Dosing and uses of Myleran, Busulfex (busulfan)
Adult dosage forms and strengths
injectable solution
- 6mg/mL
tablet
- 2mg
Chronic Myelogenous (Myeloid, Myelocytic, Granulocytic) Leukemia
Pre-medicate with anticonvulsants (e.g. benzodiazepines, phenytoin, valproic acid or levetiracetam) and antiemetic
Remission induction: 60 mcg/kg/day or 1.8 mg/m²; 4-8 mg PO qDay usual range
Maintenance doses: 1-4 mg/day to 2 mg/week PO to maintain WBC 10,000-20,000 cells/mm³ may withhold drug when leukocyte count has declined to approximately 15,000/mcL
Examine patient at monthly intervals and resume treatment with induction dosage when total leukocyte count reaches approximately 50,000/mcL
Administered as component of busulfan/cyclophosphamide: 0.8 mg/kg IV q6hr for 4 days (in combo with cyclophosphamide) until WBC count= 15,000/mm³
Administration: take on empty stomach to decrease risk of N/V
Monitor: CBC, Hgb, LFTs
Brain Malignancies (Orphan)
Treatment of primary brain malignancies
Orphan indication sponsor
- SuperGen, Inc; Two Annabel Lane, Suite 220; San Ramon, CA 94583
Stem Cell Transplantation (Orphan)
Liposomal busulfan (Busulipo)
Orphan designation for use as a conditioning regimen for patients with malignancies undergoing autologous or allogenic hematopoietic stem cell transplantation
Orphan sponsor
- Pharmalink AB; Engelbrekts kyrkogata 7B, SE-114 26; Stockholm, Sweden
Hepatic Impairment
Not studied
Renal Impairment
Not studied
Other Indications & Uses
CML associated with Philadelphia chromosome
Pediatric dosage forms and strengths
Safety and efficacy not established
Geriatric dosage forms and strengths
Chronic Myelogenous (Myeloid, Myelocytic, Granulocytic) Leukemia
Remission induction: 60 mcg/kg/day or 1.8 mg/m²; 4-8 mg PO qDay usual range
Maintenance doses: 1-4 mg/day to 2 mg/week PO to maintain WBC 10,000-20,000 cells/mm³; may withhold drug when leukocyte count has declined to approximately 15,000/mcL
Examine patient at monthly intervals and resume treatment with induction dosage when total leukocyte count reaches approximately 50,000/mcL
Administered as component of busulfan/cyclophosphamide: 0.8 mg/kg IV q6hr for 4 days (in combo with cyclophosphamide) until WBC count= 15,000/mm³
Administration: take on empty stomach to decrease risk of N/V
Monitor: CBC, Hgb, LFTs
Myleran, Busulfex (busulfan) adverse (side) effects
>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
Warnings
Black box warnings
Bone marrow suppression is a common occurrence; reduce dose or discontinue oral administration for unusual suppression (bond marrow biopsy may be necessary); hematopoietic progenitor cell transplantation is required to prevent potentially fatal complications of prolonged myelosuppression
Monitoring is very important after administering these doses
This drug should be administered under the supervision of an experienced cancer chemotherapy physician
Contraindications
Hypersensitivity, resistance to busulfan
Patients without definitive diagnosis of CML
Cautions
Bone marrow depression may occur
Seizures reported with use; initiate anticonvulsant prophylactic therapy prior to treatment with busulfan; monitor patients with history of seizure disorder, head trauma or receiving epileptogenic drugs
Cardiac temponade reported in children with thalassemia in combination with cyclophosphamide
Ovarian failure may occur
Secondary malignancies reported
Antiemetics may be recommended to prevent nausea and vomiting
Increased risk of developing hepatic veno-occlusive disease (HVOD) at AUC greater than 1,500 μM•min; monitor serum transaminases, alkaline phosphatase and bilirubin daily
Bronchopulmonary dysplasia with pulmonary fibrosis reported and can be fatal; toxicity may be additive if used with other agents that cause pulmonary toxicity; discontinue therapy if busulfan toxicity develops
Avoid pregnancy; can cause fetal harm; advise of potential risk to a fetus and use of effective contraception
Pregnancy and lactation
Pregnancy category: d
Lactation: Excretion in milk unknown/discontinue breastfeeding
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Myleran, Busulfex (busulfan)
Mechanism of action
Alkylating agent; interferes with DNA eplication and RNA transcription; cross-links DNA strands; has little immunosuppressive activity; affects myeloid cells more than lymphoid cells; very toxic to hematopoietic stem cells
Pharmacokinetics
Half-life elimination: 2.5 hr
Onset: 1-2 wk
Duration: 24 hr
Time to peak serum: 1hr (PO); 5 min (IV)
Bioavailability: 68-80% depending on age
Protein Bound: 32%
Vd: 0.6-1.0 L/kg (adults); 1.4-1.6 L/kg (children)
Metabolism: Liver
Metabolites: Methanesulfonic acid & 3-hydroxytetrahydrothiophene-1,1-dioxide
Clearance: 2.52 mL/min/kg
Excretion: Urine (25-60%)
Dialyzable: Yes
Administration
IV Preparation
Dilute and administer as intravenous infusion; do not administer as intravenous push or bolus
Do not infuse other medications simultaneously
Dilute busulfan injection in NS or D5W; do not use other diluents
Dilution volume should be 10x volume of busulfan concentrate, insuring final concentration is equal to or >0.5 mg/mL
IV Administration
Administer via a central venous catheter as a 2 hr infusion, q6hr for 4 consecutive days for a total of 16 doses
Do not use polycarbonate syringes
Storage
Store unopened ampules (injection) under refrigeration at 2-8°C
Prolonged storage (>8 hr) in D5W or NS at room temp causes 10%+ loss of potency
