Busulfan Fresenius Kabi · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-096832 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile Busulfan in combination with cyclophosphamide or melphalan In adults Adverse reactions information is derived from two clinical trials (n=103) of busulfan. 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 was 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%. 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. HVOD occurred in: 8.2% (5/61) allogeneic patients (fatal in 2 patients) and 2.5% (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 synd

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HOS-096828 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Pregnancy (see section 4.6).

HOS-096827 · has-indication-information · PDF-Seite 2

Busulfan 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. Busulfan following fludarabine (FB) is indicated as conditioning treatment prior to haematopoietic progenitor cell transplantation (HPCT) in adult patients who are candidates for a reduced-intensity conditioning (RIC) regimen. Busulfan followed by cyclophosphamide (BuCy4) or melphalan (BuMel) is indicated as conditioning treatment prior to conventional haematopoietic progenitor cell transplantation in paediatric patients.

HOS-096830 · has-interaction-information · PDF-Seite 6

No specific clinical trial was carried out to assess drug-drug interaction between intravenous busulfan and itraconazole or metronidazole. From published studies in adults, administration of itraconazole to patients receiving high-dose busulfan may result in reduced busulfan clearance. Also, there are published case reports of increased plasma levels of busulfan after administration of metronidazole. Patients who are concurrently treated with busulfan and itraconazole or metronidazole should be closely monitored for signs of busulfan toxicity. No interaction was observed when busulfan was combined with fluconazole (antifungal agent). Published studies in adults described that ketobemidone (analgesic) might be associated with high levels of plasma busulfan. Therefore special care is recommended when combining these two compounds. In adults, for the BuCy2 regimen it has been reported that the time interval between the last oral busulfan administration and the first cyclophosphamide administration may influence the development of toxicities. A reduced incidence of Hepatic Veno Occlusive Disease (HVOD) and other regimen-related toxicity have been observed in patients when the lag time between the last dose of oral busulfan and the first dose of cyclophosphamide is > 24 hours. There is no common metabolism pathway between busulfan and fludarabine. In adults, for the FB regimen, published studies did not report any mutual drug-drug interaction between intravenous busulfan and fludarabine. In paediatric population, for the BuMel regimen it has been reported that the administration of melphalan less than 24 hours after the last oral busulfan administration may influence the development of toxicities. Increases in busulfan exposure have been observed at concomitant administration of busulfan and deferasirox. The mechanism behind the interaction is not fully elucidated. It is 6 recommended to regularly monitor busulfan plasma concentrations and, if necessary, adjust the busulfan dose in patients who are or have recently been treated with deferasirox. Paracetamol is described to decrease glutathione levels in blood and tissues, and may therefore decrease busulfan clearance when used in combination (see section 4.4). Either phenytoin or benzodiazepines were administered for seizure prophylaxis in patients participating to the clinical trials conducted with intravenous busulfan (see section 4.2 and 4.4). The conc

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HOS-096831 · has-pregnancy-information · PDF-Seite 7

Women of childbearing potential Women of childbearing potential have to use effective contraception during and up to 6 months after treatment. Pregnancy HPCT is contraindicated in pregnant women; therefore, busulfan is contraindicated during pregnancy. Studies in animals have shown reproductive toxicity (embryo-foetal lethality and malformations) (see section 5.3) There are no or limited amount of data from the use of busulfan or DMA in pregnant women. A few cases of congenital abnormalities have been reported with low-dose oral busulfan, not necessarily attributable to the active substance, and third trimester exposure may be associated with impaired intrauterine growth. Breast-feeding It is unknown whether busulfan and DMA are excreted in human milk. Because of the potential for tumorigenicity shown for busulfan in human and animal studies, breast-feeding should be discontinued during treatment with busulfan. Fertility Busulfan and DMA can impair fertility in man or woman. Therefore it is advised not to father child during the treatment 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 (see section 4.4).

HOS-096829 · has-warning-information · PDF-Seite 4

The consequence of treatment with busulfan 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 4 stimulating agent (G-CSF), should be employed as medically indicated. In adults, absolute neutrophil counts < 0.5x109/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. Anaemia (haemoglobin< 8.0 g/dl) occurred in 69% of patients. In paediatric population, absolute neutrophil counts < 0.5x109/l at a median of 3 days post transplant occurred in 100% of patients and lasted 5 and 18.5 days in autologous and allogeneic transplant respectively. In children, thrombocytopenia (< 25x109/l or requiring platelet transfusion) occurred in 100% of patients. Anaemia (haemoglobin< 8.0 g/dl) occurred in 100% of patients. In children < 9 kg, a therapeutic drug monitoring may be justified on a case by case basis, in particular in extremely young children and neonates (see section 5.2). 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 busulfan should be used with caution in this type of patients. Hepatic impairment Busulfan has not been studied in patients with hepatic impairment. Since busulfan is mainly metabolized through the liver, caution should be observed when busulfan is used in patients with pre-existing impairment of liver function, especially in those with severe hepatic impairment. It is recommended when treating these patients that serum transaminase, alkaline phosphatase,

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