Myleran

Busulfan is a cancer medicine that interferes with the growth and spread of cancer cells in the body.

Busulfan taken by mouth is used to treat the symptoms of chronic myelogenous leukemia (a type of blood cancer). Busulfan injection is used together with a medicine called cyclophosphamide, to prepare your body to receive a stem cell transplant from a donor's bone marrow.

Busulfan is not a cure for leukemia.

Busulfan may also be used for purposes not listed in this medication guide.

Busulfan can lower blood cells that help your body fight infections and help your blood to clot. You may get an infection or bleed more easily. Call your doctor if you have unusual bruising or bleeding, or signs of infection (fever, chills, body aches).

Busulfan can have long lasting effects on your body. You may need frequent medical tests for a short time after you stop using this medicine.

You should not use busulfan if you are allergic to it.

To make sure you can safely take busulfan, tell your doctor if you have:

• a weak immune system (bone marrow depression) caused by other cancer medications or radiation treatment;
• epilepsy or other seizure disorder;
• history of head injury; or
• a history of lung or breathing problems.

Some people treated with busulfan have developed new forms of cancer. Talk to your doctor about your specific risks and benefits of using this medicine.

Do not use busulfan if you are pregnant. It could harm the unborn baby. Use effective birth control, and tell your doctor if you become pregnant during treatment.

Busulfan may affect fertility (your ability to have children), whether you are a man or a woman.

It is not known whether busulfan passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

>10%

Neutropenia (nearly 100%)

Myelosuppression (nearly 100%)

Thrombocytopenia (98%)

Nausea (97%)

Stomatitis (96%)

Anorexia (80%)

Diarrhea (80%)

Fever (80%)

Insomnia (80%)

Lymphopenia (79%)

Hypomagnesemia (77%)

Headache (69%)

Hyperglycemia (66%)

Hypokalemia (64%)

Abdominal pain (62%)

Anemia (62%)

Asthenia (52%)

Hypocalcemia (49%)

Chills (47%)

Dyspepsia (44%)

Tachycardia (44%)

Pain (41%)

Constipation (38%)

Hypertension (36%)

Hypersensitivity (32%)

Edema (27%)

Thrombosis (27%)

Dry mouth (26%)

Vasodilation (25%)

Mild epistaxis (25%)

Inflammation at injection site (25%)

Rectal disorder (25%)

Abdominal enlargement (23%)

Back pain (23%)

Chest pain (22%)

1-10%

Grade 3/4 Hypertension (7%, IV)

Hypotension (3%, IV)

Cardiac tamponade (2%, oral)

Third degree AV block (2%, IV)

Left heart failure (2%, IV)

Frequency Not Defined

Dizziness

Anxiety

Depression

Seizure

Cough

Dyspnea

Rhinitis

Bronchopulmonary dysplasia with pulmonary fibrosis (rare)

Aplastic anemia (rare)

Leukemia (rare)

Graft versus host disease

Adrenal gland disorder

Pruritis

Rash

Cataract

Hemorrhagic cystitis

Amenorrhea

Male infertility

Ovarian dysfunction

Postmarketing Reports

Febrile neutropenia

Tumor lysis syndrome

Thrombotic micro-angiopathy (TMA)

Severe bacterial, viral (eg, cytomegalovirus viremia), fungal infections, and sepsis

Tooth hypoplasia

Myleran is a prescription medication is used treat a certain type of chronic myelogenous leukemia (CML). It belongs to a group of drugs called alkylating agents. These work by slowing or stopping the growth of cancer cells in your body.

This medication comes in tablet form and is taken once a day, with or without food.

Common side effects include nausea, fever, diarrhea, and loss of appetite.

Oral:

Busulfan is a prescription medication used to treat a certain type of chronic myelogenous leukemia, or CML. CML is a type of cancer of the white blood cells.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Injectable: 

Busulfan is a prescription medication used in combination with other medications to destroy bone marrow and cancer cells in preparation for a bone marrow transplant in patients with chronic myelogenous leukemia, or CML. CML is a type of cancer of the white blood cells.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Before taking busulfan, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to busulfan or to any of its ingredients
• have previously received radiation therapy or treatment with other chemotherapy medications or if you have or have ever had seizures or a head injury
• have taken busulfan before, but your cancer did not respond to the medication
• are pregnant or breastfeeding

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Other drugs may interact with busulfan, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
• Signs of bleeding like throwing up blood or throw up that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; vaginal bleeding that is not normal; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop.
• Very bad belly pain.
• Very upset stomach or throwing up.
• Feeling very tired or weak.
• Chest pain.
• Seizures.
• Change in eyesight.
• For women, no period.
• Signs of a weak adrenal gland like a very bad upset stomach or throwing up, very bad dizziness or passing out, muscle weakness, feeling very tired, mood changes, not hungry, or weight loss.

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 therapythe 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.

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 advised to avoid becoming pregnant.

Applies to busulfan: intravenous solution, oral tablet

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 (the active ingredient contained in Myleran) Dose limiting myelosuppression is the main side effect with usual doses. Postmarketing reports have included febrile neutropenia and thrombotic microangiopathy.[Ref]

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.[Ref]

Respiratory

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

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.[Ref]

Cardiovascular

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.[Ref]

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.[Ref]

Ocular

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

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

Dermatologic

In one study, 31 out of 65 patients that received busulfan (the active ingredient contained in Myleran) 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.[Ref]

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.[Ref]

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).[Ref]

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. Postmarketing reports have included tumor lysis syndrome.

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.[Ref]

Hepatic

Based on clinical examination and laboratory findings, hepatic veno-occlusive disease was diagnosed in 8% (5/61) of patients treated with busulfan (the active ingredient contained in Myleran) 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%).[Ref]

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.[Ref]

Nervous system

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

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.[Ref]

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 (the active ingredient contained in Myleran) 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).[Ref]

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.[Ref]

Gastrointestinal

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

Musculoskeletal

Musculoskeletal side effects including myasthenia gravis have been reported.[Ref]

Immunologic

Postmarketing reports have included severe bacterial, viral (e.g.,cytomegalovirus viremia) and fungal infections; and sepsis.

Some side effects of Myleran may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.