Busulfex Side Effects

Generic Name: busulfan

Please note - some side effects for Busulfex may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Busulfex - for the Consumer

Busulfex

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 Busulfex:

Anxiety; back pain; constipation; diarrhea; dizziness; dry mouth; flushing or hot flashes; headache; hiccup; indigestion; loss of appetite; mild fever or chills; mild redness or swelling at the injection site; minor cough or sore throat; muscle or joint pain; nausea; runny nose; tiredness or weakness; trouble sleeping; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur when using Busulfex:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); black, tarry stools; blurred vision or other vision changes; chest pain; confusion; decreased amount of urine, painful urination, or blood in the urine; depression; fainting; fast or irregular heartbeat; hallucinations; missed menstrual period; red, swollen, or blistered skin; seizures; severe or persistent pain, redness, or swelling at the injection site; severe or persistent cough; severe or persistent dizziness or headache; severe or persistent nausea, vomiting, or diarrhea; shortness of breath or trouble breathing; signs of infection (eg, persistent fever, chills, or sore throat); sores in the mouth or trouble swallowing; unusual bruising or bleeding (eg, nosebleed); unusual pain or swelling of the legs or calves; unusual stomach pain, swelling, or weight gain; vomit that looks like coffee grounds; yellowing of the skin or eyes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

Top

Busulfex Side Effects - for the Professional

Busulfex

Dimethylacetamide (DMA), the solvent used in the Busulfex formulation, was studied in 1962 as a potential cancer chemotherapy drug. In a Phase 1 trial, the maximum tolerated dose (MTD) was 14.8 g/m2/d for four days. The daily recommended dose of Busulfex contains DMA equivalent to 42% of the MTD on a mg/m2 basis. The dose-limiting toxicities in the Phase 1 study were hepatotoxicity as evidenced by increased liver transaminase (SGOT) levels and neurological symptoms as evidenced by hallucinations. The hallucinations had a pattern of onset at one day post completion of DMA administration and were associated with EEG changes. The lowest dose at which hallucinations were recognized was equivalent to 1.9 times that delivered in a conditioning regimen utilizing Busulfex 0.8 mg/kg every 6 hours ×16 doses. Other neurological toxicities included somnolence, lethargy, and confusion. The relative contribution of DMA and/or other concomitant medications to neurologic and hepatic toxicities observed with Busulfex is difficult to ascertain.

Treatment with Busulfex at the recommended dose and schedule will result in profound myelosuppression in 100% of patients, including granulocytopenia, thrombocytopenia, anemia, or a combined loss of formed elements of the blood.

Adverse reaction information is primarily derived from the clinical study (N=61) of Busulfex and the data obtained for high-dose oral busulfan conditioning in the setting of randomized, controlled trials identified through a literature review.

Busulfex Clinical Trials

In the Busulfex (busulfan) Injection allogeneic stem cell transplantation clinical trial, all patients were treated with Busulfex 0.8 mg/kg as a two‑hour infusion every six hours for 16 doses over four days, combined with cyclophosphamide 60 mg/kg ×2 days. Ninety-three percent (93%) of evaluable patients receiving this dose of Busulfex maintained an AUC less than 1,500 µM∙min for dose 9, which has generally been considered the level that minimizes the risk of HVOD.

Table 3: Summary of the Incidence (≥20%) of Non-Hematologic Adverse Events through BMT Day +28 in Patients who Received Busulfex Prior to Allogeneic Hematopoietic Progenitor Cell Transplantation

Non-Hematological Adverse Events*	Percent Incidence
* Includes all reported adverse events regardless of severity (toxicity grades 1-4)
BODY AS A WHOLE
Fever	80
Headache	69
Asthenia	51
Chills	46
Pain	44
Edema General	28
Allergic Reaction	26
Chest Pain	26
Inflammation at Injection Site	25
Back Pain	23
CARDIOVASCULAR SYSTEM
Tachycardia	44
Hypertension	36
Thrombosis	33
Vasodilation	25
DIGESTIVE SYSTEM
Nausea	98
Stomatitis (Mucositis)	97
Vomiting	95
Anorexia	85
Diarrhea	84
Abdominal Pain	72
Dyspepsia	44
Constipation	38
Dry Mouth	26
Rectal Disorder	25
Abdominal Enlargement	23
METABOLIC AND NUTRITIONAL SYSTEM
Hypomagnesemia	77
Hyperglycemia	66
Hypokalemia	64
Hypocalcemia	49
Hyperbilirubinemia	49
Edema	36
SGPT Elevation	31
Creatinine Increased	21
NERVOUS SYSTEM
Insomnia	84
Anxiety	72
Dizziness	30
Depression	23
RESPIRATORY SYSTEM
Rhinitis	44
Lung Disorder	34
Cough	28
Epistaxis	25
Dyspnea	25
SKIN AND APPENDAGES
Rash	57
Pruritus	28

The following sections describe clinically significant events occurring in the Busulfex clinical trials, regardless of drug attribution. For pediatric information, see Special Populations – Pediatric section.

Hematologic

At the indicated dose and schedule, Busulfex produced profound myelosuppression in 100% of patients. Following hematopoietic progenitor cell infusion, recovery of neutrophil counts to ≥500 cells/mm3 occurred at median day 13 when prophylactic G-CSF was administered to the majority of participants on the study. The median number of platelet transfusions per patient on study was 6, and the median number of red blood cell transfusions on study was 4. Prolonged prothrombin time was reported in one patient (2%).

Gastrointestinal

Gastrointestinal toxicities were frequent and generally considered to be related to the drug. Few were categorized as serious. Mild or moderate nausea occurred in 92% of patients in the allogeneic clinical trial, and mild or moderate vomiting occurred in 95% through BMT Day +28; nausea was severe in 7%. The incidence of vomiting during Busulfex administration (BMT Day –7 to –4) was 43% in the allogeneic clinical trial. Grade 3-4 stomatitis developed in 26% of the participants, and Grade 3 esophagitis developed in 2%. Grade 3-4 diarrhea was reported in 5% of the allogeneic study participants, while mild or moderate diarrhea occurred in 75%. Mild or moderate constipation occurred in 38% of patients; ileus developed in 8% and was severe in 2%. Forty-four percent (44%) of patients reported mild or moderate dyspepsia. Two percent (2%) of patients experienced mild hematemesis. Pancreatitis developed in 2% of patients. Mild or moderate rectal discomfort occurred in 24% of patients. Severe anorexia occurred in 21% of patients and was mild/moderate in 64%.

Hepatic

Hyperbilirubinemia occurred in 49% of patients in the allogeneic BMT trial. Grade 3/4 hyperbilirubinemia occurred in 30% of patients within 28 days of transplantation and was considered life-threatening in 5% of these patients. Hyperbilirubinemia was associated with graft-versus-host disease in six patients and with hepatic veno-occlusive disease in 5 patients. Grade 3/4 SGPT elevations occurred in 7% of patients. Alkaline phosphatase increases were mild or moderate in 15% of patients. Mild or moderate jaundice developed in 12% of patients, and mild or moderate hepatomegaly developed in 6%.

Hepatic veno-occlusive disease

Hepatic veno-occlusive disease (HVOD) is a recognized potential complication of conditioning therapy prior to transplant. Based on clinical examination and laboratory findings, hepatic veno-occlusive disease was diagnosed in 8% (5/61) of patients treated with Busulfex in the setting of allogeneic transplantation, was fatal in 2/5 cases (40%), and yielded an overall mortality from HVOD in the entire study population of 2/61 (3%). Three of the five patients diagnosed with HVOD were retrospectively found to meet the Jones' criteria.

Graft-versus-host disease

Graft-versus-host disease developed in 18% of patients (11/61) receiving allogeneic transplants; it was severe in 3%, and mild or moderate in 15%. There were 3 deaths (5%) attributed to GVHD.

Edema

Patients receiving allogeneic transplant exhibited some form of edema (79%), hypervolemia, or documented weight increase (8%); all events were reported as mild or moderate.

Infection/Fever

Fifty-one percent (51%) of patients experienced one or more episodes of infection. Pneumonia was fatal in one patient (2%) and life-threatening in 3% of patients. Fever was reported in 80% of patients; it was mild or moderate in 78% and severe in 3%. Forty-six percent (46%) of patients experienced chills.

Cardiovascular

Mild or moderate tachycardia was reported in 44% of patients. In 7 patients (11%) it was first reported during Busulfex 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, and all episodes were associated with the central venous catheter. Hypertension was reported in 36% of patients and was Grade 3/4 in 7%. Hypotension occurred in 11% of patients and was Grade 3/4 in 3%. Mild vasodilation (flushing and hot flashes) was reported in 25% of patients. 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.

Pulmonary

Mild or moderate dyspnea occurred in 25% of patients and was severe in 2%. One patient (2%) experienced severe hyperventilation; and in 2 (3%) additional patients it was mild or moderate. Mild rhinitis and mild or moderate cough were reported in 44% and 28% of patients, respectively. Mild epistaxis events were reported in 25%. Three patients (5%) on the allogeneic study developed documented alveolar hemorrhage. All required mechanical ventilatory support and all died. Non-specific interstitial fibrosis was found on wedge biopsies performed with video assisted thoracoscopy in one patient on the allogeneic study who subsequently died from respiratory failure on BMT Day +98. Other pulmonary events, reported as mild or moderate, included pharyngitis (18%), hiccup (18%), asthma (8%), atelectasis (2%), pleural effusion (3%), hypoxia (2%), hemoptysis (3%), and sinusitis (3%).

Neurologic

The most commonly reported adverse events of the central nervous system were insomnia (84%), anxiety (75%), dizziness (30%), and depression (23%). Severity was mild or moderate except for one patient (1%) who experienced severe insomnia. One patient (1%) developed a life-threatening cerebral hemorrhage and a coma as a terminal event following multi-organ failure after HVOD. Other events considered severe included delirium (2%), agitation (2%), and encephalopathy (2%). The overall incidence of confusion was 11%, and 5% of patients were reported to have experienced hallucinations. The patient who developed delirium and hallucination on the allogeneic study had onset of confusion at the completion of Busulfex (busulfan) Injection. The overall incidence of lethargy in the allogeneic Busulfex clinical trial was 7%, and somnolence was reported in 2%. One patient (2%) treated in an autologous transplantation study experienced a seizure while receiving cyclophosphamide, despite prophylactic treatment with phenytoin.

Renal

Creatinine was mildly or moderately elevated in 21% of patients. BUN was increased in 3% of patients and to a Grade 3/4 level in 2%. Seven percent of patients experienced dysuria, 15% oliguria, and 8% hematuria. There were 4 (7%) Grade 3/4 cases of hemorrhagic cystitis in the allogeneic clinical trial.

Skin

Rash (57%) and pruritus (28%) were reported; both conditions were predominantly mild. Alopecia was mild in 15% of patients and moderate in 2%. Mild vesicular rash was reported in 10% of patients and mild or moderate maculopapular rash in 8%. Vesiculo-bullous rash was reported in 10%, and exfoliative dermatitis in 5%. Erythema nodosum was reported in 2%, acne in 7%, and skin discoloration in 8%.

Metabolic

Hyperglycemia was observed in 67% of patients and Grade 3/4 hyperglycemia was reported in 15%. Hypomagnesemia was mild or moderate in 77% of patients; hypokalemia was mild or moderate in 62% and severe in 2%; hypocalcemia was mild or moderate in 46% and severe in 3%; hypophosphatemia was mild or moderate in 17%; and hyponatremia was reported in 2%.

Other

Other reported events included headache (mild or moderate 64%, severe 5%), abdominal pain (mild or moderate 69%, severe 3%), asthenia (mild or moderate 49%, severe 2%), unspecified pain (mild or moderate 43%, severe 2%), allergic reaction (mild or moderate 24%, severe 2%), injection site inflammation (mild or moderate 25%), injection site pain (mild or moderate 15%), chest pain (mild or moderate 26%), back pain (mild or moderate 23%), myalgia (mild or moderate 16%), arthralgia (mild or moderate 13%), and ear disorder in 3%.

Deaths

There were two deaths through BMT Day +28 in the allogeneic transplant setting. There were an additional six deaths BMT Day +29 through BMT Day +100 in the allogeneic transplant setting.

Post-Marketing Experience

The following adverse reactions (reported as MedRA terms) have been identified during post-approval use of Busulfex (busulfan) Injection: febrile neutropenia; tumor lysis syndrome; thrombotic micro-angiopathy (TMA); severe bacterial, viral (e.g., cytomegalovirus viraemia) and fungal infections; and sepsis. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to establish a causal relationship to drug exposure.

Oral Busulfan Literature Review

A literature review identified four randomized, controlled trials that evaluated a high-dose oral busulfan-containing conditioning regimen for allogeneic bone marrow transplantation in the setting of CML. The safety outcomes reported in those trials are summarized in Table 4 below for a mixed population of hematological malignancies (AML, CML, and ALL).

Table 4 Summary of safety analyses from the randomized, controlled trials utilizing a high dose oral busulfan-containing conditioning regimen that were identified in a literature review.

Clift CML Chronic Phase
* TRM = Transplantation Related Mortality † VOD = Veno-Occlusive Disease of the liver ‡ GVHD = Graft versus Host Disease
TRM*	VOD†	GVHD‡	Pulmonary	Hemorrhagic Cystitis	Seizure
Death ≤100d =4.1% (3/73)	No Report	Acute≥Grade 2 =35% Chronic=41% (30/73)	1 death from Idiopathic Interstitial Pneumonitis And 1 death from Pulmonary Fibrosis	No Report	No Report
Devergie CML Chronic Phase
TRM	VOD	GVHD	Pulmonary	Hemorrhagic Cystitis	Seizure
38%	7.7% (5/65) Deaths=4.6% (3/65)	Acute≥Grade 2 =41% (24/59 at risk)	Interstitial Pneumonitis= 16.9% (11/65)	10.8% (7/65)	No report
Ringden CML, AML, ALL
TRM	VOD	GVHD	Pulmonary	Hemorrhagic Cystitis	Seizure
28%	12%	Acute≥Grade 2 GVHD=26% Chronic GVHD =45%	Interstitial Pneumonitis =14%	24%	6%
Blume CML, AML, ALL
TRM	VOD	GVHD	Pulmonary	Hemorrhagic Cystitis	Seizure
No Report	Deaths =4.9%	Acute≥Grade 2 GVHD=22% (13/58 at risk) Chronic GVHD =31% (14/45 at risk)	No Report	No Report	No Report

Top

Side Effects by Body System - for Healthcare Professionals

Hematologic

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.

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. Postmarketing reports have included febrile neutropenia and thrombotic microangiopathy.

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

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.

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.

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

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.

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.

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. 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.

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.

Immunologic

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

Top

Disclaimer: Every effort has been made to ensure that the information provided is accurate, up-to-date, and complete, but no guarantee is made to that effect. In addition, the drug information contained herein may be time sensitive and should not be utilized as a reference resource beyond the date hereof. This information does not endorse drugs, diagnose patients, or recommend therapy. This drug information is a reference resource designed as supplement to, and not a substitute for, the expertise, skill , knowledge, and judgement of healthcare practitioners in patient care. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug of drug combination is safe, effective, or appropriate for any given patient. Drugs.com does not assume any responsibility for any aspect of healthcare administered with the aid of information provided. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse, or pharmacist.