MYLERAN

MYLERAN- busulfan tablet, film coated
Aspen Global Inc.

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.

A study compared a 2-mg single IV bolus injection to a single oral dose of a 2-mg tablet of nonradioactive busulfan in 8 adult patients 13 to 60 years of age. The study demonstrated that the mean ± SD absolute bioavailability was 80% ± 20% in adults. However, the absolute bioavailability for 8 children 1.5 to 6 years of age was 68% ± 31%.

In another study of 2, 4, and 6 mg of busulfan, given as a single oral dose on consecutive days (starting with the lowest dose) in 5 adult patients, the mean dose-normalized (to 2 mg dose) area under the plasma concentration-time curve (AUC) was about 130 ng•hr/mL, while the mean intra- and inter-patient variability was about 16% and 21%, respectively. Busulfan was eliminated with a plasma terminal elimination half-life (t1/2 ) of about 2.6 hours, and demonstrated linear kinetics within the range of 2 to 6 mg for both the maximum plasma concentration (Cmax ) and AUC. The mean Cmax for the 2-, 4-, and 6-mg doses (after dose normalization to 2 mg) was about 30 ng/mL. A recent study of 4 to 8 mg as single oral doses in 12 patients showed that the mean ± SD Cmax (after dose normalization to 4 mg) was 68.2 ± 24.4 ng/mL, occurring at about 0.9 hours and the mean ± SD AUC (after dose normalization to 4 mg) was 269 ± 62 ng•hr/mL. These results are consistent with previous results. In addition, the mean ± SD elimination half-life was 2.69 ± 0.49 hours.

The elimination of busulfan appears to be independent of renal function. This probably reflects the extensive metabolism of the drug in the liver, since less than 2% of the administered dose is excreted in the urine unchanged within 24 hours. The drug is metabolized by enzymatic activity to at least 12 metabolites, among which tetrahydrothiophene, tetrahydrothiophene 12-oxide, sulfolane, and 3-hydroxysulfolane were identified. These metabolites do not have cytotoxic activity.

There is no experience with the use of dialysis in an attempt to modify the clinical toxicity of busulfan. One technical difficulty would derive from the extremely poor water solubility of busulfan.
Additionally, all studies of the metabolism of busulfan employing radiolabeled materials indicate rapid chemical reactivity of the parent compound with prolonged retention of some of the metabolites (particularly the metabolites arising from the “alkylating” portion of the molecule). The effectiveness of dialysis at removing significant quantities of unreacted drug would be expected to be minimal in such a situation.

Currently, there are no available data on the effect of food on busulfan bioavailability.

Pharmacokinetics in Hemodialysis Patients

The impact of hemodialysis on the clearance of busulfan was determined in a patient with chronic renal failure undergoing autologous stem cell transplantation. The apparent oral clearance of busulfan during a 4-hour hemodialysis session was increased by 65%, but the 24-hour oral clearance of busulfan was increased by only 11%.

The incidence of veno-occlusive disease was higher (33.3% versus 3.0%) in patients with busulfan AUC0-6hr >1,500 μM.min (Css >900 mcg/L) compared to patients with busulfan AUC0-6hr <1,500 μM.min (Css <900 mcg/L) (see WARNINGS).

Drug Interactions

Itraconazole reduced busulfan clearance by up to 25% in patients receiving itraconazole compared to patients who did not receive itraconazole. Higher busulfan exposure due to concomitant itraconazole could lead to toxic plasma levels in some patients. Fluconazole had no effect on the clearance of busulfan. Patients treated with concomitant cyclophosphamide and busulfan with phenytoin pretreatment have increased cyclophosphamide and busulfan clearance, which may lead to decreased concentrations of both cyclophosphamide and busulfan. However, busulfan clearance may be reduced in the presence of cyclophosphamide alone, presumably due to competition for glutathione.

Diazepam had no effect on the clearance of busulfan.

No information is available regarding the penetration of busulfan into brain or cerebrospinal fluid.

Biochemical Pharmacology

In aqueous media, busulfan undergoes a wide range of nucleophilic substitution reactions. While this chemical reactivity is relatively non-specific, alkylation of the DNA is felt to be an important biological mechanism for its cytotoxic effect. Coliphage T7 exposed to busulfan was found to have the DNA crosslinked by intrastrand crosslinkages, but no interstrand linkages were found.

The metabolic fate of busulfan has been studied in rats and humans using 14 C- and 35 S-labeled materials. In humans, as in the rat, almost all of the radioactivity in 35 S-labeled busulfan is excreted in the urine in the form of 35 S-methanesulfonic acid. Roberts and Warwick demonstrated that the formation of methanesulfonic acid in vivo in the rat is not due to a simple hydrolysis of busulfan to 1,4-butanediol, since only about 4% of 2,3-14 C-busulfan was excreted as carbon dioxide, whereas 2,3-14 C-1,4-butanediol was converted almost exclusively to carbon dioxide. The predominant reaction of busulfan in the rat is the alkylation of sulfhydryl groups (particularly cysteine and cysteine-containing compounds) to produce a cyclic sulfonium compound which is the precursor of the major urinary metabolite of the 4-carbon portion of the molecule, 3-hydroxytetrahydrothiophene-1,1-dioxide. This has been termed a “sulfur-stripping” action of busulfan and it may modify the function of certain sulfur-containing amino acids, polypeptides, and proteins; whether this action makes an important contribution to the cytotoxicity of busulfan is unknown.

The biochemical basis for acquired resistance to busulfan is largely a matter of speculation. Although altered transport of busulfan into the cell is one possibility, increased intracellular inactivation of the drug before it reaches the DNA is also possible. Experiments with other alkylating agents have shown that resistance to this class of compounds may reflect an acquired ability of the resistant cell to repair alkylation damage more effectively.

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