BUSULFAN MYLERAN- busulfan tablet, film coated
GlaxoSmithKline LLC
WARNING
MYLERAN is a potent drug. It should not be used unless a diagnosis of chronic myelogenous leukemia has been adequately established and the responsible physician is knowledgeable in assessing response to chemotherapy.
MYLERAN can induce severe bone marrow hypoplasia. Reduce or discontinue the dosage immediately at the first sign of any unusual depression of bone marrow function as reflected by an abnormal decrease in any of the formed elements of the blood. A bone marrow examination should be performed if the bone marrow status is uncertain.
SEE WARNINGS FOR INFORMATION REGARDING BUSULFAN-INDUCED LEUKEMOGENESIS IN HUMANS.
DESCRIPTION
MYLERAN (busulfan) is a bifunctional alkylating agent. Busulfan is known chemically as 1,4-butanediol dimethanesulfonate and has the following structural formula:
CH3 SO2 O(CH2 )4 OSO2 CH3
Busulfan is not a structural analog of the nitrogen mustards. MYLERAN is available in tablet form for oral administration. Each film-coated tablet contains 2 mg busulfan and the inactive ingredients hypromellose, lactose (anhydrous), magnesium stearate, pregelatinized starch, triacetin, and titanium dioxide.
The activity of busulfan in chronic myelogenous leukemia was first reported by D.A.G. Galton in 1953.
CLINICAL PHARMACOLOGY
Busulfan is a small, highly lipophilic molecule that easily crosses the blood brain barrier. Following absorption, 32% and 47% of busulfan are bound to plasma proteins and red blood cells, respectively.
Busulfan absorption from the gastrointestinal tract is essentially complete. This has been demonstrated in radioactive studies after both intravenous and oral administration of 35 S-busulfan, 14 C-busulfan, and 3 H-busulfan. Following intravenous administration of a single therapeutic dose of 35 S-busulfan, there was rapid disappearance of radioactivity from the blood and 90% to 95% of the 35 S-label disappeared within 3 to 5 minutes after injection. After either oral or intravenous administration of 35 S-busulfan, 45% to 60% of the radioactivity was recovered in the urine in the 48 hours after administration; the majority of the total urinary excretion occurring in the first 24 hours. Over 95% of the urinary 35 S-label occurs as 35 S-methanesulfonic acid. Oral and intravenous administration of 1,4-14 C-busulfan showed the same rapid initial disappearance of plasma radioactivity as observed following the administration of 35 S-labeled drug. Cumulative radioactivity in the urine after 48 hours was 25% to 30% of the administered dose (contrasting with 45% to 60% for 35 S-busulfan), and suggests a slower excretion of the alkylating portion of the molecule and its metabolites than for the sulfonoxymethyl moieties. Regardless of the route of administration, 1,4-14 C-busulfan yielded a complex mixture of at least 12 radiolabeled metabolites in urine; the main metabolite being 3-hydroxytetrahydrothiophene-1,1-dioxide. Pharmacokinetic studies employing 3 H-busulfan labeled on the tetramethylene chain confirmed a rapid initial clearance of the radioactivity from plasma, irrespective of whether the drug was given orally or intravenously. INDICATIONS AND USAGE
MYLERAN (busulfan) is indicated for the palliative treatment of chronic myelogenous (myeloid, myelocytic, granulocytic) leukemia
DOSAGE AND ADMINISTRATION
Busulfan is administered orally. The usual adult dose range for remission induction is 4 to 8 mg, total dose, daily. Dosing on a weight basis is the same for both pediatric patients and adults, approximately 60 mcg/kg of body weight or 1.8 mg/m2 of body surface, daily. Since the rate of fall of the leukocyte count is dose related, daily doses exceeding 4 mg per day should be reserved for patients with the most compelling symptoms; the greater the total daily dose, the greater is the possibility of inducing bone marrow aplasia.
