Busulfex Special Precautions

The consequence of treatment with Busulfex 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.
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.
Hepatic impairment: Busulfex 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 Busulfex 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, 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 Busulfex. Patients who have received prior radiation therapy, greater than or equal to three cycles of chemotherapy, or prior progenitor cell transplant may be at an increased risk (see Adverse Reactions). Caution should be exercised when using paracetamol prior to (less than 72 hours) or concurrently with Busulfex due to a possible decrease in the metabolism of busulfan (See Interactions).
As documented in clinical studies, no treated patients experienced cardiac tamponade or other specific cardiac toxicities related to Busulfex. However cardiac function should be monitored regularly in patients receiving Busulfex (see Adverse Reactions).
Occurrence of acute respiratory distress syndrome with subsequent respiratory failure associated with interstitial pulmonary fibrosis was reported in Busulfex 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. Therefore, attention should be paid to this pulmonary issue in patients with prior history of mediastinal or pulmonary radiation (see Adverse Reactions).
Periodic monitoring of renal function should be considered during therapy with Busulfex (see Adverse Reactions).
Seizures have been reported with high dose busulfan treatment. Special caution should be exercised when administering the recommended dose of Busulfex to patients with a history of seizures. Patients should receive adequate anticonvulsant prophylaxis. In adults studies, data with Busulfex were obtained when using concomitant administration of either phenytoin or benzodiazepines for seizure prophylaxis. The effect of those anticonvulsant agents on busulfan pharmacokinetics was investigated in a phase II study (see Interactions).
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 Busulfex 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 Busulfex. Ovarian suppression and amenorrhoea with menopausal symptoms commonly occur in pre-menopausal 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. DMA decreases fertility in male and female rodents (see Use in Pregnancy & Lactation and Pharmacology: Toxicology: Preclinical safety data under Actions).
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 combination with another conditioning treatment.
Effects on ability to drive and use machines: Not relevant.