Class: Alkyl sulfonate
- Solution for injection 6 mg/mL
- Tablets 2 mg
Predominantly effective against cells of the granulocytic series. Although a polyfunctional alkylating agent, it appears to interact with cellular thiol groups. The drug is cell cycle-phase nonspecific; however, alkylation of the DNA is considered an important biological mechanism for its cytotoxic effect.
C max is about 1,222 ng/mL.Oral
Concentrations in CSF are approximately equivalent to those in plasma. Busulfan is approximately 32.4% protein bound, primarily to albumin.
Metabolized predominantly by conjugation with glutathione. This conjugate is further oxidized in the liver.
About 30% excreted in urine over 48 h; negligible amounts are excreted in the feces; t ½ is 2.5 h.IV
Cl is about 2.52 mL/min/kg.
Indications and Usage
Palliative treatment of chronic myelogenous leukemia (CML) (oral); in combination with cyclophosphamide as a conditioning regimen prior to allogeneic bone marrow transplantation for CML (IV).
Severe thrombocytosis, polycythemia vera, myelofibrosis, bone marrow transplantation (oral).
Do not use unless a diagnosis of CML has been adequately established (oral); hypersensitivity to any of its components (IV, oral).
Dosage and AdministrationRemission Induction of CML
PO 4 to 8 mg/day (60 mcg/kg or 1.8 mg/m 2 /day). Withhold drug when the total leukocyte count is less than 15,000/mm 3 . During remission, treatment is resumed when a monthly WBC reaches 50,000/mm 3 .Children
PO 60 mcg/kg or 1.8 mg/m 2 once daily. Withhold drug when total leukocyte count is less than 15,000/mm 3 . During remission, treatment is resumed when a monthly WBC reaches 50,000/mm 3 .Bone Marrow Ablation
IV 0.8 mg/kg every 6 h for 16 doses (for a total dose of 12.8 mg/kg over 4 days). Base dose on ideal body weight or actual body weight, whichever is lower. For obese patients, base dosage on adjusted body weight.
- Withdraw dose from the ampule using the provided 5 micron filter needle. Remove the filter needle and use a new needle to add busulfan to the diluent.
- Dilute solution for injection with dextrose 5% or sodium chloride 0.9% , for a final busulfan concentration of about 0.5 mg/mL. Add the busulfan to the diluent; do not add the diluent to busulfan.
- Diluted busulfan solutions are stable for up to 8 h at room temperature (59° to 86°F) and for up to 12 h under refrigeration, but infusion must be completed within that time.
- Follow safe handling procedures and disposal of chemotherapy drugs. Wear gloves; avoid skin contact and inhalation of fumes.
- Infuse over 2 h. Vigorous hydration reduces the risk of renal toxicity.
- Visually inspect for particulate matter and discoloration prior to administration; do not use if particulate matter is seen.
Store tablets at 59° to 86°F. Store unopened injection ampules in refrigerator (36° to 46°F).
May decrease busulfan Cl.Itraconazole
Decreases busulfan Cl 25%, increasing serum levels and effects.Metronidazole
Busulfan trough levels may be elevated about 80%, increasing the risk of serious toxicity.Phenytoin
Increases busulfan Cl at least 15%, reducing serum levels and effects.Thioguanine
Long-term, concomitant use has resulted in hepatotoxicity and esophageal varices.
Laboratory Test Interactions
None well documented.
Tachycardia (44%); hypertension (36%); thrombosis (33%); vasodilation (25%); hypotension (11%); arrhythmia, cardiomegaly (5%); atrial fibrillation, left-sided heart failure, mild ECG abnormality, pericardial effusion, third-degree heart block, ventricular extrasystoles (2%).
Insomnia (84%); anxiety (72%); headache (69%); asthenia (51%); dizziness (30%); depression (23%); confusion (11%); lethargy (7%); hallucinations (5%); agitation, delirium, encephalopathy, somnolence (2%).
Hyperpigmentation (5% to 10%); alopecia, erythema multiforme, erythema nodosum, excessive dryness and fragility of the skin with anhidrosis, porphyria cutanea tarda, urticaria; rash (postmarketing).IV
Rash (57%); pruritus (28%); vesicular rash, vesiculobullous rash (10%); maculopapular rash, skin discoloration (8%); acne (7%); exfoliative dermatitis (5%).
Cataract, corneal thinning, lens changes (postmarketing).IV
Rhinitis (44%); pharyngitis (18%); ear disorder (3%).
Clinical syndrome similar to adrenal insufficiency.
Dry mouth, cheilosis.IV
Nausea (98%); stomatitis (97%); vomiting (95%); anorexia (85%); diarrhea (84%); abdominal pain (72%); dyspepsia (44%); constipation (38%); dry mouth (26%); rectal disorder (25%); abdominal enlargement (23%); ileus (8%); esophagitis, hematemesis, pancreatitis (2%).
Oliguria (15%); hematuria (8%); dysuria (7%); increased BUN (3%).
Anemia, leukopenia, myelosuppression, thrombocytopenia; aplastic anemia (postmarketing).IV
Cholestatic jaundice; hepatic veno-occlusive disease (VOD); centrilobular sinusoidal fibrosis, hepatocellular atrophy, hepatocellular necrosis (postmarketing).IV
Jaundice (12%); hepatic VOD after bone marrow transplantation (8%); hepatomegaly (6%).
Inflammation at injection site (25%); injection site pain (15%).
Hyperbilirubinemia, hyperuricemia, hyperuricosuria.IV
Hypomagnesemia (77%); hyperglycemia (67%); hypokalemia (64%); hypocalcemia, hyperbilirubinemia (49%); edema (36%); ALT elevation (31%); increased creatinine (21%); hypophosphatemia (17%); alkaline phosphatase increase (15%); hyponatremia (2%).
Back pain (23%); arthralgia (13%).
Interstitial pulmonary fibrosis; pneumonia (postmarketing).IV
Lung disorder (34%); cough (28%); dyspnea, epistaxis (25%); hiccup (18%); asthma (8%); hemoptysis, pleural effusion, sinusitis (3%); atelectasis, hypoxia (2%).
Myasthenia gravis; infection, mucositis, sepsis (postmarketing).IV
Fever (80%); chills (46%); pain (44%); general edema (28%); allergic reaction, chest pain (26%); graft vs host disease (18%).
Use with extreme caution in patients with prior radiation or chemotherapy.
Perform hematological testing weekly during therapy.Hematopoietic toxicity
Most frequent and serious side effect is bone marrow failure, resulting in severe pancytopenia. Recovery from busulfan-induced pancytopenia may take from 1 mo to 2 yr of age. The most consistent dose-related toxicity is bone marrow suppression. This may be manifested by anemia, leukopenia, neutropenia, thrombocytopenia, or any combination of these. Busulfan-induced bone marrow suppression may be prolonged. The WBC may continue to drop for 2 to 3 wk after therapy is discontinued and may take up to 2 mo to recover.
Monitor patients for signs of local or systemic infection or bleeding. Frequently evaluate hematologic status.
Category D .
Safety and efficacy not established.
Use with caution, usually starting at the low end of the dosage range because of the greater frequency of decreased cardiac, hepatic, or renal function, and concomitant diseases or other drug therapy.
High doses may be associated with an increased risk of developing hepatic VOD.
Malignant tumors have occurred in patients on busulfan therapy; this drug may be a human carcinogen.
A clinical syndrome closely resembling adrenal insufficiency and characterized by anorexia, melanoderma, nausea, severe fatigue, vomiting, weakness, and weight loss has developed after prolonged therapy.
Busulfan may cause cellular dysplasia in many organs, in addition to the lung. Giant hyperchromatic nuclei have been reported in the adrenal glands, bone marrow, liver, lymph nodes, pancreas, and thyroid.
Cardiac tamponade, which was often fatal, has been reported in a small number of children with thalassemia (2% in 1 series) who received high doses of busulfan and cyclophosphamide as the preparatory regimen for bone marrow transplantation and hematopoietic progenitor cell transplantation. Abdominal pain and vomiting preceded the tamponade in most patients.
Hyperuricemia and hyperuricosuria
May occur in patients with CML. Minimize adverse effects by increased hydration, urine alkalization, and the prophylactic administration of allopurinol.
Ovarian suppression and amenorrhea with menopausal symptoms
Commonly occurs during busulfan therapy in premenopausal patients. Busulfan has been associated with ovarian failure, including failure to achieve puberty in females.
A rare but important complication of busulfan therapy is the development of bronchopulmonary dysplasia with pulmonary fibrosis. Symptoms have occurred within 4 mo to 10 yr after initiation of therapy. Clinically, patients report the insidious onset of cough, dyspnea, and low-grade fever. Pulmonary function studies reveal diminished diffusion capacity and decreased pulmonary compliance.
Seizures have been reported in patients receiving high oral doses of busulfan. Risk of seizures may be reduced by prophylactic administration of phenytoin.
Bone marrow hypoplasia/aplasia, pancytopenia.
- Inform patients beginning therapy with busulfan of the importance of having periodic blood counts.
- Notify health care provider if any of the following occur: abrupt weakness; anorexia; congestion; fever; flank, stomach, or joint pain; persistent cough; shortness of breath; unusual bleeding or bruising; unusual fatigue; weight loss.
- Tell patients that diffuse pulmonary fibrosis is an infrequent but serious and potentially life-threatening complication of long-term busulfan therapy.
- Inform patients that some toxicities to busulfan include amenorrhea, drug hypersensitivity, dryness of the mucous membranes, infertility, and skin hyperpigmentation.
- Medication may cause appetite loss, darkening of skin, diarrhea, dizziness, fatigue, melanoderma, mental confusion, nausea, and vomiting that could be associated with a syndrome resembling adrenal insufficiency; notify health care provider if these become pronounced.
- Take medication at the same time each day.
- Extra fluid intake may be recommended.
- Contraceptive measures are recommended during therapy.
- If nausea or vomiting occurs, take the drug on an empty stomach.
- Explain the increased risk of a second malignancy to the patient.
- Instruct patients to promptly report the development of fever, sore throat, signs of local infection, bleeding from any site, or symptoms suggestive of anemia.
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