Busulfan

SCOPE: this entry publishes the page's primary indication only - HSCT conditioning - on both of the page's routes, each figure labelled with its own source. The UK record in this bundle is the ORAL 2 mg tablet; the intravenous figures are US labelling and must be confirmed against the UK intravenous SPC (Busilvex) before use. NO MAXIMUM DOSE is stated for conditioning in either source, so the maximum field is deliberately blank - the only "maximum" wording in the bundle ("an initial daily maximum of 4 mg") belongs to CML induction, a different indication, and must not be applied here. PARTNER AGENT: UK SPC 4.2 - "60 mg/kg per day of cyclophosphamide is usually given for two days commencing 24 h after the final dose of Busulfan"; US label 2.1 - "Cyclophosphamide 60 mg per kg intravenously as a one-hour infusion on each of two days beginning no sooner than six hours following the 16th dose of busulfan injection (Days -3 and -2). Administer hematopoietic progenitor cells on Day 0." DRUG LEVEL MONITORING: UK SPC 4.2 - "When busulfan is used as a conditioning treatment prior to haemopoietic progenitor cell transplantation, drug level monitoring is recommended." PREMEDICATION: US label 2.1 - "Premedicate patients with anticonvulsants (e.g., benzodiazepines, phenytoin, valproic acid or levetiracetam) to prevent seizures reported with the use of high dose busulfan injection. Administer anticonvulsants 12 hours prior to busulfan injection to 24 hours after the last dose of busulfan injection"; antiemetics before the first dose, continued on a fixed schedule. UK SPC 4.4 - "If high-dose Busulfan is prescribed, patients should be given prophylactic anticonvulsant therapy, preferably with a benzodiazepine rather than phenytoin." WEIGHT BASIS: US label 2.1 - clearance "is best predicted when the busulfan injection dose is administered based on adjusted ideal body weight"; IBW (kg) men = 50 + 0.91 x (height in cm - 152), women = 45 + 0.91 x (height in cm - 152); for obese or severely obese patients AIBW = IBW + 0.25 x (actual weight - IBW). UK SPC 4.2 - "Dosing based on body surface area or adjusted ideal body weight should be considered in the obese." IV PREPARATION: US label 2.3 - dilute with 0.9% sodium chloride or 5% dextrose, diluent quantity ten times the volume of busulfan injection, giving a final busulfan concentration of approximately 0.5 mg per mL; the vial is 60 mg/10 mL (6 mg per mL). ORAL BIOAVAILABILITY: UK SPC 4.2 - varies "from 47% to 103% (mean 80%) in adults and from 22% to 120% (mean 68%) in children". INTERACTIONS AFFECTING DOSE: US label 7 - metronidazole, itraconazole, iron chelating agents and acetaminophen (paracetamol) decrease busulfan clearance, phenytoin increases it; UK SPC 4.4 - patients on conventional-dose busulfan with itraconazole or metronidazole should be closely monitored for toxicity with weekly blood counts. OTHER ORAL INDICATIONS IN THE SAME UK SPC, quoted for completeness and NOT this page's primary indication - the ceilings below belong to these regimens only: chronic myeloid leukaemia induction in adults "0.06 mg/kg/day, with an initial daily maximum of 4 mg, which may be given as a single dose", continued until the total leucocyte count has fallen to between 15 and 25 x 10^9/L (typically 12 to 20 weeks), with CML maintenance "on average 0.5 to 2 mg/day"; polycythaemia vera "4 to 6 mg daily, continued for 4 to 6 weeks"; myelofibrosis "usual initial dose is 2 to 4 mg daily"; essential thrombocythaemia "2 to 4 mg per day", interrupting treatment if the total leucocyte count falls below 5 x 10^9/L or the platelet count below 500 x 10^9/L. "Lower doses of Busulfan should be used if it is administered in conjunction with other cytotoxic agents." Busulfan "is an active cytotoxic agent for use only under the direction of physicians experienced in the administration of such agents" - dose against the local transplant protocol.

PER-SURFACE-AREA REGIMEN - NO PER-KG FIGURE. UK SPC 4.2, paediatric population: "The conventional dosage plan for conditioning before haemopoietic stem cell transplantation is 30 to 37.5 mg/m2 every 6 hours for 4 days, starting seven days prior to transplantation. The dosing of cyclophosphamide is the same as for adults." Because this is a body-surface-area regimen, no per-kg value is given to the weight calculator. The US label's paediatric intravenous figures cannot fill that gap either: they are age-banded and were AUC-targeted starting doses in an open-label, uncontrolled pharmacokinetic study, not a licensed fixed dose - US label 8.4 describes 24 patients aged 5 months to 16 years (median 3 years) in whom "Busulfan dosing was targeted to achieve an area under the plasma concentration curve (AUC) of 900 to 1350 microM.min with an initial dose of 0.8 mg per kg or 1.0 mg per kg (based on Actual Body Weight (ABW)) if the patient was greater than 4 or less than or equal to 4 years, respectively. The dose was adjusted based on plasma concentration after completion of dose 1. Patients received busulfan doses every six hours as a two-hour infusion over four days for a total of 16 doses, followed by cyclophosphamide 50 mg per kg once daily for four days. After one rest day, hematopoietic progenitor cells were infused. All patients received phenytoin as seizure prophylaxis." The target AUC was achieved at dose 1 in 71% (17/24) of those patients. FORMULATION: UK SPC 4.2 - "There are other formulations available which may be more suitable for paediatric patients"; oral bioavailability in children ranges "from 22% to 120% (mean 68%)", so drug level monitoring is recommended for conditioning. CML: US label 8.4 - "The effectiveness of busulfan in the treatment of CML has not been specifically studied in pediatric patients." SAFETY: cardiac tamponade has been reported in paediatric patients with thalassaemia given high doses of oral busulfan with cyclophosphamide, usually preceded by abdominal pain and vomiting (US label 5.5; UK SPC 4.8). Confirm every paediatric dose against the local transplant protocol and a children's formulary before prescribing.