s
Pharmacotherapeutic group: Alkyl sulfonates, ATC code: L01AB01.
Mechanism of action
Busulfan is a potent cytotoxic agent and a bifunctional alkylating agent. In aqueous media, release of the methanesulphonate groups produces carbonium ions which can alkylate DNA, thought to be an important biological mechanism for its cytotoxic effect.
Clinical efficacy and safety
Documentation of the safety and efficacy of Busilvex in combination with cyclophosphamide in the BuCy2 regimen prior to conventional allogeneic and/or autologous HPCT derive from two clinical trials (OMC-BUS-4 and OMC-BUS-3).
Two prospective, single arm, open-label, uncontrolled phase II studies were conducted in patients with haematological disease, the majority of whom had advanced disease.
Diseases included were acute leukaemia past first remission, in first or subsequent relapse, in first remission (high risk), or induction failures; chronic melogenous leukaemia in chronic or advanced phase; primary refractory or resistant relapsed Hodgkin's disease or non-Hodgkin's lymphoma, and myelodysplastic syndrome.
Patients received doses of 0.8 mg/kg busulfan every 6 hours infusion for a total 16 doses followed by cyclophosphamide at 60 mg/kg once per day for two days (BuCy2 regimen).
The primary efficacy parameters in these studies were myeloablation, engraftment, relapse, and survival.
In both studies, all patients received a 16/16 dose regimen of Busilvex. No patients were discontinued from treatment due to adverse reactions related to Busilvex.
All patients experienced a profound myelosuppression. The time to Absolute Neutrophil Count (ANC) greater than 0.5x109 /l was 13 days (range 9-29 days) in allogenic patients (OMC-BUS 4), and 10 days (range 8-19 days) in autologous patients (OMC-BUS 3). All eva luable patients engrafted. There is no primary or secondary graft rejection. Overall mortality and non- relapse mortality at more than 100 days post-transplant was (8/61) 13% and (6/61) 10% in allotransplanted patients, respectively. During the same period there was no death in autologous recipients.
Paediatric population
Documentation of the safety and efficacy of Busilvex in combination with cyclophosphamide in the BuCy4 or with melphalan in the BuMel regimen prior to conventional allogeneic and/or autologous HPCT derives from clinical trial F60002 IN 101 G0.
The patients received the dosing mentioned in section 4.2.
All patients experienced a profound myelosuppression. The time to Absolute Neutrophil Count (ANC) greater than 0.5x109/l was 21 days (range 12-47 days) in allogenic patients, and 11 days (range 10-15 days) in autologous patients. All children engrafted. There is no primary or secondary graft rejection. 93% of allogeneic patients showed complete chimerism. There was no regimen-related death through the first 100-day post-transplant and up to one year post-transplant.
5.2 Pharmacokinetic properties
The pharmacokinetics of Busilvex has been investigated. The information presented on metabolism and elimination is based on oral busulfan.
Pharmacokinetics in adults
Absorption
The pharmacokinetics of intravenous busulfan was studied in 124 eva luable patients following a 2-hour intravenous infusion for a total of 16 doses over four days. Immediate and complete availability of the dose is obtained after intravenous infusion of busulfan. Similar blood exposure was observed when comparing plasma concentrati |
