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Busilvex is a brand name for Busulfan. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: Busilvex followed by cyclophosphamide (BuCy2) is indicated as conditioning treatment prior to conventional haematopoietic progenitor cell transplantation (HPCT) in adult patients when the combination is considered the best available option. Busilvex following fludarabine (FB) is indicated as conditioning treatment…
Verbatim from this product's EMA label. Tap a section to expand.
Busilvex administration should be supervised by a physician experienced in conditioning treatment prior to haematopoietic progenitor cell transplantation. Busilvex is administered prior to the haematopoietic progenitor cell transplantation (HPCT).
5). Busilvex is administered as a two-hour infusion every 6 hours over 4 consecutive days for a total of 16 doses prior to cyclophosphamide or melphalan and haematopoietic progenitor cell transplantation (HPCT). Elderly patients Patients older than 50 years of age (n=23) have been successfully treated with Busilvex without dose- adjustment.
However, for the safe use of Busilvex in patients older than 60 years only limited information is available. 2) for elderly patients as for adults (< 50 years old) should be used. Busilvex in combination with fludarabine (FB) In adults The recommended dose and schedule of administration is: - fludarabine administered as a single daily one-hour infusion at 30 mg/m² for 5 consecutive days or 40 mg/m² for 4 consecutive days.
2 mg/kg as a single daily three-hour infusion immediately after fludarabine for 2 or 3 consecutive days. Paediatric population (0 to 17 years) The safety and efficacy of FB in pediatric population has not been established. Elderly patients The administration of FB regimen has not been specifically investigated in elderly patients.
However, more than 500 patients aged ≥ 55 years were reported in publications with FB conditioning regimens, yielding efficacy outcomes similar to younger patients. No dose adjustment was deemed necessary. Obese patients In adults For obese patients, dosing based on adjusted ideal body weight (AIBW) should be considered.
91x (height in cm-152). 25x (actual body weight - IBW). Medicinal product no longer authorised 4 Patients with renal impairment Studies in renally impaired patients have not been conducted, however, as busulfan is moderately excreted in the urine, dose modification is not recommended in these patients.
2). Patients with hepatic impairment Busilvex as well as busulfan has not been studied in patients with hepatic impairment. 4). Method of administration Precautions to be taken before handling or administering the medicinal product Busilvex must be diluted prior to administration.
5 mg/ml busulfan should be achieved. Busilvex should be administered by intravenous infusion via central venous catheter. 6. Busilvex should not be given by rapid intravenous, bolus or peripheral injection. All patients should be pre-medicated with anticonvulsant medicinal products to prevent seizures reported with the use of high dose busulfan.
Summary of the safety profile Busilvex in combination with cyclophosphamide or melphalan In adults Adverse events information is derived from two clinical trials (n=103) of Busilvex. Serious toxicities involving the haematologic, hepatic and respiratory systems were considered as expected consequences of the conditioning regimen and transplant process.
These include infection and Graft-versus host disease (GVHD) which although not directly related, were the major causes of morbidity and mortality, especially in allogeneic HPCT.
Blood and lymphatic system disorders:
Myelo-suppression and immuno-suppression were the desired therapeutic effects of the conditioning regimen. Therefore all patients experienced profound cytopenia: leucopenia 96%, thrombocytopenia 94%, and anemia 88%. The median time to neutropenia was 4 days for both autologous and allogeneic patients.
The median duration of neutropenia was 6 days and 9 days for autologous and allogeneic patients.
Immune system disorders:
The incidence of acute graft versus host disease (a-GVHD) data was collected in OMC-BUS-4 study (allogeneic)(n=61). A total of 11 patients (18%) experienced a-GVHD. The incidence of a-GVHD grades I-II was 13% (8/61), while the incidence of grade III-IV was 5% (3/61).
Acute GVHD wasMedicinal product no longer authorised 8 rated as serious in 3 patients. Chronic GVHD (c-GVHD) was reported if serious or the cause of death, and was reported as the cause of death in 3 patients. Infections and infestations: 39% of patients (40/103) experienced one or more episodes of infection, of which 83% (33/40) were rated as mild or moderate.
Pneumonia was fatal in 1% (1/103) and life-threatening in 3% of patients. Other infections were considered severe in 3% of patients. Fever was reported in 87% of patients and graded as mild/moderate in 84% and severe in 3%. 47% of patients experienced chills which were mild/moderate in 46% and severe in 1%.
The consequence of treatment with Busilvex at the recommended dose and schedule is profound myelosuppression, occurring in all patients. Severe granulocytopenia, thrombocytopenia, anaemia, or any combination thereof may develop. Frequent complete blood counts, including differential white blood cell counts, and platelet counts should be monitored during the treatment and until recovery is achieved.
Prophylactic or empiric use of anti-infectives (bacterial, fungal, viral) should be considered for the prevention and management of infections during the neutropenic period. Platelet and red blood cell support, as well as the use of growth factors such as granulocyte colony stimulating agent (G-CSF), should be employed as medically indicated.
5x109/l at a median of 4 days post transplant occurred in 100% of patients and recovered at median day 10 and 13 days following autologous and allogeneic transplant respectively (median neutropenic period of 6 and 9 days respectively).
Thrombocytopenia (< 25x109/l or requiring platelet transfusion) occurred at a median of 5-6 days in 98% of patients. 0 g/dl) occurred in 69% of patients. 5 days in autologous and allogeneic transplantMedicinal product no longer authorised 5 respectively.
In children, thrombocytopenia (< 25x109/l or requiring platelet transfusion) occurred in 100% of patients. 0 g/dl) occurred in 100% of patients. 2). The Fanconi anaemia cells have hypersensitivity to cross-linking agents. There is limited clinical experience of the use of busulfan as a component of a conditioning regimen prior to HSCT in children with Fanconi’s anaemia.
Therefore Busilvex should be used with caution in this type of patients. Hepatic impairment Busilvex as well as busulfan has not been studied in patients with hepatic impairment. Since busulfan is mainly metabolized through the liver, caution should be observed when Busilvex is used in patients with pre-existing impairment of liver function, especially in those with severe hepatic impairment.
1. 6).
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It is recommended to administer anticonvulsants 12 h prior to Busilvex to 24 h after the last dose of Busilvex. In adult and paediatric studies, patients received either phenytoin or benzodiazepines as seizure prophylaxis treatment.
5). Antiemetics should be administered prior to the first dose of Busilvex and continued on a fixed schedule according to local practice through its administration.
Hepato-biliary disorders: 15% of SAEs involved liver toxicity. HVOD is a recognized potential complication of conditioning therapy post-transplant. Six of 103 patients (6%) experienced HVOD. 5% (1/42) of autologous patients. Elevated bilirubin (n=3) and elevated AST (n=1) were also observed.
Two of the above four patients with serious serum hepatotoxicity were among patients with diagnosed HVOD.
Respiratory, thoracic and mediastinal disorders:
One patient experienced a fatal case of acute respiratory distress syndrome with subsequent respiratory failure associated with interstitial pulmonary fibrosis in the Busilvex studies. Paediatric population Adverse events information are derived from the clinical study in paediatrics (n=55).
Serious toxicities involving the hepatic and respiratory systems were considered as expected consequences of the conditioning regimen and transplant process.
Immune system disorders:
The incidence of acute graft versus host disease (a-GVHD) data was collected in allogeneic patients (n=28). A total of 14 patients (50%) experienced a-GVHD. 6% (1/28). Chronic GVHD was reported only if it is the cause of death: one patient died 13 months post-transplant.
Infections and infestations:
Infections (documented and non documented febrile neutropenia) were experienced in 89% of patients (49/55). Mild/moderate fever was reported in 76% of patients.
Hepato-biliary disorders:
Grade 3 elevated transaminases were reported in 24% of patients. Veno occlusive disease (VOD) was reported in 15% (4/27) and 7% (2/28) of the autologous and allogenic transplant respectively. VOD observed were neither fatal nor severe and resolved in all cases.
Busilvex in combination with fludarabine (FB) In adults The safety profile of Busilvex combined with fludarabine (FB) has been examined through a review of adverse events reported in published data from clinical trials in RIC regimen.
In these studies, a total of 1574 patients received FB as a reduced intensity conditioning (RIC) regimen prior to haematopoietic progenitor cell transplantation. Myelo-suppression and immuno-suppression were the desired therapeutic effects of the conditioning regimen and consequently were not considered undesirable effects.
2%]. 1% and the highest frequency of stomatitis was 11%.
Renal and urinary disorders:
It has been suggested that conditioning regimens containing fludarabine were associated with higher incidence of opportunistic infections after transplantation because of the immunosuppressive effect of fludarabine. Late haemorrhagic cystitis occurring 2 weeks post-transplant are likely related to viral infection / reactivation.
1%. 4%. The treatment-related mortality/non-relapse mortality (TRM/NRM) reported until day+100 post- transplant has also been examined through a review of published data from clinical trials. It was considered as deaths that could be attributable to secondary side effects after HPCT and not related to the relapse/progression of the underlying haematological malignancies.
The most frequent causes of reported TRM/NRMs were infection/sepsis, GVHD, pulmonary […]
It is recommended when treating these patients that serum transaminase, alkaline phosphatase, and bilirubin should be monitored regularly 28 days following transplant for early detection of hepatotoxicity. Hepatic veno-occlusive disease is a major complication that can occur during treatment with Busilvex.
8). 5). As documented in clinical studies, no treated patients experienced cardiac tamponade or other specific cardiac toxicities related to Busilvex. 8). Occurrence of acute respiratory distress syndrome with subsequent respiratory failure associated with interstitial pulmonary fibrosis was reported in Busilvex studies in one patient who died, although, no clear aetiology was identified.
In addition, busulfan might induce pulmonary toxicity that may be additive to the effects produced by other cytotoxic agents. 8). 8). Seizures have been reported with high dose busulfan treatment. Special caution should be exercised when administering the recommended dose of Busilvex to patients with a history of seizures.
Patients should receive adequate anticonvulsant prophylaxis. In adults and children studies, data with Busilvex were obtained when using concomitant administration of either phenytoin or benzodiazepines for seizure prophylaxis. 5). The increased risk of a second malignancy should be explained to the patient.
On the basis of human data, busulfan has been classified by the International Agency for Research on Cancer (IARC) as a human carcinogen. The World Health Organisation has concluded that there is a causal relationship between busulfan exposure and cancer.
Leukaemia patients treated with busulfan developed many different cytological abnormalities, and some developed carcinomas. Busulfan is thought to be leukemogenic. Fertility Busulfan can impair fertility. Therefore, men treated with Busilvex are advised not to father a child during and up to 6 months after treatment and to seek advice on cryo-conservation of sperm prior to treatment because of the possibility of irreversible infertility due to therapy with Busilvex.
Ovarian suppression and amenorrhoea with menopausal symptoms commonly occur in pre-menopausalMedicinal product no longer authorised 6 patients. Busulfan treatment in a pre-adolescent girl prevented the onset of puberty due to ovarian failure.
Impotence, sterility, azoospermia, and testicular atrophy have been reported in male patients. The solvent dimethylacetamide (DMA) may also impair fertility. 3). Cases of thrombotic microangiopathy after hematopoietic cell transplantation (HCT), including fatal cases, have been reported in high-dose conditioning regimens in which busulfan was administered in […]