Myleran Side Effects

Generic Name: busulfan

Please note - some side effects for Myleran may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Side Effects of Myleran - for the Consumer

Myleran

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Myleran:

Darkening of the skin; diarrhea; dizziness; dry mouth, nose, and throat.

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); abrupt weakness; chest pain; confusion; congestion; decreased ability to fight infection; fever, chills, or sore throat; infertility; loss of appetite; missed menstrual period; nausea; persistent cough; seizures; shortness of breath; stomach or joint pain; unusual bruising or bleeding; unusual tiredness or fatigue; vision changes; vomiting; weight loss; yellowing of the skin or eyes.

Myleran Side Effects - for the Professional

Myleran

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.

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. Hepatic veno-occlusive disease has been observed in patients receiving busulfan.

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 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 have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to busulfan.

Blood and Lymphatic: Aplastic anemia.

Eye: Cataracts, corneal thinning, lens changes.

Hepatobiliary Tract and Pancreas: Centrilobular sinusoidal fibrosis, hepatic veno-occlusivedisease, hepatocellular atrophy, hepatocellular necrosis, hyperbilirubinemia.

Non-site Specific: Infection, mucositis, sepsis.

Respiratory: Pneumonia.

Skin: Rash. An increased local cutaneous reaction has been observed in patients receiving radiotherapy soon after busulfan.

Side Effects by Body System

Hematologic

Hematologic side effects including myelosuppression resulting in leukopenia, thrombocytopenia and anemia, comprise the most frequent toxic effects that have been reported with the use of busulfan. Dose limiting myelosuppression is the main side effect with usual doses.

Myelosuppression can develop suddenly and may be prolonged, but is usually reversible. Myelosuppression is most frequently the result of a failure to discontinue further drug administration in the face of an undetected decrease in leukocyte or platelet counts. During high dose therapy, neutrophils start to increase on approximately the 19th day and platelets on approximately the 30th day. In one study, four out of 243 patients treated with busulfan developed leukemia.

Respiratory

Corticosteroids have been reported to have been beneficial in arresting or reversing the fibrosis in some cases.

Respiratory side effects including lung damage have frequently been reported (approximately 33% of patients with the higher doses used for bone marrow transplant). While reported only rarely, interstitial pulmonary fibrosis (busulfan lung) warrants the immediate discontinuation of busulfan administration. Presentation of symptoms is delayed by several years in many patients. There is a slow onset of cough, dyspnea and low grade fever. (However, the clinician needs to rule out infection or leukemia in the lungs.) Next, patients may present with pulmonary insufficiency, tachypnea and cyanosis which may eventually be fatal. A single case of pulmonary alveolar proteinosis has also been reported.

Cardiovascular

Cardiovascular side effects including mild or moderate tachycardia have been reported in 44% of patients. In 7 patients (11%) it was first reported during busulfan administration. Other rhythm abnormalities, which were all mild or moderate, included arrhythmia (5%), atrial fibrillation (2%), ventricular extrasystoles (2%), and third degree heart block (2%).

Mild or moderate thrombosis occurred in 33% of patients. (All episodes were associated with the central venous catheter.)

Hypertension (36%), mild vasodilation (flushing and hot flashes) (25%), and hypotension (11%) have also been reported.

Other cardiovascular events included cardiomegaly (5%), mild ECG abnormality (2%), Grade 3/4 left-sided heart failure in one patient (2%), and moderate pericardial effusion (2%). (These events were reported primarily in the post-cyclophosphamide phase.)

One case of endocardial fibrosis has been reported.

The case of endocardial fibrosis was reported in a 79-year-old woman who received a total dose of 7,200 mg 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

The drug has also been reported to induced cataracts in rats.

Ocular side effects including cataracts and vision changes have been reported rarely after prolonged administration.

Dermatologic

Dermatologic side effects including hyperpigmentation (usually seen in skin folds near nails and hands) have been reported (5% to 10%). Urticaria, erythema multiforme, erythema nodosum, alopecia, porphyria cutanea tarda, and excessive dryness and fragility of the skin with anhidrosis have also been reported.

In one study, 31 out of 65 patients that received busulfan prior to bone marrow transplantation had some degree of alopecia. In 19 of these patients, the alopecia was extensive. While all patients received the same dosage per kg, patients that had higher blood concentrations developed more extensive alopecia.

Hyperpigmentation has most frequently been reported in patients with a dark complexion.

Some cases of alopecia have been permanent.

Metabolic

The symptoms of the syndrome (which resembles adrenal insufficiency) have sometimes been reversible after the drug has been withdrawn. Adrenal responsiveness to exogenously administered ACTH has usually been normal. However, pituitary function testing with metyrapone revealed a blunted 17-hydroxycorticosteroid excretion in two patients. Following the discontinuation of the drug (which was associated with clinical improvement), rechallenge with metyrapone revealed normal pituitary-adrenal function.

Adverse effects due to the increased urate pool can be minimized by increased hydration, urine alkalinization and the prophylactic administration of a xanthine oxidase inhibitor (e.g., allopurinol).

Metabolic side effects including several cases of a clinical syndrome closely resembling adrenal insufficiency, characterized by weakness, severe fatigue, anorexia, weight loss, melanoderma, nausea, and vomiting, have been reported after prolonged therapy.

While 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.

Hepatic

Hepatic side effects including hepatic veno-occlusive disease have been reported. Esophageal varices have been reported in patients receiving busulfan in combination with thioguanine. Jaundice and hepatitis have also been reported.

Based on clinical examination and laboratory findings, hepatic veno-occlusive disease was diagnosed in 8% (5/61) of patients treated with busulfan in the setting of allogeneic transplantation, was fatal in 2/5 cases (40%), and yielded an overall mortality from hepatic veno-occlusive disease in the entire study population of 2/61 (3%).

Nervous system

Nervous system side effects including seizures have generally been reported after the third or fourth day in patients receiving high dose therapy.

In one study of 28 bone marrow transplant recipients that had received busulfan, 3 cases of convulsions have been reported. Two of the 3 patients that experienced the convulsions had been pretreated with anticonvulsants. Another study reported 2 patients out of 130 experienced seizures. There have been 16 cases of busulfan-related seizures reported in the literature. Prophylactic anticonvulsant therapy (phenytoin) should be considered in patients receiving high dose busulfan.

Oncologic

Oncologic side effects including cytologic and histologic changes in the urinary and respiratory tracts as well as the uterine cervix and liver have been reported. The International Agency for Research on Cancer (IARC) has classified the activity of busulfan as sufficient to indicate potential carcinogenicity (in short-term tests). Two cases of endometrial cancer have been reported (each case followed two years of treatment).

Other

Other side effects in patients receiving allogenic transplant were some form of edema (79%), hypervolemia, or documented weight increase (8%). All events were reported as mild or moderate.

Genitourinary

Genitourinary side effects including hemorrhagic cystitis, gynecomastia, amenorrhea, ovarian and testicular atrophy (resulting in sterility) have been reported.

Gastrointestinal

Gastrointestinal side effects including dryness of the oral mucous membranes and cheilosis have been reported.

Musculoskeletal

Musculoskeletal side effects including myasthenia gravis have been reported.

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