Myleran busulfan 2 mg Tablet, Film Coated, 25-count — NDC 80725-620-25 (Billing 80725-0620-25)

WARNINGS 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. Busulfa… [Excerpted — this section continues on DailyMed.]

ADVERSE REACTIONS To report SUSPECTED ADVERSE REACTIONS, contact Waylis Therapeutics LLC Toll-Free at 1-888-514-4727 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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. 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.

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.

Ocular Busulfan is capable of inducing cataracts in rats and there have been several reports indicating that this is a rare complication in humans. Dermatologic Hyperpigmentation is the most common adverse skin reaction and occurs in 5% to 10% of patients, particularly those with a dark complexion. 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. 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).

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.

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… [Excerpted — this section continues on DailyMed.]

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.

PRECAUTIONS 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.

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 be informed 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. 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 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 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. 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 varice… [Excerpted — this section continues on DailyMed.]