Myleran (Tablets) Instructions for Use

Marketing Authorization Holder

Aspen Pharma Trading, Limited (Ireland)

Manufactured By

Excella, GmbH & Co. KG (Germany)

Packaging and Quality Control Release

EXCELLA, GmbH & Co.KG (Germany)

Or

SCOPINPHARM, LLC (Russia)

ATC Code

L01AB01 (Busulfan)

Active Substance

Busulfan (Rec.INN registered by WHO)

Dosage Form

Myleran

Tablets, film-coated, 2 mg: 25 pcs.

Dosage Form, Packaging, and Composition

Tablets, film-coated white, round, biconvex, with the engraving “GX EF3” on one side and “M” on the other side.

Excipients: anhydrous lactose – 92.5 mg, pregelatinized corn starch – 5 mg, magnesium stearate – 0.5 mg.

Coating composition Opadry white OY-S-7322 (hypromellose, titanium dioxide, triacetin).

25 pcs. – dark glass bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Antitumor drug. Alkylating compound

Pharmacotherapeutic Group

Antineoplastic agent, alkylating compound

Pharmacological Action

Busulfan is a bifunctional alkylating agent.

The mechanism of action of busulfan is believed to be due to its binding to DNA; diguanyl derivatives have been isolated, but the formation of cross-links has not been confirmed.

The reasons for the unique selective effect of busulfan on granulocytopoiesis have not been fully established.

Although the drug does not achieve a cure, it significantly reduces the total number of granulocytes and leads to relief of disease symptoms and improvement in the general condition of patients.

Busulfan therapy has been shown to be more effective than splenic irradiation in terms of survival and maintenance of hemoglobin levels; in terms of effect on spleen size, the effectiveness of both methods did not differ.

Pharmacokinetics

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

The pharmacokinetic parameters of busulfan were also studied in patients taking high doses of the drug (1 mg/kg every 6 hours for 4 days).

The 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 its own metabolic rate upon repeated administration.

Steady-state plasma concentrations of busulfan range from 0.5 to 2.0 µg/ml (2-8 µmol).

C_max was 3.1-5.9 µg/ml in a patient who received a total dose of 16 mg/kg, and 3.8-9.7 µg/ml in two patients who received a total dose of 20 mg/kg.

In patients receiving high doses of busulfan, its metabolites were found in the urine: 3-hydroxysulfolane, 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 concentrations.

The ratio of busulfan concentrations in cerebrospinal fluid and plasma averages 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%, respectively.

Indications

• Chronic myeloid leukemia in the chronic phase of the disease.

Busulfan induces long-term remission in polycythemia vera, especially when accompanied by marked thrombocytosis.

Busulfan may be effective in individual cases of essential thrombocythemia and myelofibrosis.

ICD codes

Dosage Regimen

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 a patient requires 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.

The tablet should not be divided into parts.

Chronic myeloid leukemia. Remission induction in adults treatment is usually started immediately after diagnosis.

The dose is 0.06 mg/kg/day; the maximum initial dose is 4 mg/day, which can be administered as a single dose.

The individual response to Busulfan is variable; some patients may have high sensitivity of bone marrow cells to the drug.

During remission induction, blood tests should be monitored at least once a week.

The dose should be increased only if there is no adequate effect after 3 weeks of treatment.

Treatment should be continued until the total white blood cell count decreases to 15-25 x 10⁹/L (usually within 12-20 weeks).

Then treatment can be interrupted; after that, a further decrease in the white blood cell count may occur for another 2 weeks.

Continuing treatment at the induction dose beyond this point or after the platelet count drops below 100 x 10⁹/L carries a significant risk of prolonged 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 white blood cell count increases to 50 x 10⁹/L or when disease symptoms appear.

Some specialists prefer continuous maintenance therapy.

Continuous treatment is more justified for short remission durations.

The goal of treatment is to maintain the white blood cell count at a level of 10-15 x 10⁹/L; blood cell counts should be monitored at least once every 4 weeks.

The usual maintenance dose is 0.5-2 mg/day, but in individual cases it may be significantly lower.

NOTE: Busulfan should be prescribed in lower doses if used in combination with other cytotoxic agents.

Children

Chronic myeloid leukemia is rare in children.

Busulfan can be used to treat Philadelphia chromosome-positive (Ph’-positive) leukemia.

The juvenile Ph’-negative variant responds poorly to busulfan therapy.

Polycythemia vera

The usual dose is 4-6 mg/day; treatment is carried out for 4-6 weeks with careful monitoring of blood cell counts, especially platelets.

If relapses develop, course therapy can be resumed or, alternatively, maintenance therapy can be carried out at a dose of approximately half the induction dose.

If the treatment of polycythemia is mainly carried out by venesection, then short courses may be prescribed to control the platelet count.

Myelofibrosis

The usual 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

The usual dose is 2-4 mg/day.

Treatment should be discontinued if the total white blood cell count falls below 5 x 10⁹/L or the platelet count is less than 500 x 10⁹/L.

Adverse Reactions

There are no modern clinical data for this drug that could 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 drugs used in combination with it.

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

Blood and lymphatic system disorders: very common: dose-dependent bone marrow suppression, manifested by leukopenia and especially thrombocytopenia; rare: aplastic anemia, usually after long-term use of standard doses, as well as when using high doses of busulfan.

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

Eye disorders rare: lens changes and cataract, which may be bilateral; corneal thinning was observed after bone marrow transplantation preceded by high-dose busulfan therapy.

Cardiac disorders common: cardiac tamponade in patients with thalassemia receiving high doses of busulfan.

Respiratory, thoracic and mediastinal disorders rare: interstitial pulmonary fibrosis.

Diffuse interstitial pulmonary fibrosis with progressive dyspnea and persistent non-productive cough occurs rarely, usually after long-term treatment over several years.

Histological features include atypical changes in alveolar and bronchiolar epithelium and the presence of giant cells with large hyperchromatic nuclei.

If toxic lung damage is detected, the prognosis, even despite discontinuation of busulfan, is unfavorable – in this situation, corticosteroids are of little benefit.

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 have also been described.

Subsequent radiation therapy may enhance subclinical lung damage caused by busulfan.

Other cytotoxic drugs may cause additive toxic lung damage.

Gastrointestinal disorders very common: nausea, vomiting, diarrhea, and ulceration of the oral mucosa when using high doses of busulfan.

Symptoms can probably be alleviated by using fractional doses.

Hepatobiliary disorders very common: hyperbilirubinemia, jaundice, hepatic veno-occlusive disease and centrilobular sinusoidal fibrosis with hepatocellular atrophy and necrosis when using high doses; rare: cholestatic jaundice and liver function disorders when using conventional doses, centrilobular sinusoidal fibrosis.

It is believed that in usual therapeutic doses, Busulfan does not have a significant toxic effect on the liver.

However, a retrospective analysis of pathological data from patients who received a low dose of busulfan for at least two years for chronic granulocytic leukemia revealed the presence of centrilobular sinusoidal fibrosis.

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

Skin and subcutaneous tissue disorders: common: alopecia during high-dose therapy, hyperpigmentation; rare: alopecia when using conventional doses, skin reactions, including urticaria, erythema multiforme, erythema nodosum, late cutaneous porphyria, allopurinol-type rash, as well as excessive dryness and brittleness of the skin with complete anhidrosis, dryness of the oral mucosa and cheilosis, Sjögren’s syndrome.

More pronounced skin radiation changes in patients receiving radiation therapy soon after high-dose busulfan therapy.

Cases of hyperpigmentation have been described, particularly 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.

Renal and urinary disorders: common: hemorrhagic cystitis during high-dose therapy in combination with cyclophosphamide.

Reproductive system and breast disorders: very common: ovarian function suppression and amenorrhea with menopausal symptoms in premenopausal patients during high-dose therapy; severe and persistent ovarian failure, including lack of puberty after administration of high doses to young girls and pre-adolescent girls.

Sterility, azoospermia and testicular atrophy in men receiving Busulfan; uncommon: ovarian function suppression and amenorrhea with menopausal symptoms in premenopausal patients during conventional dose therapy.

In very rare cases, restoration of ovarian function was observed while continuing treatment; very rare: gynecomastia.

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

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

This syndrome sometimes disappears after discontinuation of busulfan.

In patients treated with busulfan, numerous histological and cytological changes have been found, including widespread dysplasia of the cervical epithelium, bronchial epithelium, and epithelium of other locations.

In most cases, such changes occur as a result of long-term therapy, but transient epithelial abnormalities have also been described after short-term high-dose therapy.

Contraindications

• Patients with previously identified resistance to busulfan;
• Patients with hypersensitivity to any component of this drug.

Use in Pregnancy and Lactation

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 had a teratogenic effect in animal studies and has potential teratogenic properties in humans.

Several cases of congenital malformations have been described, which were not necessarily associated with busulfan; use of the drug in the third trimester of pregnancy may be accompanied by impaired fetal growth.

At the same time, many cases of healthy children being born after exposure to busulfan in vivo even during the first trimester of pregnancy are known.

Women taking this drug are not recommended to breastfeed.

Pediatric Use

Treatment with high doses of busulfan in girls during childhood and adolescence led to ovarian failure, including lack of puberty.

Special Precautions

Busulfan is a cytotoxic agent that should be used only under the supervision of physicians experienced in the use of such drugs.

If the outer shell is intact, the use of busulfan tablets does not pose a risk.

The tablets should not be divided into parts.

When using busulfan tablets, the recommendations for the use of cytotoxic drugs should be followed.

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

As a rule, Busulfan is not used in combination with radiotherapy or soon after a course of radiotherapy.

Busulfan is not effective in the blast transformation phase.

If patients with possible toxic lung damage require general anesthesia, the concentration of inhaled oxygen should be maintained at the lowest safe level; in the postoperative period, external respiratory function should be carefully monitored and maintained.

Patients with chronic myeloid leukemia often have hyperuricemia and/or hyperuricosuria, which should be eliminated before prescribing busulfan.

During treatment with busulfan, prevention of hyperuricemia and uric acid nephropathy is necessary, including adequate fluid intake and the use of allopurinol.

Special caution should be exercised when using busulfan to treat polycythemia vera 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 prescription is necessary, the courses of therapy should be as short as possible.

When treating with high doses of busulfan, patients should take anticonvulsants prophylactically; benzodiazepine drugs are preferred over phenytoin.

When busulfan and itraconazole are taken simultaneously, the patient’s condition should be carefully monitored for the timely detection of signs of busulfan intoxication.

Monitoring during treatment with busulfan, regular monitoring of the complete blood count is necessary to avoid severe myelosuppression and irreversible bone marrow aplasia.

Mutagenic and carcinogenic properties various chromosomal aberrations have been observed in patients taking Busulfan.

According to the WHO conclusion, there is a causal relationship between exposure to busulfan and the development of cancer.

In patients who took Busulfan for a long time, widespread epithelial dysplasia was detected; some changes were similar to precancerous.

Several cases of malignant tumors have been described in patients receiving Busulfan.

There is evidence that Busulfan, like other alkylating agents, has a leukemogenic effect.

Although acute leukemia is probably a component of the natural course of polycythemia vera, long-term therapy with an alkylating agent may increase the risk of its development.

Teratogenic properties Busulfan had a teratogenic effect in animal studies and has potential teratogenic properties in humans.

Several cases of congenital malformations have been described, which were not necessarily associated with busulfan; use of the drug in the third trimester of pregnancy may be accompanied by impaired fetal growth.

At the same time, many cases of healthy children being born after exposure to busulfan in vivo even during the first trimester of pregnancy are known.

Fertility in premenopausal women, suppression of ovarian function and amenorrhea with menopausal symptoms are often observed. In rare cases, restoration of ovarian function has been reported during continued treatment.

Treatment with high doses of busulfan in girls during childhood and adolescence has led to ovarian insufficiency, including failure to undergo puberty.

Busulfan impairs spermatogenesis in animal experiments; in men, cases of sterility, azoospermia, and testicular atrophy have been described.

Effect on the ability to drive vehicles and machinery

There are no data on the effect of busulfan on the ability to drive a car or operate complex machinery. Considering the pharmacological properties of the drug, such an effect is unlikely.

Overdose

Symptoms the manifestation of acute dose-limiting toxicity of busulfan in humans is myelosuppression. When Busulfan is used in high doses in combination with bone marrow transplantation, the dose-limiting factor becomes toxicity to the gastrointestinal tract with damage to the mucous membranes, nausea, vomiting, diarrhea, and anorexia.

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

Treatment no antidote is known. There is no information on the possible effectiveness of dialysis.

If signs of toxicity to hematopoiesis are present, appropriate symptomatic therapy is carried out.

Drug Interactions

The combination of busulfan with other pneumotoxic cytotoxic drugs may enhance the toxic effect on lung tissue.

Prescribing phenytoin to patients taking high doses of busulfan may lead to a reduction in the effect of the latter.

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

Storage Conditions

List A.

The drug should be stored at a temperature below 25°C (77°F), in a place inaccessible to children.

Unused tablets should be disposed of in accordance with the rules for the disposal of hazardous and toxic substances.

Shelf Life

The shelf life is 3 years. Do not use the drug after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.