Chemical formula: C₆H₁₄O₆S₂ Molecular mass: 246.302 g/mol PubChem compound: 2478
Busulfan interacts in the following cases:
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, 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 busulfan. 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. Caution should be exercised when using paracetamol prior to (less than 72 hours) or concurrently with busulfan due to a possible decrease in the metabolism of busulfan
Busulfan can impair fertility. Therefore, men treated with busulfan 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 busulfan. 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.
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 regimenrelated toxicity have been observed in patients when the lag time between the last dose of oral busulfan and the first dose of cyclophosphamide is >24hours. 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.
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.
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 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.
Paracetamol is described to decrease glutathione levels in blood and tissues, and may therefore decrease busulfan clearance when used in combination.
Either phenytoin or benzodiazepines were administered for seizure prophylaxis in patients participating to the clinical trials conducted with intravenous busulfan. The concomitant systemic administration of phenytoin to patients receiving high-dose of oral busulfan has been reported to increase busulfan clearance, due to induction of glutathion-S-transferase whereas no interaction has been reported when benzodiazepines such as diazepam, clonazepam or lorazepam have been used to prevent seizures with high-dose busulfan. No evidence of an induction effect of phenytoin has been seen on Busilvex data. A phase II clinical trial was performed to evaluate the influence of seizure prophylaxis treatment on intravenous busulfan pharmacokinetics. In this study, 24 adult patients received clonazepam (0.025-0.03 mg/kg/day as IV continuous infusions) as anticonvulsant therapy and the PK data of these patients were compared to historical data collected in patients treated with phenytoin. The analysis of data through a population pharmacokinetic method indicated no difference on intravenous busulfan clearance between phenytoin and clonazepam based therapy and therefore similar busulfan plasma exposures were achieved whatever the type of seizure prophylaxis.
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.
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.
Seizures have been reported with high dose busulfan treatment. Special caution should be exercised when administering the recommended dose of busulfan to patients with a history of seizures. Patients should receive adequate anticonvulsant prophylaxis. In adults and children studies, data with busulfan 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.
HPCT is contraindicated in pregnant women; therefore, busulfan is contraindicated during pregnancy. Studies in animals have shown reproductive toxicity (embryo-fetal lethality and malformations).
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.
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 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 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.
Women of childbearing potential have to use effective contraception during and up to 6 months after treatment.
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.
Busulfan can lead to suppression of ovarian function and amenorrhoea in women and suppression of spermatogenesis in men.
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.
h2 ®. Summary of the safety profile
Adverse events 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 syndrome with subsequent respiratory failure associated with interstitial pulmonary fibrosis in the busulfan 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. The incidence of a-GVHD grades I-II was 46.4% (13/28), while the incidence of grade III-IV was 3.6% (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.
The safety profile of busulfan 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.
Infections and infestations: The occurrence of infectious episodes or reactivation of opportunistic infectious agents mainly reflects the immune status of the patient receiving a conditioning regimen. The most frequent infectious adverse reactions were Cytomegalovirus (CMV) reactivation [range: 30.7%-80.0%], Epstein-Barr Virus (EBV) reactivation [range: 2.3%-61%], bacterial infections [range: 32.0%-38.9%] and viral infections [range: 1.3%-17.2%].
Gastrointestinal disorders: The highest frequency of nausea and vomiting was 59.1% 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. Haemorrhagic cystitis including haemorrhagic cystitis induced by viral infection was reported in a range between 16% and 18.1%.
Hepato-biliary disorders: VOD was reported with a range between 3.9% and 15.4%.
The treatment-related mortality/non-relapse mortality (TRM/NRM) reported until day+100 posttransplant 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 disorders and organ failure.
h2 ®. Summaries of adverse reactions
Frequencies are defined as: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100) or not known (cannot be estimated from the available data). Undesirable effects coming from post-marketing survey have been implemented below with the incidence “not known”.
Adverse reactions reported both in adults and paediatric patients as more than an isolated case are listed below, by system organ class and by frequency. Within each frequency grouping, adverse events are presented in order of decreasing seriousness.
Very common: Rhinitis, Pharyngitis
Very common: Neutropenia, Thrombocytopenia, Febrile neutropenia, Anaemia, Pancytopenia
Very common: Allergic reaction
Not known: Hypogonadism**
Very common: Anorexia, Hyperglycaemia, Hypocalcaemia, Hypokalaemia, Hypomagnesaemia, Hypophosphatemia
Common: Hyponatraemia
Very common: Anxiety, Depression, Insomnia
Common: Confusion
Uncommon: Delirium, Nervousness, Hallucination, Agitation
Very common: Headache, Dizziness
Uncommon: Seizure, Encephalopathy, Cerebral haemorrhage
Not known: Cataract, Corneal thinning, Lens disorders***
Very common: Tachycardia
Common: Arrhythmia, Atrial fibrillation, Cardiomegaly, Pericardial effusion, Pericarditis
Uncommon: Ventricular extrasystoles, Bradycardia
Very common: Hypertension, Hypotension, Thrombosis, Vasodilatation
Uncommon: Femoral artery thrombosis, Capillary leak syndrome
Very common: Dyspnoea, Epistaxis, Cough, Hiccup
Common: Hyperventilation, Respiratory failure, Alveolar haemorrhages, Asthma, Atelectasis, Pleural effusion
Uncommon: Hypoxia
Not known: Interstitial lung disease**
Very common: Stomatitis, Diarrhoea, Abdominal pain, Nausea, Vomiting, Dyspepsia, Ascites, Constipation, Anus discomfort
Common: Haematemesis, Ileus, Oesophagitis
Uncommon: Gastrointestinal haemorrhage
Not known: Tooth hypoplasia**
Very common: Hepatomegaly, Jaundice
Common: Veno occlusive liver disease *
Very common: Rash, Pruritis, Alopecia
Common: Skin desquamation, Erythema, Pigmentation disorder
Very common: Myalgia, Back pain, Arthralgia
Very common: Dysuria, Oligurea
Common: Haematuria, Moderate renal Insufficiency
Not known: Premature menopause, Ovarian failure**
Very common: Asthenia, Chills, Fever, Chest pain, Oedema, Oedema general, Pain, Pain or inflammation at injection site, Mucositis
Very common: Transaminases increased, Bilirubin increased, GGT increased, Alkaline phosphatases increased, Weight increased, Abnormal breath sounds, Creatinine elevated
Common: Bun increase, Decrease ejection fraction
* veno occlusive liver disease is more frequent in paediatric population.
** reported in post marketing with IV busulfan
*** reported in post marketing with oral busulfan
The incidence of each adverse reactions presented in the following list has been defined according to the highest incidence observed in published clinical trials in RIC regimen for which the population treated with FB was clearly identified, whatever the schedules of busulfan administrations and endpoints. Adverse reactions reported as more than an isolated case are listed below, by system organ class and by frequency.
Very common: Viral infection, CMV reactivation, EBV reactivation, Bacterial infection
Common: Invasive fungal infection, Pulmonary infection
Not known*: Brain abscess, Cellulitis, Sepsis
Not known*: Febrile neutropenia
Very common: Hypoalbuminaemia, Electrolyte disturbance, Hyperglycaemia
Not known*: Anorexia
Not known*: Agitation, Confusional state, Hallucination
Common: Headache, Nervous system disorders [Not Elsewhere Classified]
Not known*: Cerebral haemorrhage, Encephalo-pathy
Not known*: Atrial fibrillation
Common: Hyper-tension
Common: Pulmonary haemorrhage
Not known*: Respiratory failure
Very common: Nausea, Vomiting, Diarrhoea, Stomatitis
Not known*: Gastro-intestinal haemorrhage, Tooth hypoplasia*
Very common: Veno occlusive liver disease
Not known*: Jaundice, Liver disorders
Common: Rash
Very common: Haemorrhagic cystitis**
Common: Renal disorder
Not known*: Oliguria
Very common: Mucositis
Not known*: Asthenia, Oedema, Pain
Very common: Transaminases increased, Bilirubine increased, Alkaline phosphatases increased
Common: Creatinine elevated
Not known*: Blood lactate dehydrogenase increased, Blood uric acid increased, Blood urea increased, GGT increased, Weight increased
* reported in post marketing experience
** include haemorrhagic cystitis induced by viral infection
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 list of adverse reactions originated from the use of busulfan, or busulfan in combination with other therapeutic agents.
Common: Leukaemia secondary to oncology chemotherapy
Very common: Dose-related bone marrow failure, manifesting as leukopenia and particularly thrombocytopenia
Rare: Aplastic anaemia
Rare: At high-dose: convulsion
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 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. 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.
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 list 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
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