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busulfan
Overview
What is MYLERAN?
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 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.
What does MYLERAN look like?
What are the available doses of MYLERAN?
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What should I talk to my health care provider before I take MYLERAN?
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How should I use MYLERAN?
MYLERAN (busulfan) is indicated for the palliative treatment of chronic myelogenous (myeloid, myelocytic, granulocytic) leukemia.
Busulfan is administered orally. The usual adult dose range for 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/m 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.
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 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.
What interacts with MYLERAN?
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What are the warnings of MYLERAN?
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What are the precautions of MYLERAN?
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What are the side effects of MYLERAN?
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What should I look out for while using MYLERAN?
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.
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. 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.
What might happen if I take too much MYLERAN?
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 LD single 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 LD there 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.
How should I store and handle MYLERAN?
Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Manufactured and Distributed by: Carlsbad, CA 92008 Marketed/ Packaged by: Camarillo, CA 93012 USARevised: 06/12CTI-12 Rev. C Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Manufactured and Distributed by: Carlsbad, CA 92008 Marketed/ Packaged by: Camarillo, CA 93012 USARevised: 06/12CTI-12 Rev. C Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Manufactured and Distributed by: Carlsbad, CA 92008 Marketed/ Packaged by: Camarillo, CA 93012 USARevised: 06/12CTI-12 Rev. C Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Manufactured and Distributed by: Carlsbad, CA 92008 Marketed/ Packaged by: Camarillo, CA 93012 USARevised: 06/12CTI-12 Rev. C 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 76388-713-25).Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) (see USP Controlled Room Temperature).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 76388-713-25).Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) (see USP Controlled Room Temperature).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 76388-713-25).Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) (see USP Controlled Room Temperature).
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
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 μM.min (C >900 mcg/L) compared to patients with busulfan AUC <1,500 μM.min (C <900 mcg/L) (see WARNINGS).
Non-Clinical Toxicology
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.
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. 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.
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.
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.
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.
To report SUSPECTED ADVERSE REACTIONS, contact Aspen Global Inc. Toll-Free at 1-855-800-8165 or FDA at 1-800-FDA-1088 or
.
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
While we update our database periodically, we cannot guarantee it is always updated to the latest version.
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