Busulfan (Systemic)
VA CLASSIFICATION
Primary: AN100
Commonly used brand name(s): Busulfex; Myleran.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
Category:
Antineoplastic—
Indications
Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.
Accepted
Leukemia, chronic myelogenous (myeloid, myelocytic, granulocytic) (treatment)—Busulfan is indicated for palliative treatment of chronic myelogenous leukemia. It is not useful in the blastic crisis phase. {01}
Conditioning regimen (treatment adjunct)—Busulfan injection is indicated in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for treatment of chronic myelogenous leukemia{08}.
[Leukemia, acute nonlymphocytic (treatment) ]1—Busulfan is used for treatment of acute nonlymphocytic leukemia {02}.
1 Not included in Canadian product labeling.
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Molecular weight—
246.29
pH
3.4 to 3.9, for a > 0.5% solution in 0.9% sodium chloride USP or 5% dextrose in water USP.
Solubility
Soluble in water at 0.1 gram/L{08}.
Mechanism of action/Effect:
Busulfan is a bifunctional alkylating agent of the alkylsulfonate type and is cell cycle–phase nonspecific. Its mechanism of action is not clear but is thought to consist of alkylation and cross-linking of strands of DNA{01} and myelosuppression.
Absorption:
Completely absorbed from the gastrointestinal tract {01}. Radioactivity is detected in the blood 1/2 to 2 hours after oral administration of radiolabeled busulfan {01}.
Distribution:
Busulfan distributes equally into both plasma and cerebrospinal fluid {08}.
Protein binding:
Low (32.4%){08}irreversible binding to plasma elements, primarily to albumin.
Biotransformation:
Primarily hepatic; undergoes conjugation with glutathione both spontaneously and by glutathione S-transferase (GST) catalysis. This conjugate then undergoes further oxidative metabolism{08}.
Half-life:
About 2.5 hours.
Onset of action:
A clinical response usually begins within 1 to 2 weeks after initiation of therapy.
Elimination:
Renal, slow, 30% in 48 hours, almost entirely as metabolites {01}.
In dialysis—There has been one report that busulfan is dialyzable {08}; however, dialysis is likely to have minimal effect because of poor water solubility of busulfan and prolonged retention of metabolites{01}.
Precautions to Consider
Carcinogenicity
Secondary malignancies are potential delayed effects of many antineoplastic agents, although it is not clear whether the effect is related to their mutagenic or immunosuppressive action. The effect of dose and duration of therapy is also unknown, although risk seems to increase with long-term use. Although information is limited, available data seem to indicate that the carcinogenic risk is greatest with the alkylating agents.
Busulfan has been associated with development of acute leukemia in humans {01}{08}.
Mutagenicity
Busulfan is mutagenic in mice {01}{08}. It has been reported to cause chromosome aberrations in human cells {01}{08}.
Pregnancy/Reproduction
Fertility—
Gonadal suppression, resulting in amenorrhea or azoospermia, may occur in patients taking antineoplastic therapy, especially with the alkylating agents. In general, these effects appear to be related to dose and length of therapy and may be irreversible. Prediction of the degree of testicular or ovarian function impairment is complicated by the common use of combinations of several antineoplastics, which makes it difficult to assess the effects of individual agents.
Busulfan produces sterility in the male and female offspring of rats due to germinal cell aplasia in testes and ovaries {01}{08}. It has also been associated with impairment of gonadal function in humans (ovarian suppression and amenorrhea with menopausal symptoms in premenopausal patients; sterility, azoospermia, and testicular atrophy in males) {01}{08}.
Pregnancy—
Adequate and well-controlled studies in humans have not been done {01}{08}. Although several successful pregnancies have been reported, one case of neonatal abnormalities has been reported in which the mother received radiation and combination chemotherapy including busulfan {01}. In addition, there have been reports of small infants, especially after use of busulfan during the third trimester, and there is one report of mild anemia and neutropenia at birth after maternal administration of busulfan from the eighth week of pregnancy to term {01}.
First trimester: It is usually recommended that use of antineoplastics, especially combination chemotherapy, be avoided whenever possible, especially during the first trimester. Although information is limited because of the relatively few instances of antineoplastic administration during pregnancy, the mutagenic, teratogenic, and carcinogenic potential of these medications must be considered.
Other hazards to the fetus include adverse reactions seen in adults.
In general, use of a contraceptive is recommended during cytotoxic drug therapy.
Teratogenic anomalies have occurred in the offspring of mice, rats, and rabbits, including cleft palate, heart vessel, rib, and vertebral anomalies, and malformations in the musculoskeletal system, body weight gain, and size{08}.
FDA Pregnancy Category D {01}{08} .
Breast-feeding
Although very little information is available regarding distribution of antineoplastic agents into breast milk, breast-feeding is not recommended during chemotherapy because of the risks to the infant (adverse effects, mutagenicity, carcinogenicity). It is not known whether busulfan is distributed into breast milk {01}{08}.
Pediatrics
Safety and efficacy have not been established. Clearance has been demonstrated to be greater in children than in adults, necessitating the development of alternative dosing regimens. Cardiac tamponade has been reported for patients with thalassemia receiving high doses of oral busulfan and cyclophosphamide {08}.
Geriatrics
Appropriate studies on the relationship of age to the effects of busulfan have not been performed in the geriatric population. However, geriatrics-specific problems that would limit the usefulness of this medication in the elderly are not expected.
Dental
The bone marrow depressant effects of busulfan may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. Dental work, whenever possible, should be completed prior to initiation of therapy or deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene during treatment, including caution in use of regular toothbrushes, dental floss, and toothpicks.
Busulfan may also cause stomatitis associated with considerable discomfort.
Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Allopurinol or
Colchicine or
» Probenecid or
» Sulfinpyrazone (busulfan may raise the concentration of blood uric acid; dosage adjustment of antigout agents may be necessary to control hyperuricemia and gout; allopurinol may be preferred to prevent or reverse busulfan-induced hyperuricemia because of risk of uric acid nephropathy with uricosuric antigout agents)
» Blood dyscrasia–causing medications (see Appendix II ) (leukopenic and/or thrombocytopenic effects of busulfan may be increased with concurrent or recent therapy if these medications cause the same effects; dosage adjustment of busulfan, if necessary, should be based on blood counts )
» Bone marrow depressants, other (see Appendix II ) or
» Radiation therapy (additive bone marrow depression may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively)
» Acetaminophen (reduced busulfan clearance may occur if acetaminophen is administered <72 hours before or at the same time as busulfan{08})
» Itraconazole (decreased busulfan clearance of up to 25% may occur{08}monitor for busulfan toxicity{09})
» Phenytoin (increased busulfan clearance of 15% or more may occur{08})
Vaccines, killed virus (because normal defense mechanisms may be suppressed by busulfan therapy, the patient's antibody response to the vaccine may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year)
» Vaccines, live virus (because normal defense mechanisms may be suppressed by busulfan therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patient's hematologic status and only with the knowledge and consent of the physician managing the busulfan therapy. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. Patients with leukemia in remission should not receive live virus vaccine until at least 3 months after their last chemotherapy. In addition, immunization with oral poliovirus vaccine should be postponed in persons in close contact with the patient, especially family members)
Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
With diagnostic test results
Cytology studies of lung, bladder, breast, or uterine cervix tissue (cytologic dysplasia caused by busulfan may be severe enough to cause difficulty in interpretation {01})
With physiology/laboratory test values
Alkaline phosphatase, serum and
Alanine aminotransferase (ALT [SGPT]), serum and
Aspartate transaminase (AST [SGOT]), serum and
Billirubin, serum (levels may be increased{08})
Complete blood count with differential, blood and
Neutrophils, blood and
Platelets, blood (counts may be decreased {08})
Calcium, serum and
Magnesium, serum and
Potassium, serum (concentrations may be decreased{08})
Busulfan, plasma and
Creatinine, serum and
Blood urea nitrogen and
Glucose, serum and
Uric acid in blood and urine (concentrations may be increased)
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
Risk-benefit should be considered when the following medical problems exist
» Bone marrow depression
» Chickenpox, existing or recent (including recent exposure) or
» Herpes zoster (risk of severe generalized disease)
» Gout, history of or
» Urate renal stones, history of (risk of hyperuricemia)
» Infection
» Sensitivity to busulfan
» Seizures, history of or
» Head trauma (prophylactic anticonvulsant therapy should be started prior to initiating busulfan injection {01})
» Thalassemia (cardiac tamponade, preceded by abdominal pain and vomiting, has been reported in pediatric patients receiving busulfan and cyclophosphamide therapy{08})
» Caution should be used also in patients who have had previous cytotoxic drug therapy or radiation therapy or who have evidence of myelofibrosis. (increased risk of hepatic veno-occlusive disease)
Caution should be used in patients with hepatic or renal impairment due to a lack of studies in these groups
Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
Alanine aminotransferase values, serum {01}{08} and
Alkaline phosphatase values, serum {01}{08} and
Bilirubin concentrations, serum {01}{08} (recommended at periodic intervals to detect possible hepatotoxicity, including hepatic veno-occlusive disease {01} and recommended daily through transplant day 28 with busulfan injection for bone marrow transplantation{08})
» Hematocrit or hemoglobin and
» Leukocyte count, total and, if appropriate, differential and
Neutrophil count, absolute and
Platelet count (determinations recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently; because of severe and delayed myelosuppression caused by busulfan, frequent monitoring is necessary so that therapy can be withdrawn promptly when indicated{01}and recommended daily with busulfan injection, until engraftment is complete{08})
Uric acid concentrations, serum (recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)
Side/Adverse Effects
Note: Many “side effects” of antineoplastic therapy are unavoidable and represent the medication's pharmacologic action. Some of these (for example, leukopenia and thrombocytopenia) are actually used as parameters to aid in individual dosage titration.
Busulfan can cause cellular dysplasia in many tissues, including lungs, lymph nodes, pancreas, thyroid, adrenal gland, liver, bone marrow, bladder, breast, and uterine cervix {01}.
Seizures have been reported in 2 of 130 patients receiving very high investigational doses (1 mg per kg of body weight [mg/kg] four times a day for four days, total dose 16 mg/kg) {01}{07}.
Hepatic veno-occlusive disease has been reported following investigational use of very high doses of busulfan in combination with other chemotherapy prior to bone marrow transplantation {01}{08}.
Continuous treatment with a combination of busulfan and thioguanine in approximately 330 patients was associated with esophageal varices along with abnormal hepatic function tests and evidence of nodular regenerative hyperplasia on liver biopsy in 12 patients after six to forty-five months of therapy. No hepatic toxicity was found in the busulfan alone arm of the study. {01}{06}
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence more frequent (> 50%)
Anemia {01}{08}
leukopenia {01}
or infection (fever or chills ; cough or hoarseness; lower back or side pain; painful or difficult urination)—usually asymptomatic, anemia and leukopenia occur in 100% of patients
stomatitis{08} (inflammation of the oral mucosa)—occurs with busulfan injection
thrombocytopenia {01}{08} (unusual bleeding or bruising; black, tarry stools ; blood in urine or stools; pinpoint red spots on skin)—occurs in 100% of patients
Note: Onset of leukopenia is usually 10 to 15 days after initiation of therapy {01} (leukocyte counts usually increase transiently before this {01}), with nadir of white cell count at 11 to 30 days; white cell counts may continue to fall for more than 1 month after withdrawal but usually recover within 12 to 20 weeks {01}.
Bone marrow depression may be severe and progressive, leading to pancytopenia {01}. Recovery from pancytopenia after withdrawal of busulfan may take 1 month to 2 years {01}.
Symptoms of bone marrow depression may also indicate transformation of chronic myelocytic leukemia into the acute blastic form {01}.
Incidence less frequent (5 – 50%)
—occurring with long-term use or high dosage
Allergic reaction{08} (fast or irregular breathing; puffiness or swelling around face; shortness of breath; sudden, severe decrease in blood pressure )—occurs with busulfan injection
bronchopulmonary dysplasia with pulmonary fibrosis {01}{08} (fever; cough; shortness of breath )
chest pain
dyspnea (shortness of breath)
edema{08} (swelling of fingers, hands, arms, lower legs, or feet)—occurs with busulfan injection
hyperuricemia {01}or uric acid nephropathy (joint pain; lower back or side pain; swelling of feet or lower legs)
tachycardia (rapid heartbeat)
thrombosis (tingling in lower legs, hands, or feet)
vasodilation ( dizziness; light-headedness; sweating){08}
Note: Bronchopulmonary dysplasia with pulmonary fibrosis usually occurs 8 months to 10 years (average 4 years) after initiation of therapy and is usually fatal within 6 months after diagnosis {01}. Associated with decreased diffusion capacity and pulmonary compliance {01}. Histologically resembles changes following pulmonary irradiation {01}. Lung biopsy may be necessary to establish the diagnosis {01}.
Hyperuricemia or uric acid nephropathy occurs most commonly during initial treatment of patients with leukemia, as a result of rapid cell breakdown which leads to elevated serum uric acid concentrations {01}.
Incidence rare (< 5%)
Cataracts (blurred vision)—occur after prolonged administration {01}
esophagitis (heartburn; difficulty swallowing)
hematemesis (vomiting blood)
pancreatitis ( severe upper abdominal and back pain)
{08}
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent (> 50%)
Abdominal pain
amenorrhea and ovarian suppression {01}{08} (missed or irregular menstrual periods)
anorexia ( loss of appetite and weight loss)
anxiety {08} —occurs with busulfan injection
asthenia {08} (general fatigue ; muscle pain)— occurs with busulfan injection
diarrhea
headache{08} —occurs with busulfan injection
insomnia {08} ( trouble in sleeping)— occurs with busulfan injection
nausea
rash {08}
vomiting
{08}
Incidence less frequent (5 – 50%)
—occurring with long-term use
Confusion {01}{08}
constipation
darkening of skin —5 to 10% {01}
depression
dry mouth
epistaxis (bloody nose)
inflammation at injection site
pain
pharyngitis or cough (sore throat or cough)
pruritus (itching)
rhinitis (stuffy nose; runny nose; sneezing)
{08}
Note: All of the above, as well as darkening of skin, may occur after prolonged therapy and may resemble adrenocortical insufficiency, although adrenocortical function is not suppressed in most patients. Symptoms are sometimes reversible on withdrawal of busulfan. Adrenal responsiveness to exogenous adrenocorticotropic hormone (ACTH) is usually normal, but pituitary function testing with metyrapone has shown blunted urinary 17-hydroxycorticosteroid excretion in some patients that returned to normal when busulfan was discontinued. {01}
Those indicating the need for medical attention if they occur after medication is discontinued
Bone marrow depression
pancytopenia
or thrombocytopenia (unusual bleeding or bruising ; black, tarry stools; blood in urine or stools; pinpoint red spots on skin; fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination)
pulmonary fibrosis (fever; cough; shortness of breath)
Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).
Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute
Bone marrow hypoplasia/aplasia {08}
pancytopenia {08}
Treatment of overdose
Induction of vomiting or gastric lavage followed by administration of charcoal if ingestion of oral busulfan is recent {01}.
Glutathione—Consider as treatment of overdose based on busulfan metabolism by conjugation with glutathione{08}
Hematopoietic progenitor cell transplantation—In the absence of hematopoietic progenitor cell transplantation, the normal dosage of busulfan injection constitutes an overdose of busulfan {01}.
Dialysis—There has been one report that busulfan is dialyzable {08}.
Monitoring of hematologic status and supportive measures if necessary {01}{08}.
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Busulfan (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):
Before using this medication
» Conditions affecting use, especially:
Sensitivity to busulfan
Pregnancy—Use not recommended because of mutagenic, teratogenic, and carcinogenic potential; advisability of using contraception; telling physician immediately if pregnancy is suspected
Breast-feeding—Not recommended because of risk of serious side effects
Other medications, especially acetaminophen, itraconazole, blood dyscrasia-causing medications, live vaccines, phenytoin, probenecid, sulfinpyrazone, other bone marrow depressants, or previous cytotoxic drug therapy or radiation therapy
Other medical problems, especially bone marrow depression, chickenpox, herpes zoster, or other infections gout, head injury or history of seizures, thalassemia, urate kidney stones
Proper use of this medication
» Importance of not taking more or less medication than the amount prescribed
Taking each dose at the same time each day to ensure uniform effect
Importance of ample fluid intake and subsequent increase in urine output to aid in excretion of uric acid
» Possible nausea and vomiting; importance of continuing medication despite stomach upset
Checking with physician if vomiting occurs shortly after dose is taken
» Proper dosing
Missed dose: Not taking at all; not doubling doses
» Proper storage
Precautions while using this medication
» Importance of close monitoring by the physician
» Avoiding immunizations unless approved by physician; other persons in patient's household should avoid immunizations with oral poliovirus vaccine; avoiding persons who have taken oral poliovirus vaccine or wearing a protective mask that covers nose and mouth
Caution if bone marrow depression occurs
» Avoiding exposure to persons with infections, especially during periods of low blood counts; checking with physician immediately if fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination occurs
» Checking with physician immediately if unusual bleeding or bruising; black, tarry stools; blood in urine or stools; or pinpoint red spots on skin occur
Caution in use of regular toothbrush, dental floss, or toothpick; physician, dentist, or nurse may suggest alternatives; checking with physician before having dental work done
Not touching eyes or inside of nose unless hands washed immediately before
Using caution to avoid accidental cuts with use of sharp objects such as safety razor or fingernail or toenail cutters
Avoiding contact sports or other situations where bruising or injury might occur
Caution if any laboratory tests required; possible interference with tissue study results
Side/adverse effects
May cause adverse effects such as lung or blood problems; importance of discussing possible effects with physician
Signs of potential side effects, especially allergic reaction, anemia, bronchopulmonary dysplasia with pulmonary fibrosis, cataracts, chest pain, dyspnea, edema, esophagitis, hematemesis, hyperuricemia, infection, leukopenia, stomatitis, thrombocytopenia, tachycardia, thrombosis, uric acid nephropathy, and vasodilation
Physician or nurse can help in dealing with side effects
General Dosing Information
Patients receiving busulfan should be under supervision of a physician experienced in cancer chemotherapy {01}{08}.
Dosage must be adjusted to meet the individual requirements of each patient, based on clinical response and degree of bone marrow depression.
Development of uric acid nephropathy in patients with leukemia may be prevented by adequate oral hydration and, in some cases, administration of allopurinol {01}. Alkalinization of urine may be necessary if serum uric acid concentrations are elevated {01}.
Busulfan therapy should be discontinued at the first sign of interstitial pulmonary fibrosis {01}.
Busulfan injection should be administered only under supervision of a physician who is experienced in allogeneic hematopoietic stem cell transplantation and in the use of antineoplastic agents {08}
Dosing busulfan injection based on actual body weight, ideal body weight or other factors can produce significant differences in busulfan injection clearance among lean, normal and obese patients. The dose of busulfan injection is based on ideal body weight (IBW) or actual body weight, whichever is lower. For obese or severely obese patients, busulfan injection should be administered based on adjusted ideal body weight (AIBW) as follows{08}:
• IBW (males) = 50 + 0.91 × (height in cm - 152)
• IBW (females) = 45 + 0.91 × (height in cm - 152)
• AIBW = IBW + 0.25 × (actual weight in kg - IBW)
Rapid infusion of busulfan injection is not recommended. Infusion pumps should be used to administer busulfan injection solution. Before and after each infusion, flush the catheter line with approximately 5 mL of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP {08}.
Busulfan is known to cross the blood brain barrier and induce seizures. In cases in which other anticonvulsants must be used, busulfan plasma levels should be monitored{08}.
If high-dose busulfan is prescribed, patients should be given prophylactic anticonvulsant therapy, administration preferably with a benzodiazepine rather than an enzyme-inducing anticonvulsant (e.g., phenytoin). Phenytoin use may result in a decrease in the myeloablative effect of busulfan due to increased busulfan clearance{09}{10}. (See Drug interactions)
Because of the delayed effect, it is recommended that busulfan therapy be discontinued or dosage reduced at the first sign of a sudden large decrease in leukocyte (particularly granulocyte) count to prevent irreversible bone marrow depression {01}.
Special precautions are recommended in patients who develop thrombocytopenia as a result of administration of busulfan. These may include extreme care in performing invasive procedures; regular inspection of intravenous sites, skin (including perirectal area), and mucous membrane surfaces for signs of bleeding or bruising; limiting frequency of venipuncture and avoiding intramuscular injections; testing urine, emesis, stool, and secretions for occult blood; care in use of regular toothbrushes, dental floss, toothpicks, safety razors, and fingernail and toenail cutters; avoiding constipation; and using caution to prevent falls and other injuries. Such patients should avoid alcohol and aspirin intake because of the risk of gastrointestinal bleeding. Platelet transfusions may be required.
Patients who develop leukopenia should be observed carefully for signs of infection. Antibiotic support may be required. In neutropenic patients who develop fever, broad-spectrum antibiotic coverage should be initiated empirically, pending bacterial cultures and appropriate diagnostic tests.
Safety considerations for handling this medication
There is limited but increasing evidence and concern that personnel involved in preparation and administration of parenteral antineoplastic agents may be at some risk because of the potential mutagenicity, teratogenicity, and/or carcinogenicity of these agents, although the actual risk is unknown. USP advisory panels recommend cautious handling both in preparation and disposal of antineoplastic agents. Precautions that have been suggested include: • Use of a biological containment cabinet during reconstitution and dilution of parenteral medications and wearing of disposable surgical gloves and masks.
• Use of proper technique to prevent contamination of the medication, work area, and operator during transfer between containers (including proper training of personnel in this technique).
• Cautious and proper disposal of needles, syringes, vials, ampuls, and unused medication.
A number of medical centers have developed detailed guidelines for handling of antineoplastic agents.
Oral Dosage Forms
BUSULFAN TABLETS USP
Usual adult dose
Chronic myelocytic leukemia
Induction:
Oral, 1.8 mg per square meter of body surface or 60 mcg (0.06 mg) per kg of body weight a day until the white cell count falls below 15,000 cells per cubic millimeter {01}. Usual dosage range is 4 to 8 mg per day but may range from 1 to 12 mg per day {01}. During remission, treatment is resumed when a monthly white cell count reaches 50,000 cells per cubic millimeter {01}.
Note: Some patients may be unusually sensitive to busulfan and develop myelosuppression more rapidly than usual {01}. Therefore, frequent and careful monitoring of blood counts is necessary {01}. The total leukocyte count decreases exponentially at a constant busulfan dose, so a weekly plot of leukocyte count on semi-logarithmic graph paper can aid in predicting when leukocyte counts will reach 15,000 and busulfan should be discontinued {01}.
Maintenance:
Oral, 1 to 3 mg per day {01}.
Note: Maintenance therapy with busulfan is recommended only when a remission is shorter than 3 months {01}.
Usual pediatric dose
Chronic myelocytic leukemia
Induction: Oral, 60 to 120 mcg (0.06 to 0.12 mg) per kg of body weight or 1.8 to 4.6 mg per square meter of body surface per day.
Note: Dosage is titrated to reduce and maintain a leukocyte count of about 20,000 cells per cubic millimeter.
Strength(s) usually available
U.S.—
2 mg (Rx) [Myleran (scored)]
Canada—
2 mg (Rx) [Myleran (scored)]
Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 25 °C (59 and 77 °F), unless otherwise specified by manufacturer. Store in a well-closed container.
Parenteral Dosage Forms
BUSULFAN INJECTION
Usual adult dose
Chronic myelocytic leukemia—Conditioning regimen: Intravenous (over two hours), 0.8 mg per kg of ideal or actual body weight (whichever is lower), every six hours, for four days, for a total of 16 doses, in combination with 60 mg of cyclophosphamide per kg of body weight daily for two days, given over one hour, starting six hours after the last dose of busulfan is administered.
Note: For obese or severely obese patients, busulfan injection should be administered based on adjusted ideal body weight {08}.
Strength(s) usually available
U.S.—
6 mg/ml (Rx) [Busulfex (N,N-dimethylacetamide 33% W/W, polyethylene glycol 400 67% W/W)]
Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F){08}.
Preparation of dosage form:
Busulfan injection should be diluted with either 0.9% sodium chloride USP or 5% dextrose in water USP, maintaining a diluent concentration that is 10 times the volume of busulfan. Final busulfan concentration should be ³ 0.5 mg/mL {08}.
Remove the calculated volume of busulfan injection with a syringe fitted with a needle and the five micron nylon filter supplied with the ampule. Remove the needle and filter and replace with a new needle. Dispense the contents of the syringe into an intravenous bag (or syringe) already containing the calculated amount of either 0.9% sodium chloride or 5% dextrose in water. Make sure the drug flows into and through the solution. Always add busulfan injection to the diluent and not diluent to busulfan injection. Mix thoroughly by inverting several times {08}.
Stability:
Diluted solutions of busulfan injection are stable at room temperature (25 °C) for up to eight hours but the infusion must be completed by that time. When refrigerated (2-8 °C), diluted solutions of busulfan injection are stable for up to 12 hours but the infusion must be completed within that time {08}.
Note: Dimethylacetamide (DMA), the solvent used in the busulfan injection formulation, can cause increased transaminases and neurologic symptoms. The contribution of DMA to neurologic and hepatic toxicities observed with busulfan injection is unknown {08}.
Revised: 10/05/1999
References
Note: References used in the development and subsequent revisions of this monograph have not been incorporated into the database and therefore are not listed below.
- Myleran package insert (BW—US), Rev 2/91.
- Hematology-Oncology Advisory Panel (1985–1990) Memorandum No. 22, 1989.
- Marcus RE, Goldman JM. Convulsions due to high-dose busulphan. Lancet 1984; 2: 1463.
- Martell RW, Sher C, Jacobs P, et al. High-dose busulfan and myoclonic epilepsy. Ann Intern Med 1987; 106: 173.
- Rushing D et al. Hydroxyurea versus busulfan in the treatment of chronic myelogenous leukemia. Am J Clin Oncol 1982; 5: 307-13.
- Key NS, Emerson PM, Allan NC, et al. Oesophageal varices associated with busulphan-thioguanine combination therapy for chronic myeloid leukaemia. Lancet 1987; 2: 1050-2.
- Murphy CP, Harden EA, Thompson JM. Generalized seizures secondary to high-dose busulfan therapy. Ann Pharmacother 1992; 26: 30-1.
- Busulfan NDA (Orphan Medical—US), Approved 2/10/99, Available from: http://www.fda.gov/cder/approval/index.htm.
- Busulfan product monograph (Myleran, Glaxo Wellcome—Canada), Rev 8/98, Rec 3/99.
- Reviewer's consensus on monograph revision of 9/99.
