Myleran 2 mg

Early pharmacokinetic studies were carried out with radioactively labelled busulfan. More recently, gas liquid chromatography with selected ion monitoring has been used to quantitate busulfan in biological fluids. Absorption of busulfan shows intra-individual variation. Both zero and first-order absorption, one compartment open models have been fitted to pharmacokinetic data. The mean half-life for drug elimination was 2.57 hours.

More recently, automated solid phase extraction with liquid chromatography mass spectrometry analysis has been used to quantitate busulfan in plasma. In a study of 12 patients administered single oral dose of busulfan 4 to 8 mg, the mean (dose adjusted to 4 mg) maximum plasma concentration (68±24 ng/ml) occurred between 0.5 and 2 hours after administration. The mean terminal plasma elimination half-life was 2.7±0.5 hours.

The bioavailability of oral busulfan shows large intra-individual variation ranging from 22% to 120% in adults and children.

The pharmacokinetics of busulfan have also been studied in patients following high-dose administration (1 mg/kg administered orally every 6 hours for 4 days). The mean elimination half-life was 2.3 hours after the final busulfan dose, but 3.4 hours after the first dose. The mean steady-state plasma concentration was 1.1 µg/mL after 2 to 3 doses 6 hours apart. Due to the variable absorption kinetics observed, it was not possible to evaluate the order of kinetics.

The primary mode of elimination of busulfan is through extensive metabolism and very little (1-2%) of the drug is excreted unchanged in the urine. In humans, busulfan is at least partly metabolized via the glutathione route. The urinary metabolites of busulfan have been identified as 3-hydroxysulpholane, tetrahydrothiophene 1-oxide and sulpholane, in patients treated with high-dose busulfan. The clinical activity of these compounds, however, remains unclear.

Busulfan given in high doses has recently been shown to enter the cerebrospinal fluid (CSF) in concentrations comparable to those found in plasma, with a mean CSF:plasma ratio of 1.3:1. The saliva:plasma distribution of busulfan was 1.1:1.

The level of busulfan bound reversibly to plasma proteins has been variably reported to range from insignificant to approximately 55%. Irreversible binding of drug to blood cells and plasma proteins has been reported to be 47% and 32%, respectively.

The chief toxic effect is a dosage-related myelosuppression which may cause leukopenia and thrombocytopenia (hemorrhage) and eventually lead to pancytopenia.

Aplastic anemia (sometimes irreversible) has been reported rarely, often following long-term conventional doses and also high doses of busulfan.

Hyperbilirubinemia, jaundice and hepatic veno-occlusive disease and centrilobular sinusoidal fibrosis with hepatocellular atrophy and necrosis have been observed in patients receiving high dose busulfan (see Warnings).

Interstitial pulmonary fibrosis has been reported rarely, but it is a clinically significant adverse effect when observed and calls for immediate discontinuation of further administration of the drug. The role of corticosteroids in arresting or reversing the fibrosis has been reported to be beneficial in some cases and without effect in others.

The lung pathology may be complicated by superimposed infections.

Pulmonary ossification and dystrophic calcification have also been reported.

Cardiac tamponade has been reported in a small number of patients with thalassemia who received high doses of busulfan and cyclophosphamide as the preparatory regimen for bone marrow transplantation (see Warnings).

One case of endocardial fibrosis has been reported in a 79 year-old woman who received a total dose of 7200 mg over a period of 9 years for the management of chronic myelogenous leukemia. At autopsy, she was found to have endocardial fibrosis of the left ventricle in addition to interstitial pulmonary fibrosis.

Other complications of therapy include instances of nausea, vomiting, diarrhea, dryness of the oral mucous membranes and cheilosis, glossitis, urticaria, erythema multiforme, erythema nodosum, porphyria cutanea tarda, myasthenia gravis, cholestatic jaundice, impotence, sterility, amenorrhea, gynecomastia, excessive dryness and fragility of the skin with anhidrosis, alopecia and, hemorrhagic cystitis. Seizures have been observed in patients receiving higher than recommended doses of busulfan (see Precautions, General).

Busulfan is capable of inducing cataracts in rats and there have been several reports indicating that this is a rare complication in humans. In the few cases reported in humans, cataracts have occurred only after prolonged administration of busulfan.

Corneal thinning has been reported with the investigational use of high-dose busulfan prior to bone marrow transplantation.

Esophageal varices have been reported in patients receiving continuous busulfan and thioguanine therapy for treatment of chronic myelogenous leukemia (see Precautions, Drug Interactions).

Hyperpigmentation is the most common adverse skin reaction and occurs in 5 to 10% of patients, particularly those with a dark complexion. It is often most marked on the neck, upper trunk, nipples, abdomen and palmar creases.

Hyperuricemia and/or hyperuricosuria are not uncommon in patients with chronic myelogenous leukemia. Additional rapid destruction of granulocytes may accompany the initiation of chemotherapy and increase the urate pool. The risk of uric acid nephropathy can be minimized by increased hydration, urine alkalinization, and the prophylactic administration of a xanthine oxidase inhibitor such as allopurinol.

In a few cases, a clinical syndrome closely resembling adrenal insufficiency and characterized by weakness, severe fatigue, anorexia, weight loss, nausea and vomiting, and melanoderma has developed after prolonged busulfan therapy. The symptoms have sometimes been reversible when busulfan was withdrawn. Adrenal responsiveness to exogenously administered ACTH has usually been normal. However, pituitary function testing with metyrapone revealed a blunted urinary 17-hydroxycorticosteroid excretion in two patients. Following the discontinuation of busulfan (which was associated with clinical improvement), rechallenge with metyrapone revealed normal pituitary-adrenal function.

Busulfan may cause additive pulmonary toxicity when administered with other cytotoxic drugs.

Busulfan may cause additive myelosuppression when used with other myelosuppressive drugs.

The administration of phenytoin to patients receiving high-dose busulfan may result in a decrease in the myeloblative effect, due to increased busulfan clearance.

In one study, 12 of approximately 330 patients receiving continuous busulfan and thioguanine therapy for treatment of chronic myelogenous leukemia were found to have esophageal varices associated with abnormal liver function tests. Subsequent liver biopsies were performed in 4 of these patients, all of which showed evidence of nodular regenerative hyperplasia. Duration of combination therapy prior to the appearance of esophageal varices ranged from 6 to 45 months. However, subsequent large clinical trials have demonstrated increasing evidence that thioguanine alone results in severe liver toxicity, negating the influence of busulfan.

The concomitant systemic administration of itraconazole to patients receiving high-dose busulfan may result in reduced busulfan clearance.

A reduced incidence of hepatic veno-occlusive disease and other regimen-related toxicities have been observed in patients treated with high-dose busulfan and cyclophosphamide when the first dose of cyclophosphamide has been delayed for >24 hours after the last dose of busulfan.

It is recommended that evaluation of the hemoglobin or hematocrit, total white blood cell count and differential count, and quantitative platelet count be obtained weekly while the patient is on busulfan therapy. In cases where the cause of fluctuation in the formed elements of the peripheral blood is obscure, bone marrow examination may be useful for evaluation of marrow status. A decision to increase, decrease, continue, or discontinue a given dose of busulfan should be based not only on the absolute hematologic values, but also on the rapidity with which changes are occurring. The dosage of busulfan may need to be reduced if combined with other drugs whose primary toxicity is myelosuppression. Occasionally, patients may be unusually sensitive to busulfan administered at standard dosages and suffer neutropenia or thrombocytopenia after a relatively short exposure to the drug. Busulfan should not be used where facilities for complete blood counts, including quantitative platelet counts, are not available at weekly (or more frequent) intervals.

It is not known whether busulfan or its metabolites are excreted in human milk. Mothers receiving busulfan should not breast feed their infants. Because of the potential for tumorigenicity shown in animal and human studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Use of busulfan should be restricted to patients for whom complete blood counts are available at intervals of at least 1 week. The most careful hematological control is essential since large doses may produce irreversible depression of the bone marrow which may not be obvious for 4 to 6 months.

The most consistent, dose-related toxicity is bone marrow suppression. This may be manifested by anemia, leukopenia, thrombocytopenia or any combination of these. It is imperative that patients be instructed to report promptly the development of fever, sore throat, signs of local infection, bleeding from any site or symptoms suggestive of anemia. Any one of these findings may indicate busulfan toxicity; however, they may also indicate transformation of the disease to an acute blastic form. Since busulfan may have a delayed effect on the bone marrow, it is important to withdraw the medication temporarily at the first sign of an abnormally large or exceptionally rapid fall in any of the formed elements of the blood.

Seizures have been reported in patients receiving very high, investigational doses of busulfan. As with any potentially epileptogenic drug, caution should be exercised when administering very high doses of busulfan to patients with a history of seizure disorder, head trauma, or receiving other potentially epileptogenic drugs. Some investigators have used prophylactic anticonvulsivant therapy in this setting.

Teratogenic Effects: see Warnings.

Nonteratogenic Effects: There have been reports in the literature of small infants being born after the mothers received busulfan during pregnancy, in particular, during the third trimester. One case was reported where an infant had mild anemia and neutropenia at birth after busulfan was administered to the mother from the eighth week of pregnancy to term.

Patients beginning therapy with busulfan should be informed of the importance of having periodic blood counts and to immediately report any unusual fever or bleeding. Aside from the major toxicity of myelosuppression, patients should be instructed to report any difficulty in breathing, persistent cough or congestion. They should be told that diffuse pulmonary fibrosis is an infrequent but serious and potentially life-threatening complication of long-term busulfan therapy. Patients should be alerted to report any signs of abrupt weakness, unusual fatigue, anorexia, weight loss, nausea and vomiting, and melanoderma that could be associated with a syndrome resembling adrenal insufficiency. Patients should never be allowed to take the drug without medical supervision and they should be informed that other encountered toxicities to busulfan include infertility, amenorrhea, skin hyperpigmentation, drug hypersensitivity, dryness of the mucous membranes and rarely cataract formation. Patients of childbearing potential should be advised to avoid becoming pregnant. Mothers receiving Myleran should not breast feed their infants. The increased risk of a secondary malignancy should be explained to the patient.

As with all cytotoxic chemotherapy, adequate contraceptive precautions should be used when either partner is receiving busulfan.

Busulfan may cause fetal harm when administered to a pregnant woman. Although there have been a number of cases reported where apparently normal children have been born after busulfan treatment during pregnancy, one case has been cited where a malformed baby was delivered by a mother treated with busulfan. During the pregnancy that resulted in the malformed infant, the mother received x-ray therapy early in the first trimester, mercaptopurine until the third month, then busulfan until delivery.

When cytotoxic drugs are used in pregnancy, the possible teratogenic effect on the fetus should be kept in mind. Delay treatment as long as possible and certainly until after the first 3 months of pregnancy. Women of childbearing potential should be advised to avoid becoming pregnant. In every individual case the expected benefit of treatment to the mother must be weighed against the possible risks to the fetus.

There is evidence from animal studies that busulfan produces foetal abnormalities and adverse effects on off-spring, including defects of the musculoskeletal system, reduced body weight and size, and impairment of gonadal development and effects on fertility.

In pregnant rats, busulfan produces sterility in both male and female offspring, due to the absence of germinal cells in testes and ovaries. Germinal cell aplasia or sterility in offspring of mothers receiving busulfan during pregnancy has not been reported in humans.

Effects on Fertility: Ovarian suppression and amenorrhea with menopausal symptoms commonly occur during busulfan therapy in premenopausal patients. In very rare cases, recovery of ovarian failure has been reported with continuing treatment. Treatment with high-dose busulfan has been associated with severe and persistent ovarian failure, including failure to achieve puberty after administration to young girls and pre-adolescents. Busulfan interferes with spermatogenesis in experimental animals and there have been clinical reports of sterility, azoospermia and testicular atrophy in male patients.

Purpuric hemorrhages.

The hematologic status should be closely monitored and vigorous supportive measures instituted if necessary. Induction of vomiting or gastric lavage followed by administration of charcoal would be indicated if ingestion were recent.

Dialysis should be considered in the management of overdose as there is one report of successful dialysis of busulfan.

If high-dose busulfan is used in association with bone marrow transplantation, gastrointestinal toxicity becomes dose limiting with mucositis, nausea, vomiting, diarrhea and anorexia.