where its concentrations are comparable to plasma. The average ratio of busulfan concentrations in cerebrospinal fluid and plasma is 1.3: 1. The ratio of busulfan concentrations in saliva and plasma is 1.1 : 1.

The degree of reversible binding to plasma proteins varies from insignificant to 55%. The degree of irreversible binding to blood cells and plasma proteins is 47% and 32%.

Indications

-chronic myeloid leukemia in the chronic phase of the disease.

Busulfan causes long-term remission in true polycythemia, especially with severe thrombocytosis.

Busulfan may be effective in some cases for essential thrombocythemia and myelofibrosis.

Use during pregnancy and lactation

The use of the drug during pregnancy is possible only if the intended benefit to the mother outweighs the potential risk to the fetus.

Teratogenic properties: busulfan has been shown to have a teratogenic effect in animal studies and has potential teratogenic properties in humans. Several cases of congenital malformations have been described that were not necessarily associated with busulfan; the use of the drug in the third trimester of pregnancy may be accompanied by impaired fetal growth. At the same time, there are many known cases of healthy babies being born after in vivo exposure to busulfan, even during the first trimester of pregnancy.

Women taking this medicine are not recommended to breastfeed their baby.

Contraindications

-patients with previously identified busulfan resistance;

— patients with hypersensitivity to any component of this drug.

Side effects

For this drug, there are no current clinical data that can be used to determine the frequency of side effects. The frequency of side effects may vary depending on the dose of Busulfan received by the patient, as well as on other medications used in combination with it.

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

From the hematopoietic and lymphatic system:  very common: dose-dependent bone marrow depression, manifested by leukopenia and especially thrombocytopenia; rare: aplastic anemia, usually after prolonged use of standard doses, as well as when using high doses of busulfan.

Nervous system disorders: rare: convulsions when using high doses; very rare: severe myasthenia gravis.

From the side of the visual organs: rare: lens changes and cataracts that may be bilateral; corneal thinning was observed after bone marrow transplantation, which was preceded by high-dose busulfan therapy.

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

Respiratory, thoracic and mediastinal disorders: rare: interstitial lung fibrosis. Diffuse interstitial pulmonary fibrosis with progressive dyspnea and persistent unproductive cough occurs rarely, usually after prolonged treatment for several years. Histological signs include atypical changes in the epithelium of the alveoli and bronchioles and the presence of giant cells with large hyperchromatic nuclei. If toxic lung damage is detected, the prognosis, even despite the withdrawal of busulfan, is unfavorable – in this situation, there is little benefit from the use of corticosteroids. Interstitial pulmonary fibrosis usually develops gradually, but can also have an acute course. This pulmonary pathology can be complicated by infections. Ossification and dystrophic calcification of the lungs are also described. It is possible that subsequent radiation therapy may increase the subclinical lung damage caused by busulfan. Other cytotoxic drugs can cause additive toxic lung damage.

From the gastrointestinal tract:  very common: nausea, vomiting, diarrhea and ulceration of the oral mucosa when using high doses of busulfan. Symptoms can probably be alleviated by applying fractional doses.

Hepatobiliary disorders:  very common: hyperbilirubinemia, jaundice, hepatic vein occlusion and centrolobular sinusoidal fibrosis with hepatocellular atrophy and necrosis when using high doses; rare: cholestatic jaundice and liver function disorders when using normal doses, centrolobular sinusoidal fibrosis.

It is believed that busulfan does not have a significant toxic effect on the liver in normal therapeutic doses. At the same time, a retrospective analysis of pathoanatomical data on patients who received a low dose of busulfan for at least two years for chronic granulocytic leukemia revealed the presence of centrolobular sinusoidal fibrosis.

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

Skin and subcutaneous tissue disorders:  common: alopecia at high doses, hyperpigmentation; rare: alopecia at normal doses, skin reactions including urticaria, erythema multiforme, erythema nodosum, late cutaneous porphyria, allopurinol-type rash, as well as excessive dryness and fragility of the skin with complete anhidrosis, dryness of the oral mucosa and cheilosis, Sjogren’s syndrome. More pronounced radiation skin changes in patients receiving radiation therapy shortly after treatment with high doses of busulfan.

Cases of hyperpigmentation are described, in particular in dark-skinned patients. It is often most pronounced on the neck, upper torso, nipples, abdomen, and palmar folds. Hyperpigmentation may be part of a clinical syndrome.

From the side of the kidneys and urinary tract:  frequent: hemorrhagic cystitis in the treatment of high doses in combination with cyclophosphamide.

From the side of the reproductive system and mammary glands:  very common: ovarian suppression and amenorrhea with menopausal symptoms in premenopausal patients treated with high doses; severe and persistent ovarian insufficiency, including lack of puberty after high doses to young girls and girls under adolescence. Sterility, azoospermia and testicular atrophy in men treated with busulfan; infrequent: ovarian suppression and amenorrhea with menopausal symptoms in premenopausal patients treated with conventional doses. In very rare cases, recovery of ovarian function was observed with continued treatment; very rare: gynecomastia.

The study of busulfan in animal experiments revealed its toxic effect on the reproductive system.

General violations:  very rare: clinical syndrome (weakness, severe fatigue, anorexia, weight loss, nausea and vomiting, hyperpigmentation of the skin), similar to adrenal insufficiency (Addison’s disease), but without biochemical signs of adrenal suppression, hyperpigmentation of the mucous membranes and hair loss; rare: widespread epithelial dysplasia (observed in rare cases after long-term busulfan therapy). This syndrome sometimes disappears after busulfan withdrawal.

Numerous histological and cytological changes were found in patients treated with busulfan, including widespread dysplasia of the cervical epithelium, bronchi, and epithelium of other localization.In most cases, such changes occur during long-term therapy, but transient epithelial abnormalities are also described after short-term treatment with high doses.

Interaction

The combination of busulfan with other pulmonotoxic cytostatic drugs may increase the toxic effect on lung tissue.

use of phenytoin to patients taking high doses of busulfan may reduce the effect of the latter.

Concomitant use of busulfan and itraconazole may reduce the clearance of busulfan.

How to take, course of use and dosage

Busulfan is usually prescribed in courses or continuously. The dose is selected individually for each patient, depending on the clinical condition and hematological parameters. If the patient needs a dose of less than 2 mg / day (less than one tablet), the drug can be taken not daily, but at intervals of one or more days. You can’t divide a tablet into parts.

Chronic myeloid leukemia. Induction of remission in adults: treatment usually begins immediately after diagnosis.

The dose is 0.06 mg / kg / day; the maximum initial dose is 4 mg / day, it can be administered in one dose.

Individual reactions to busulfan are variable; some patients may have high sensitivity of bone marrow cells to the drug. During the induction of remission, blood tests should be monitored at least once a week.

The dose should be increased only if there is no proper effect after 3 weeks of treatment. Treatment should be continued until the total number of white blood cells decreases to 15-25 x 109/l (usually within 12-20 weeks). Then the treatment can be interrupted; after that, a further decrease in the number of white blood cells may occur for another 2 weeks. Continuation of treatment at an induction dose after this point or after a decrease in the platelet count of less than 100 x 109/l is associated with a significant risk of long-term and possibly irreversible bone marrow aplasia.

Maintenance therapy in adults:

Long-term remission of leukemia can be achieved without subsequent busulfan therapy; additional courses of treatment are usually carried out when the number of white blood cells increases to 50 x 109/l or when symptoms of the disease appear.

Some specialists prefer to conduct continuous maintenance therapy. Permanent treatment is more reasonable if the duration of remissions is short.

The goal of treatment is to maintain the number of white blood cells at the level of 10-15 x 109/l; the number of blood cells should be monitored at least once every 4 weeks. Usually, the maintenance dose is 0.5-2 mg / day, but in individual cases it can be significantly lower.

NOTE: busulfan should be administered at lower doses if it is used in combination with other cytotoxic agents.

Children:

Chronic myeloid leukemia in children is rare.

Busulfan can be used to treat Philadelphia chromosome leukemia (Ph’-positive). The juvenile Ph ‘ – negative variant responds poorly to busulfan therapy.

True polycythemia:

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

If relapses occur, a course of therapy may be resumed or, alternatively, maintenance therapy may be provided at a dose of approximately half the induction dose.

If polycythemia is mainly treated by venesection, short courses may be prescribed to control the platelet count.

Myelofibrosis:

Usually, the initial dose is 2-4 mg/day of busulfan.

Careful monitoring of hematological parameters is necessary, given the very high sensitivity of bone marrow cells in myelofibrosis.

Essential thrombocythemia:

Usually the dose is 2-4 mg / day.

Treatment should be discontinued if the total white blood cell count is reduced to less than 5 x 109/l or the platelet count is less than 500 x 109/l.

Overdose

Symptoms: the manifestation of acute dose-limiting toxicity of busulfan in humans is myelosuppression. If busulfan is used in a high dose in combination with bone marrow transplantation, the dose-limiting factor is a toxic effect on the gastrointestinal tract with mucosal damage, nausea, vomiting, diarrhea and anorexia.

The main manifestation of chronic drug overdose is bone marrow suppression and pancytopenia.

Treatment: the antidote is unknown. There is no information about the possible effectiveness of dialysis.

If there are signs of a toxic effect on hematopoiesis, appropriate symptomatic therapy is performed.

Special instructions

Busulfan is a cytotoxic agent that should only be used under the supervision of doctors who have experience using such drugs.

With an intact outer shell, the use of busulfan tablets does not pose a risk. Tablets should not be divided into parts. When using busulfan tablets, follow the recommendations for the use of cytotoxic drugs.

Busulfan should be discontinued if there are signs of toxic effects on lung tissue.

As a rule, busulfan is not used in combination with radiotherapy or shortly after the course of radiotherapy.

Busulfan is not effective in the blast transformation stage.

If patients with possible toxic lung damage require general anesthesia, then the concentration of inhaled oxygen should be maintained at the lowest safe level; in the postoperative period, it is necessary to carefully monitor and maintain the function of external respiration.

Patients with chronic myeloid leukemia often have hyperuricemia and / or hyperuricosuria, which should be eliminated before busulfan is prescribed. During treatment with busulfan, prevention of hyperuricemia and uric acid nephropathy is necessary, including the consumption of sufficient fluids and the use of allopurinol.

Special care should be taken when using busulfan for the treatment of true polycythemia and essential thrombocythemia, given the carcinogenic properties of the drug. For these diseases, it is not recommended to use busulfan in young patients or in the absence of symptoms. If busulfan is necessary, the course of therapy should be as short as possible.

When treated with high doses of busulfan, patients should take anticonvulsants for preventive purposes; it is preferable to prescribe benzodiazepine-type drugs than phenytoin.

When taking busulfan and itraconazole at the same time, the patient’s condition should be carefully monitored in order to detect signs of busulfan intoxication in a timely manner.

Monitoring: during treatment with busulfan, a general blood count should be monitored regularly to avoid severe myelosuppression and irreversible bone marrow aplasia.

Mutagenic and carcinogenic properties: Various chromosomal aberrations were observed in patients taking busulfan.

According to the WHO, there is a causal relationship between busulfan exposure and cancer development. Patients who took busulfan for a long time showed widespread epithelial dysplasia; some changes were similar to precancerous ones. Several patients treated with busulfan have been reported to develop malignancies.

There is evidence that busulfan, like other alkylating agents, has a leukemic effect. Although acute leukemia is probably a component of the natural course of true polycythemia, long-term treatment with an alkylating agent may increase the risk of its development.

Teratogenic properties: busulfan has been shown to have a teratogenic effect in animal studies and has potential teratogenic properties in humans. Several cases of congenital malformations have been described that were not necessarily associated with busulfan; the use of the drug in the third trimester of pregnancy may be accompanied by impaired fetal growth. At the same time, there are many known cases of healthy babies being born after in vivo exposure to busulfan, even during the first trimester of pregnancy.

Fertility: premenopausal women often experience ovarian suppression and amenorrhea with menopausal symptoms. In rare cases, ovarian function was restored with continued treatment.

Treatment with high doses of busulfan in girls in childhood and adolescence resulted in ovarian failure, including the absence of puberty.

Busulfan disrupts spermatogenesis in experimental animals; cases of sterility, azoospermia, and testicular atrophy have been reported in men.

Influence on the ability to drive motor vehicles and manage mechanisms

There is no data on the effect of busulfan on the ability to drive a machine and work with complex equipment. Given the pharmacological properties of the drug, such an effect is unlikely.

Form of production

Coated tablets,2 mg: 25 pcs.

Storage conditions

List A. The drug should be stored at temperatures below 25°C, out of the reach of children. Unused tablets should be disposed of in accordance with the rules for the disposal of hazardous and toxic substances.

Expiration date

Shelf life is 3 years. Do not use the product after the expiration date indicated on the package.

Active ingredient

Busulfan

Conditions of release from pharmacies

By prescription

Dosage form

Tablets