Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Aspen Pharma Trading Limited, 3016 Lake Drive, Citywest Business Campus, Dublin 24, Ireland
Busulfan should not be used in patients whose disease has demonstrated resistance to busulfan.
Busulfan should not be given to patients who have previously suffered a hypersensitivity reaction to the busulfan or any other component of the preparation.
Busulfan is an active cytotoxic agent for use only under the direction of physicians experienced in the administration of such agents.
Immunisation using a live organism vaccine has the potential to cause infection in immunocompromised hosts. Therefore, immunisations with live organism vaccines are not recommended.
Busulfan should be discontinued if lung toxicity develops (see section 4.8).
Busulfan should not generally be given in conjunction with or soon after radiotherapy.
Busulfan is ineffective once blast transformation has occurred.
If anaesthesia is required in patients with possible pulmonary toxicity, the concentration of inspired oxygen should be kept as low as safely as possible and careful attention given to post-operative respiratory care.
Hyperuricaemia and/or hyperuricosuria are not uncommon in patients with chronic myeloid leukaemia and should be corrected before starting treatment with Busulfan. During treatment, hyperuricaemia and the risk of uric acid nephropathy should be prevented by adequate prophylaxis, including adequate hydration and the use of allopurinol.
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. However, caution is recommended.
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.
The medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Patients who are concurrently treated with the conventional dose of busulfan and itraconazole or metronidazole should be closely monitored for signs of busulfan toxicity. At concomitant use of these agents with busulfan weekly blood counts are recommended (see section 4.5).
Careful attention must be paid to monitoring the blood counts throughout treatment to avoid the possibility of excessive myelosuppression and the risk of irreversible bone marrow aplasia (see section 4.8).
Hepatic veno-occlusive disease is a major complication that can occur during treatment with Busulfan. Patients who have received prior radiation therapy, for three or more cycles of chemotherapy, or prior progenitor cell transplant may be at an increased risk of developing hepatic veno-occlusive disease (see section 4.8).
If high-dose Busulfan is prescribed, patients should be given prophylactic anticonvulsant therapy, preferably with a benzodiazepine rather than phenytoin.
Concomitant administration of itraconazole or metronidazole with high-dose busulfan has been reported to be associated with an increased risk of busulfan toxicity (see section 4.5). Co-administration of metronidazole and high-dose busulfan is not recommended. Co-administration of itraconazole with high-dose busulfan should be at the discretion of the prescribing physician and should be based on a risk/benefit assessment.
A reduced incidence of hepatic veno-occlusive disease and other regimen-related toxicities have been observed in patients treated with high-dose Busulfan and cyclophosphamide when the first dose of cyclophosphamide has been delayed for >24 hours after the last dose of Busulfan.
See section 6.6.
Busulfan is genotoxic in non-clinical studies (see section 5.3).
Various chromosome aberrations have been noted in cells from patients receiving busulfan.
On the basis of human studies, Busulfan was considered by the International Agency for Research on cancer to show sufficient evidence for carcinogenicity. The World Health Association has concluded that there is a causal relationship between Busulfan exposure and cancer.
Widespread epithelial dysplasia has been observed in patients treated with long-term Busulfan, with some of the changes resembling precancerous lesions.
A number of malignant tumours have been reported in patients who have received Busulfan treatment.
The evidence is growing that Busulfan, in common with other alkylating agents, is leukaemogenic. In a controlled prospective study in which 2 years' Busulfan treatment was given as an adjuvant to surgery for lung cancer, long-term follow-up showed an increased incidence of acute leukaemia compared with the placebo-treated group. The incidence of solid tumours was not increased.
Although acute leukaemia is probably part of the natural history of polycythaemia vera, prolonged alkylating agent therapy may increase the incidence.
Very careful consideration should be given to the use of busulfan for the treatment of polycythaemia vera and essential thrombocythaemia in view of the drug’s carcinogenic potential. The use of busulfan for these indications should be avoided in younger or asymptomatic patients. If the drug is considered necessary treatment courses should be kept as short as possible.
Vaccinations with live organism vaccines are not recommended in immunocompromised individuals (see section 4.4).
The effects of other cytotoxics producing pulmonary toxicity may be additive.
The administration of phenytoin to patients receiving high-dose Busulfan may result in a decrease in the myeloblative effect.
In patients receiving high-dose busulfan it has been reported that co-administration of itraconazole decreases clearance of busulfan by approximately 20 % with corresponding increases in plasma busulfan levels. In combination with metronidazole (1200 mg, given as 400 mg three times daily) busulfan values are increased in approximately 80% (see section 4.4). Fluconazole had no effect on busulfan clearance. Consequently, high-dose Busulfan in combination with itraconazole or metronidazole is reported to be associated with an increased risk of busulfan toxicity (see section 4.4).
A reduced incidence of hepatic veno-occlusive disease and other regimen-related toxicities have been observed in patients treated with high-dose Busulfan and cyclophosphamide when the first dose of cyclophosphamide has been delayed for >24 hours after the last dose of busulfan.
Paracetamol is described to decrease glutathione levels in blood and tissues, and may therefore decrease busulfan clearance when used in combination.
Busulfan can lead to suppression of ovarian function and amenorrhoea in women and suppression of spermatogenesis in men (see section 4.8 and 5.3).
As with all cytotoxic chemotherapy, adequate contraceptive precautions should be advised when either partner is receiving Busulfan.
The use of Busulfan should be avoided during pregnancy whenever possible. In animal studies (see section 5.3) it has the potential for teratogenic effects, whilst exposure during the latter half of pregnancy resulted in impairment of fertility in offspring. In every individual case the expected benefit of treatment to the mother must be weighed against the possible risk to the foetus.
A few cases of congenital abnormalities, not necessarily attributable to busulfan, have been reported and third trimester exposure may be associated with impaired intra-uterine growth. However, there have also been many reported cases of apparently normal children born after exposure to Busulfan in utero, even during the first trimester.
It is not known whether Busulfan or its metabolites are excreted in human breast milk. Mothers receiving Busulfan should not breast-feed their infants.
There are no data on the effect of Busulfan on driving performance or the ability to operate machinery. A detrimental effect on these activities cannot be predicted from the pharmacology of the drug.
For this product there is no modern clinical documentation which can be used as support for determining the frequency of undesirable effects. Undesirable effects may vary in their incidence depending on the dose received and also when given in combination with other therapeutic agents.
The following convention has been utilised for the classification of frequency: Very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1000), very rare (<1/10,000) and not known (frequency cannot be estimated from the available data).
The following table of adverse reactions originated from the use of busulfan, or busulfan in combination with other therapeutic agents.
Common: Leukaemia secondary to oncology chemotherapy (see section 4.4)
Very common: Dose-related bone marrow failure, manifesting as leukopenia and particularly thrombocytopenia
Rare: Aplastic anaemia
Rare: At high-dose: convulsion (see section 4.4 and 4.5)
Very rare: Myasthenia gravis
Rare: Lens disorder and cataract (which may be bilateral) corneal thinning (reported after bone marrow transplantation preceded by high-dose Busulfan treatment)
Common: At high-dose: cardiac tamponade in patients with thalassaemia
Very common: At high-dose: idiopathic pneumonia syndrome
Common: Interstitial lung disease following long term conventional dose use
Very common: At high-dose: nausea, vomiting, diarrhoea, mouth ulceration
Rare: At conventional dose: nausea, vomiting, diarrhoea, mouth ulceration, which may possibly be ameliorated by using divided doses. Dry mouth
Not known: Tooth hypoplasia
Very common: At-high-dose: hyperbilirubinaemia, jaundice, venoocclusive liver disease (see section 4.4 and 4.5) and biliary fibrosis with hepatic atrophy and necrosis
Rare: Jaundice and abnormal hepatic function, at conventional dose. Biliary fibrosis
Common: Alopecia at high-dose. Skin hyperpigmentation (see also General disorders and administration site conditions)
Rare: Alopecia at conventional dose, skin reactions including urticaria, erythema multiforme, erythema nodosum, porphyrianon-acute, rash, dry skin and fragility of the skin with complete anhydrosis cheilosis, Sjögren’s syndrome. An increased radiation skin injury in patients receiving radiotherapy soon after high-dose Busulfan
Common: At high-dose: in combination with cyclophosphamide cystitis haemorrhagic
Very common: Ovarian disorder and amenorrhoea with menopausal symptoms in pre-menopausal patients at high-dose; severe and persistent ovarian failure, including failure to achieve puberty after administration to young girls and pre-adolescents at high-dose. Male infertility, azoospermia and testicular atrophy in male patients receiving Busulfan
Uncommon: Ovarian disorder and amenorrhoea with menopausal symptoms in pre-menopausal patients at conventional dose. In very rare cases, recovery of ovarian function has been reported with continuing treatment
Very rare: Gynaecomastia
Rare: Dysplasia
Aplastic anaemia (sometimes irreversible) has been reported rarely, typically following long-term conventional doses and also high doses of Busulfan.
Pulmonary toxicity after either high or conventional dose treatment typically presents with non-specific non-productive cough, dyspnoea and hypoxia with evidence of abnormal pulmonary physiology. Other cytotoxic agents may cause additive lung toxicity (see section 4.5). It is possible that subsequent radiotherapy can augment subclinical lung injury caused by busulfan. Once pulmonary toxicity is established the prognosis is poor despite busulfan withdrawal and there is little evidence that corticosteroids are helpful.
Idiopathic pneumonia syndrome is a non-infectious diffuse pneumonia which usually occurs within three months of high-dose Busulfan conditioning prior to allogeneic or autologous haemopoietic transplant. Diffuse alveolar haemorrhage may also be detected in some cases after broncholavage. Chest X-rays or CT scans show diffuse or non-specific focal infiltrates and biopsy shows interstitial pneumonitis and diffuse alveolar damage and sometimes fibrosis.
Interstitial pneumonitis may occur following conventional dose use and lead to pulmonary fibrosis. This usually occurs after prolonged treatment over a number of years. The onset is usually insidious but may also be acute. Histological features include atypical changes of the alveolar and bronchiolar epithelium and the presence of giant cells with large hyperchromatic nuclei. The lung pathology may be complicated by superimposed infections. Pulmonary ossification and dystrophic calcification have also been reported.
Busulfan is not generally considered to be significantly hepatotoxic at normal therapeutic doses. However, retrospective review of postmortem reports of patients who had been treated with low-dose busulfan for at least two years for chronic myeloid leukaemia showed evidence of centrilobular sinusoidal fibrosis.
Hyperpigmentation occurs, particularly in those with a dark complexion. It is often most marked on the neck, upper trunk, nipples, abdomen and palmar creases. This may also occur as part of a clinical syndrome (see General disorders and administration site conditions).
Studies of busulfan treatment in animals have shown reproductive toxicity (see section 5.3).
Clinical syndrome (weakness, severe fatigue, anorexia, weight loss, nausea and vomiting and hyperpigmentation of the skin) resembling adrenal insufficiency (Addison’s disease) but without biochemical evidence of adrenal suppression, mucous membrane hyperpigmentation or hair loss (see Skin and subcutaneous tissue disorders) has been seen in a few cases following prolonged Busulfan therapy. The syndrome has sometimes resolved when busulfan has been withdrawn.
Many histological and cytological changes have been observed in patients treated with busulfan, including widespread dysplasia affecting uterine cervical, bronchial and other epithelia. Most reports relate to long-term treatment but transient epithelial abnormalities have been observed following short-term, high-dose treatment.
The following table of adverse reactions originated from the intravenous use of busulfan in combination with cyclophosphamide or melphalan.
Very common: Hypersensitivity
Very common: Hyperglycaemia, hypocalcaemia, hypokalaemia, hypomagnesaemia, hypophosphataemia
Common: Hyponatraemia
Very common: Anxiety, depression, insomnia
Common: Confusional state
Uncommon: Delirium, nervousness, hallucination, agitation
Very common: Headache, dizziness
Uncommon: Encephalopathy, cerebral haemorrhage
Very common: Tachycardia
Common: Arrhythmia, atrial fibrillation, cardiomegaly, pericarditis
Uncommon: Ventricular extrasystoles, bradycardia
Very common: Hypertension, hypotension, thrombosis, vasodilation
Uncommon: Femoral artery thrombosis, capillary leak syndrome
Common: Hyperventilation, respiratory failure, asthma, atelectasis, pleural effusion
Very common: Abdominal pain, dyspepsia, ascites, constipation, anorectal discomfort
Common: Haematemesis, ileus, oesophagitis
Uncommon: Gastrointestinal haemorrhage
Very common: Hepatomegaly
Very common: Myalgia, back pain, arthralgia
Very common: Dysuria, oliguria
Common: Haematuria, moderate renal insufficiency
Very common: Chills, pyrexia, chest pain, oedema, general oedema, pain
Very common: Weight increased, abnormal breath sounds, blood creatinine increased
Common: Blood urea increased, decreased ejection fraction
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Not applicable.
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