Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/4216
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MYLERAN (Tablet)
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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/mof 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. A decrease in the
leukocyte count is not usually seen during the first 10 to 15 days of
treatment; the leukocyte count may actually increase during this period and
it should not be interpreted as resistance to the drug, nor should the dose
be increased. Since the leukocyte count may continue to fall for more than
1 month after discontinuing the drug, it is important that busulfan be
discontinued prior to the total leukocyte
count falling into the normal range. When the total leukocyte count has declined
to approximately 15,000/mcL, the drug should be withheld. With
a constant dose of busulfan, the total leukocyte count declines exponentially;
a weekly plot of the leukocyte count on semi-logarithmic graph paper aids
in predicting the time when therapy should be discontinued. With the recommended
dose of busulfan, a normal leukocyte count is usually achieved in 12 to 20 weeks. During
remission, the patient is examined at monthly intervals and treatment resumed
with the induction dosage when the total leukocyte count reaches approximately
50,000/mcL. When remission is shorter than 3 months, maintenance therapy
of 1 to 3 mg daily may be advisable in order to keep the hematological
status under control and prevent rapid relapse. Procedures
for proper handling and disposal of anticancer drugs should be considered.
Several guidelines on this subject have been published. There
is no general agreement that all of the procedures recommended in the guidelines
are necessary or appropriate.
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MYLERAN (busulfan) is a bifunctional alkylating agent. Busulfan
is known chemically as 1,4-butanediol dimethanesulfonate and has the following
structural formula: CHSOO(CH)OSOCH 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.
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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
ofS-busulfan,C-busulfan, andH-busulfan.
Following intravenous administration of a single therapeutic dose ofS-busulfan,
there was rapid disappearance of radioactivity from the blood and 90% to 95%
of theS-label disappeared within 3 to 5 minutes after injection.
After either oral or intravenous administration ofS-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 urinaryS-label occurs
asS-methanesulfonic acid. Oral and intravenous administration
of 1,4-C-busulfan showed the same rapid initial disappearance
of plasma radioactivity as observed following the administration ofS-labeled
drug. Cumulative radioactivity in the urine after 48 hours was 25% to
30% of the administered dose (contrasting with 45% to 60% forS-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-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 employingH-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 (t)
of about 2.6 hours, and demonstrated linear kinetics within the range
of 2 to 6 mg for both the maximum plasma concentration (C)
and AUC. The mean Cfor 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 C(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.<br/>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 AUC>1,500��M.min (C>900 mcg/L)
compared to patients with busulfan AUC<1,500��M.min
(C<900 mcg/L) (see WARNINGS).<br/>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.<br/>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 usingC- andS-labeled
materials. In humans, as in the rat, almost all of the radioactivity inS-labeled
busulfan is excreted in the urine in the form ofS-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-C-busulfan was excreted as carbon
dioxide, whereas 2,3-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.<br/>Clinical Studies: Although not curative, busulfan reduces the total granulocyte
mass, relieves symptoms of the disease, and improves the clinical state of
the patient. Approximately 90% of adults with previously untreated chronic
myelogenous leukemia will obtain hematologic remission with regression or
stabilization of organomegaly following the use of busulfan. It has been shown
to be superior to splenic irradiation with respect to survival times and maintenance
of hemoglobin levels, and to be equivalent to irradiation at controlling splenomegaly. It
is not clear whether busulfan unequivocally prolongs the survival of responding
patients beyond the 31 months experienced by an untreated group of historical
controls. Median survival figures of 31 to 42 months have been reported
for several groups of patients treated with busulfan, but concurrent control
groups of comparable, untreated patients are not available. The median survival
figures reported from different studies will be influenced by the percentage
of���poor risk���patients initially entered into the particular
study. Patients who are alive 2 years following the diagnosis of chronic
myelogenous leukemia, and who have been treated during that period with busulfan,
are estimated to have a mean annual mortality rate during the second to fifth
year which is approximately two thirds that of patients who received either
no treatment, conventional x-ray orP-irradiation, or chemotherapy
with minimally active drugs. Busulfan is clearly less
effective in patients with chronic myelogenous leukemia who lack the Philadelphia
(Ph) chromosome. Also, the
so-called���juvenile���type of chronic myelogenous leukemia, typically
occurring in young children and associated with the absence of a Philadelphia
chromosome, responds poorly to busulfan. The drug is of no benefit in patients
whose chronic myelogenous leukemia has entered a���blastic���phase. MYLERAN
should not be used in patients whose chronic myelogenous leukemia has demonstrated
prior resistance to this drug. MYLERAN is of no value
in chronic lymphocytic leukemia, acute leukemia, or in the���blastic
crisis���of chronic myelogenous leukemia.
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MYLERAN is contraindicated in patients in whom a definitive
diagnosis of chronic myelogenous leukemia has not been firmly established. MYLERAN
is contraindicated in patients who have previously suffered a hypersensitivity
reaction to busulfan or any other component of the preparation.
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MYLERAN is supplied as
white, film-coated, round, biconvex tablets containing 2 mg busulfan
in amber glass bottles with child-resistant closures. One side is imprinted
with "GX EF3" and the other side is imprinted with an "M.��� Bottle
of 25 (NDC 0173-0713 -25). Store
at 25��C (77��F); excursions permitted to 15��to 30��C (59��to 86��F) (see USP Controlled Room Temperature).
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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.
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General: The most consistent,
dose-related toxicity is bone marrow suppression. This may be manifest 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, 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. Patients
should never be allowed to take the drug without close medical supervision. Seizures have been reported in patients
receiving busulfan. As with any potentially epileptogenic drug, caution should
be exercised when administering busulfan to patients with a history of seizure
disorder, head trauma, or receiving other potentially epileptogenic drugs.
Some investigators have used prophylactic anticonvulsant therapy in this setting.<br/>Information for Patients: 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
beinformed that other encountered toxicities to busulfan include infertility,
amenorrhea, skin hyperpigmentation, drug hypersensitivity, dryness of the
mucous membranes, and rarely, cataract formation. Women of childbearing potential
should be advised to avoid becoming pregnant. The increased risk of a second
malignancy should be explained to the patient.<br/>Laboratory Tests: 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 bloodis 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 must 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 this agent is combined with other drugs whose primary
toxicity is myelosuppression. Occasional patients may be unusually sensitive
to busulfan administered at standard dosage 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.<br/>Drug Interactions: Busulfan may cause additive myelosuppression when used with
other myelosuppressive drugs. In one study, 12 of approximately
330 patients receiving continuous busulfan and thioguanine therapy for
treatment of chronic myelogenous leukemia were found to have portal hypertension
and 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.
With the present analysis of the data, no cases of hepatotoxicity have appeared
in the busulfan-alone arm of the study. Long-term continuous therapy with
thioguanine and busulfan should be used with caution. Busulfan-induced
pulmonary toxicity may be additive to the effects produced by other cytotoxic
agents. The concomitant systemic administration of
itraconazole to patients receiving high-dose MYLERAN may result in reduced
busulfan clearance (see CLINICAL PHARMACOLOGY). Patients should be monitored
for signs of busulfan toxicity when itraconazole is used concomitantly with
MYLERAN.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: See WARNINGS section. The World Health Organization has
concluded that there is a causal relationship between busulfan exposure and
the development of secondary malignancies.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category
D. See WARNINGS section.<br/>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.<br/>Nursing Mothers: It is not known whether
this drug is excreted in human milk. Because of the potential for tumorigenicity
shown for busulfan 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.<br/>Pediatric Use: See INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION
sections.<br/>Geriatric Use: Clinical studies of busulfan did not include sufficient
numbers of subjects aged 65 and over to determine whether they respond differently
from younger subjects. Other reported clinical experience has not identified
differences in responses between the elderly and younger patients. In general,
dose selection for an elderly patient should be cautious, usually starting
at the low end of the dosing range, reflecting the greater frequency of decreased
hepatic, renal, or cardiac function, and of concomitant disease or other drug
therapy.
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There is no known antidote to busulfan. The principal toxic
effects are bone marrow depression and pancytopenia. 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 may be considered
in the management of overdose as there is 1 report of successful dialysis
of busulfan (see CLINICAL PHARMACOLOGY). Gastrointestinal
toxicity with mucositis, nausea, vomiting, and diarrhea has been observed
when MYLERAN was used in association with bone marrow transplantation. Oral
LDsingle doses in mice are 120 mg/kg. Two distinct types
of toxic response are seen at median lethal doses given intraperitoneally.
Within a matter of hours there are signs of stimulation of the central nervous
system with convulsions and death on the first day. Mice are more sensitive
to this effect than are rats. With doses at the LDthere is also
delayed death due to damage to the bone marrow. At 3 times the LD,
atrophy of the mucosa of the large intestine is found after a week, whereas
that of the small intestine is little affected. After doses in the order of
10 times those used therapeutically were added to the diet of rats, irreversible
cataracts were produced after several weeks. Small doses had no such effect.
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busulfan
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MYLERAN (Tablet)
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Hematological Effects: The most frequent, serious,
toxic effect of busulfan is dose-related myelosuppression resulting in leukopenia,
thrombocytopenia, and anemia. Myelosuppression is most frequently the result
of a failure to discontinue dosage in the face of an undetected decrease in
leukocyte or platelet counts. Aplastic anemia (sometimes
irreversible) has been reported rarely, often following long-term conventional
doses and also high doses of MYLERAN.<br/>Pulmonary: 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.<br/>Cardiac: Cardiac tamponade has been reported in a small number of
patients with thalassemia who received 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 7,200 mg of busulfan 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.<br/>Ocular: Busulfan is capable of inducing cataracts in rats and there
have been several reports indicating that this is a rare complication in humans.<br/>Dermatologic: Hyperpigmentation is the most common adverse skin reaction
and occurs in 5% to 10% of patients, particularly those with a dark complexion.<br/>Metabolic: 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 2 patients. Following the discontinuation
of busulfan (which was associated with clinical improvement), rechallenge
with metyrapone revealed normal pituitary-adrenal function. 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. Adverse effects can be minimized
by increased hydration, urine alkalinization, and the prophylactic administration
of a xanthine oxidase inhibitor such as allopurinol.<br/>Hepatic Effects: Esophageal varices have
been reported in patients receiving continuous busulfan and thioguanine therapy
for treatment of chronic myelogenous leukemia (see PRECAUTIONS: Drug Interactions).
Hepatic veno-occlusive disease has been observed in patients receiving busulfan
(see WARNINGS).<br/>Miscellaneous: Other reported adverse
reactions include: urticaria, erythema multiforme, erythema nodosum, alopecia,
porphyria cutanea tarda, excessive dryness and fragility of the skin with
anhidrosis, dryness of the oral mucous membranes and cheilosis, gynecomastia,
cholestatic jaundice, and myasthenia gravis. Most of these are single case
reports, and in many, a clear cause-and-effect relationship with busulfan
has not been demonstrated. Seizures (see PRECAUTIONS:
General) have been observed in patients receiving higher than recommended
doses of busulfan.<br/>Observed During Clinical Practice: The following events
have been identified during post-approval use of busulfan. Because they are
reported voluntarily from a population of unknown size, estimates of frequency
cannot be made. These events have been chosen for inclusion due to a combination
of their seriousness, frequency of reporting, or potential causal connection
to busulfan.<br/>Blood and Lymphatic: Aplastic anemia.<br/>Eye: Cataracts, corneal thinning, lens changes.<br/>Hepatobiliary Tract and Pancreas: Centrilobular sinusoidal fibrosis, hepatic veno-occlusivedisease, hepatocellular atrophy, hepatocellular necrosis, hyperbilirubinemia
(see WARNINGS).<br/>Non-site Specific: Infection, mucositis, sepsis.<br/>Respiratory: Pneumonia.<br/>Skin: Rash. An increased local cutaneous reaction has been observed
in patients receiving radiotherapy soon after busulfan.
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The most frequent, serious
side effect of treatment with busulfan is the induction of bone marrow failure
(which may or may not be anatomically hypoplastic) resulting in severe pancytopenia.
The pancytopenia caused by busulfan may be more prolonged than that induced
with other alkylating agents. It is generally felt that the usual cause of
busulfan-induced pancytopenia is the failure to stop administration of the
drug soon enough; individual idiosyncrasy to the drug does not seem to be
an important factor. MYLERAN should be used with
extreme caution and exceptional vigilance in patients whose bone marrow reserve
may have been compromised by prior irradiation or chemotherapy, or whose marrow
function is recovering from previous cytotoxic therapy. Although
recovery from busulfan-induced pancytopenia may take from 1 month to
2 years, this complication is potentially reversible, and the patient
should be vigorously supported through any period of severe pancytopenia. A
rare, important complication of busulfan therapy is the development of bronchopulmonary
dysplasia with pulmonary fibrosis. Symptoms have been reported to occur within
8 months to 10 years after initiation of therapy���the average
duration of therapy being 4 years. The histologic findings associated
with���busulfan lung���mimic those seen following pulmonary irradiation.
Clinically, patients have reported the insidious onset of cough, dyspnea,
and low-grade fever. In some cases, however, onset of symptoms may be acute.
Pulmonary function studies have revealed diminished diffusion capacity and
decreased pulmonary compliance. It is important to exclude more common conditions
(such as opportunistic infections or leukemic infiltration of the lungs) with
appropriate diagnostic techniques. If measures such as sputum cultures, virologic
studies, and exfoliative cytology fail to establish an etiology for the pulmonary
infiltrates, lung biopsy may be necessary to establish the diagnosis.Treatment
of established busulfan-induced pulmonary fibrosis is unsatisfactory; in most
cases the patients have died within 6 months after the diagnosis was
established. There is no specific therapy for this complication. MYLERAN should
be discontinued if this lung toxicity develops. The administration of corticosteroids
has been suggested, but the results have not been impressive or uniformly
successful. Busulfan may cause cellular dysplasia in
many organs in addition to the lung. Cytologic abnormalities characterized
by giant, hyperchromatic nuclei have been reported in lymph nodes, pancreas,
thyroid, adrenal glands, liver, and bone marrow. This cytologic dysplasia
may be severe enough to cause difficulty in interpretation of exfoliative
cytologic examinations from the lung, bladder, breast, and the uterine cervix. In
addition to the widespread epithelial dysplasia that has been observed during
busulfan therapy, chromosome aberrations have been reported in cells from
patients receiving busulfan. Busulfan is mutagenic
in mice and, possibly, in humans. Malignant tumors
and acute leukemias have been reported in patients who have received busulfan
therapy, and this drug may be a human carcinogen. The World Health Organization
has concluded that there is a causal relationship between busulfan exposure
and the development of secondary malignancies. Four cases of acute leukemia
occurred among 243 patients treated with busulfan as adjuvant chemotherapy
following surgical resection of bronchogenic carcinoma. All 4 cases were from
a subgroup of 19 of these 243 patients who developed pancytopenia while
taking busulfan 5 to 8 years before leukemia became clinically apparent. These
findings suggest that busulfan is leukemogenic, although its mode of action
is uncertain. Ovarian suppression and amenorrhea with
menopausal symptoms commonly occur during busulfan therapy in premenopausal
patients. Busulfan has been associated with ovarian failure including failure
to achieve puberty in females. Busulfan interferes with spermatogenesis in
experimental animals, and there have been clinical reports of sterility, azoospermia,
and testicular atrophy in male patients. Hepatic veno-occlusive
disease, which may be life threatening, has been reported in patients receiving
busulfan, usually in combination with cyclophosphamide or other chemotherapeutic
agents prior to bone marrow transplantation. Possible risk factors for the
development of hepatic veno-occlusive disease include: total busulfan dose
exceeding 16 mg/kg based on ideal body weight, and concurrent use of
multiple alkylating agents (see CLINICAL PHARMACOLOGY and Drug Interactions). A
clear cause-and-effect relationship with busulfan has not been demonstrated.
Periodic measurement of serum transaminases, alkaline phosphatase, and bilirubin
is indicated for early detection of hepatotoxicity. A reduced incidence of
hepatic veno-occlusive disease and other regimen-related toxicities have been
observed in patients treated with high-dose MYLERAN and cyclophosphamide when
the first dose of cyclophosphamide has been delayed for>24 hours after
the last dose of busulfan (see CLINICAL PHARMACOLOGY and Drug Interactions). Cardiac
tamponade has been reported in a small number of patients with thalassemia
(2% in one series) who received busulfan and cyclophosphamide as the preparatory
regimen for bone marrow transplantation. In this series, the cardiac tamponade
was often fatal. Abdominal pain and vomiting preceded the tamponade in most
patients.<br/>Pregnancy: Pregnancy Category D.
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. 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. There
are no adequate and well-controlled studies in pregnant women. If this drug
is used during pregnancy, or if the patient becomes pregnant while taking
this drug, the patient should be apprised of the potential hazard to the fetus.
Women of childbearing potential should be advisedto avoid becoming pregnant.
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MYLERAN (busulfan) is
indicated for the palliative treatment of chronic myelogenous (myeloid, myelocytic,
granulocytic) leukemia.
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MYLERAN
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