"The U.S. Food and Drug Administration today approved Imbruvica (ibrutinib) to treat patients with mantle cell lymphoma (MCL), a rare and aggressive type of blood cancer.
MCL is a rare form of non-Hodgkin lymphoma and represents about 6 "...
Busulfex Side Effects Center
Medical Editor: John P. Cunha, DO, FACOEP
Busulfex (busulfan) is used to treat the symptoms of chronic myelogenous leukemia (a type of blood cancer). It is not a cure for leukemia. It is a cancer (antineoplastic) medication. Common side effects include nausea, vomiting, diarrhea, constipation, loss of appetite, mouth sores, stomach/abdominal pain, dizziness, swelling ankles/feet/hand, flushing, headache, or trouble sleeping.
The usual adult dose of Busulfex is 0.8 mg/kg of ideal body weight or actual body weight, whichever is lower, administered every six hours for four days (a total of 16 doses). Busulfex may interact with acetaminophen, itraconazole, or phenytoin. Tell your doctor all medications and supplements you use. Busulfex is not recommended for use during pregnancy. It may harm a fetus. Discuss birth control with your doctor. If you become pregnant or think you may be pregnant, tell your doctor. It is unknown if this drug passes into breast milk. Because of the possible risk to the infant, breastfeeding while using this drug is not recommended.
Our Busulfex (busulfan) Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
What is Patient Information in Detail?
Easy-to-read and understand detailed drug information and pill images for the patient or caregiver from Cerner Multum.
Busulfex in Detail - Patient Information: Side Effects
Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.
Call your doctor at once if you have a serious side effect such as:
- pale skin, feeling light-headed or short of breath, trouble concentrating;
- easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin;
- signs of infection such as fever, chills, sore throat, flu symptoms, loss of appetite, weight loss, unusual weakness, mouth and throat ulcers, rapid and shallow breathing;
- weight gain, stomach swelling or tenderness, jaundice (yellowing of the skin or eyes);
- coughing up blood;
- stomach pain, vomiting, sharp chest pain, trouble breathing;
- lower back pain, blood in your urine, urinating less than usual or not at all;
- confusion, jerking muscle movements, muscle tightness or contraction, overactive reflexes, muscle weakness or limp feeling, leg discomfort, numbness or tingly feeling around your mouth;
- fast, slow, or uneven heart rate;
- weak pulse, feeling short of breath, confusion, fainting;
- seizure (convulsions); or
- persistent cough, congestion, low fever, feeling short of breath (these symptoms may occur several months or years after using busulfan).
Less serious side effects may include:
- diarrhea, constipation, nausea, upset stomach;
- flushing (warmth, redness, or tingly feeling);
- swelling or irritation around the IV needle;
- missed menstrual periods; or
- hair loss, darkened skin color.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Read the entire detailed patient monograph for Busulfex (Busulfan) »
What is Patient Information Overview?
A concise overview of the drug for the patient or caregiver from First DataBank.
Busulfex Overview - Patient Information: Side Effects
Nausea, vomiting, diarrhea, constipation, loss of appetite, mouth sores, stomach/abdominal pain, dizziness, swelling ankles/feet/hand, flushing, headache, or trouble sleeping may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.
Nausea and vomiting can be severe. In some cases, your doctor may prescribe medication to prevent or relieve nausea and vomiting. Eating several small meals, not eating before treatment, or limiting activity may help lessen some of these effects.
Many people using this medication develop serious side effects. However, your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Careful monitoring by your doctor may decrease your risk.
Tell your doctor immediately if any of these unlikely but serious side effects occur: signs of liver disease (such as persistent nausea/vomiting, severe stomach/abdominal pain, yellowing skin/eyes, dark urine), mental/mood changes (such as depression, hallucinations, anxiety, confusion), muscle cramps, increased thirst/urination, fast/irregular heartbeat, coughing up blood, bloody urine, seizures, pain/redness/swelling at injection site.
Tell your doctor immediately if any of these rare but serious side effects occur: fainting, missed menstrual periods, shrinking testicles.
Busulfan has rarely caused very serious (possibly fatal) lung disease. Tell your doctor immediately if you develop symptoms of lung disease, including chest pain, shortness of breath, persistent cough.
Busulfan may cause other cancers (such as acute leukemia, tumors). Consult your doctor for more details. Tell your doctor immediately if you notice any symptoms of cancer, including unusual lumps, sudden weight loss.
A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.
This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.
In the US -
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.
Read the entire patient information overview for Busulfex (Busulfan)»
What is Prescribing information?
The FDA package insert formatted in easy-to-find categories for health professionals and clinicians.
Busulfex FDA Prescribing Information: Side Effects
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 x 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 x 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|
|BODY AS A WHOLE|
|Inflammation at Injection Site||25|
|METABOLIC AND NUTRITIONAL SYSTEM|
|SKIN AND APPENDAGES|
|*Includes all reported adverse events regardless of severity (toxicity grades 1-4)|
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 ¾ 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 graftversus- 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 ¾ 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 multiorgan 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.
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 (see Clinical Studies). 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 busulfancontaining conditioning
regimen that were identified in a literature review.
|CML Chronic Phase|
|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|
|CML Chronic Phase|
|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|
|CML, AML, ALL|
|28%||12%||Acute ≥ Grade 2 GVHD=26% Chronic GVHD =45%||Interstitial Pneumonitis =14%||24%||6%|
|CML, AML ,ALL|
|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|
|*TRM = Transplantation Related Mortality
**VOD = Veno-Occlusive Disease of the liver
***GVHD = Graft versus Host Disease
Read the entire FDA prescribing information for Busulfex (Busulfan) »
Additional Busulfex Information
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