4.1. Therapeutic indications

• Busulfan, followed by cyclophosphamide (BuCy2), is indicated as a 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 a 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 a conditioning treatment, prior to conventional haematopoietic progenitor cell transplantation, in paediatric patients.

4.2. Posology and method of administration

Busulfan administration should be supervised by a physician, experienced in conditioning treatment, prior to haematopoietic progenitor cell transplantation.

Busulfan is administered prior to the haematopoietic progenitor cell transplantation (HPCT).

Posology

Busulfan in combination with cyclophosphamide or melphalan

In adults:

The recommended dose and schedule of administration is:

- 0.8 mg/kg body weight (BW) of busulfan, as a two-hour infusion, every 6 hours, over 4 consecutive days, for a total of 16 doses, followed by cyclophosphamide at 60 mg/kg/day, over 2 days, initiated for at least 24 hours, following the 16th dose of Busulfan (see section 4.5).

Paediatric population (0 to 17 years):

The recommended dose of Busulfan is as follows:

Actual body weight (kg)

Busulfan dose (mg/kg)

< 9

1.0

9 to < 16

1.2

16 to 23

1.1

> 23 to 34

0.95

> 34

0.8

followed by:

- 4 cycles of 50 mg/kg body weight (BW) cyclophosphamide (BuCy4) or

- one administration of 140 mg/m2 melphalan (BuMel), initiated for at least 24 hours, following the 16th dose of Busulfan (see section 4.5).

Busulfan 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 busulfan without dose-adjustment. However, for the safe use of busulfan in patients older than 60 years, only limited information is available. The same dose (see section 5.2) for elderly patients, as for adults (< 50 years old), should be used.

Busulfan 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.

- Busulfan will be administered at 3.2 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 fludarabine in the pediatric population has not been established.

Elderly patients:

Administration of the fludarabine regimen has not specifically been investigated in elderly patients. However, more than 500 patients aged ≥ 55 years were reported in publications concerning fludarabine 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.

Ideal body weight (IBW) is calculated as follows:

IBW men (kg) = 50 + 0.91x (height in cm-152)

IBW women (kg) = 45 + 0.91x (height in cm-152)

Adjusted ideal body weight (AIBW) is calculated as follows:

AIBW= IBW+0.25x (actual body weight - IBW)

Paediatric population:

This medicinal product is not recommended for obese children and adolescents with a body mass index weight (kg)/(m2) > 30 kg/m2 until further data become available.

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.

However, caution is recommended (see sections 4.8 and 5.2).

Patients with hepatic impairment

Busulfan has not been studied in patients with hepatic impairment.

Caution is recommended, particularly in those patients with severe hepatic impairment (see section 4.4).

Method of Administration

Precautions to be taken before handling or administering the medicinal product:

Busulfan must be diluted prior to administration. A final concentration of approximately 0.5 mg/ml busulfan should be achieved. Busulfan should be administered by intravenous infusion via a central venous catheter.

For instructions on dilution of the medicinal product before administration, see section 6.6.

Busulfan 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.

It is recommended to administer anticonvulsants 12 h prior to Busulfan to 24 h after the last dose of Busulfan.

In adult and paediatric studies, patients received either phenytoin or benzodiazepines as seizure prophylaxis treatment (see sections 4.4 and 4.5).

Antiemetics should be administered prior to the first dose of Busulfan and continued on a fixed schedule according to local practice through its administration.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Pregnancy (see section 4.6).

4.4. Special warnings and precautions for use

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 and 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.

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 these 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, 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 (see section 4.8).

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 (see section 4.5).

As documented in clinical studies, no treated patients experienced cardiac tamponade or other specific cardiac toxicities related to busulfan. However, cardiac function should be monitored regularly in patients receiving Busulfan (see section 4.8).

Occurrence of acute respiratory distress syndrome, with subsequent respiratory failure associated with interstitial pulmonary fibrosis, was reported in busulfan studies in one patient who died, although, no clear aetiology was identified. In addition, busulfan may 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 section 4.8).

Periodic monitoring of renal function should be considered during therapy with Busulfan (see section 4.8).

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 (see section 4.5).

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 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 (see sections 4.6 and 5.3).

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 combination with another conditioning treatment.

4.5. Interaction with other medicinal products and other forms of interaction

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 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.

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 the 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 (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 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 busulfan 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.

No interaction was observed when busulfan was combined with 5 HT3 antiemetics such as ondansetron or granisetron.

4.6. Fertility, pregnancy and lactation

Pregnancy

HPCT is contraindicated in pregnant women. Therefore, Busulfan is contraindicated during pregnancy. Studies in animals have shown reproductive toxicity (embryo-fetal 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.

Women of childbearing potential

Women of childbearing potential have to use effective contraception during and up to 6 months after treatment.

Breast-feeding

It is unknown whether busulfan and DMA are excreted in human breast milk. Due to 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 men or women. Therefore, it is advised not to father a child during the treatment and up to 6 months after treatment and to seek advice on cryo-conservation of sperm prior to treatment due to the possibility of irreversible infertility (see section 4.4).

4.7. Effects on ability to drive and use machines

Not applicable.

4.8. Undesirable effects

Summary of the safety profile

Busulfan in combination with cyclophosphamide or melphalan

In adults:

Adverse event information is derived from two clinical trials (n=103) for 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 nondocumented 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.

Busulfan in combination with fludarabine (FB)

In adults:

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 a 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 post-transplant, has also been examined through a review of published data from clinical trials. It was considered, as deaths 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.

Tabulated 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 surveys have been implemented in the tables with the incidence “not known”.

Busulfan in combination with cyclophosphamide or melphalan

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.

System organ class

Very common

Common

Uncommon

Not known

Infections and infestations

Rhinitis

Pharyngitis

Blood and lymphatic system disorders

Neutropenia

Thrombocytopenia

Febrile neutropenia

Anaemia

Pancytopenia

Immune system disorders

Allergic reaction

Endocrine disorders

Hypogonadism **

Metabolism and nutrition disorders

Anorexia

Hyperglycaemia

Hypocalcaemia

Hypokalaemia

Hypomagnesaemia

Hypophosphatemia

Hyponatraemia

Psychiatric disorders

Anxiety

Depression

Insomnia

Confusion

Delirium

Nervousness

Hallucination

Agitation

Nervous system disorders

Headache

Dizziness

Seizure

Encephalopathy

Cerebral haemorrhage

Eye disorders

Cataract

Corneal thinning

Lens disorders***

Cardiac disorders

Tachycardia

Arrhythmia

Atrial fibrillation

Cardiomegaly

Pericardial effusion

Pericarditis

Ventricular extrasystoles

Bradycardia

Vascular disorders

Hypertension

Hypotension

Thrombosis

Vasodilatation

Femoral artery thrombosis

Capillary leak syndrome

Respiratory thoracic and mediastinal disorders

Dyspnoea

Epistaxis

Cough

Hiccup

Hyperventilation

Respiratory failure

Alveolar haemorrhages

Asthma

Atelectasis

Pleural effusion

Hypoxia

Interstitial lung disease**

Pulmonary Hypertension

Gastrointestinal disorders

Stomatitis

Diarrhoea

Abdominal pain

Nausea

Vomiting

Dyspepsia

Ascites

Constipation

Anus discomfort

Haematemesis

Ileus

Oesophagitis

Gastrointestinal haemorrhage

Tooth hypoplasia**

Hepato-biliary disorders

Hepatomegaly

Jaundice

Veno occlusive liver disease *

Skin and subcutaneous tissue disorders

Rash

Pruritis

Alopecia

Skin desquamation

Erythema

Pigmentation disorder

Musculoskeletal and connective tissue disorders

Myalgia

Back pain

Arthralgia

Renal and urinary disorders

Dysuria

Oliguria

Haematuria

Moderate renal

Insufficiency

Reproductive system and breast disorders

Premature menopause

Ovarian failure**

General disorders and administration site conditions

Asthenia

Chills

Fever

Chest pain

Oedema

Oedema general

Pain

Pain or inflammation at injection site

Mucositis

Investigations

Transaminases increased

Bilirubin increased

GGT increased

Alkaline phosphatases increased

Weight increased

Abnormal breath sounds

Creatinine elevated

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

Busulfan in combination with fludarabine (FB)

The incidence of each adverse reaction presented in the following table has been defined according to the highest incidence observed in published clinical trials on 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.

System organ class

Very common

Common

Not known*

Infections and infestations

Viral infection

CMV reactivation

EBV reactivation

Bacterial infection

Invasive fungal infection

Pulmonary infection

Brain abscess

Cellulitis

Sepsis

Blood and lymphatic system disorders

Febrile neutropenia

Metabolism and nutrition disorders

Hypoalbuminaemia

Electrolyte disturbance

Hyperglycaemia

Anorexia

Psychiatric disorders

Agitation

Confusional state

Hallucination

Nervous system disorders

Headache

Nervous system disorders [Not Elsewhere Classified]

Cerebral haemorrhage

Encephalopathy

Cardiac disorders

Atrial fibrillation

Vascular disorders

Hypertension

Respiratory thoracic and mediastinal disorders

Pulmonary haemorrhage

Respiratory failure

Gastro-intestinal disorders

Nausea

Vomiting

Diarrhoea

Stomatitis

Gastro-intestinal haemorrhage

Tooth hypoplasia*

Hepato-biliary disorders

Veno occlusive liver disease

Jaundice

Liver disorders

Skin and subcutaneous tissue disorders

Rash

Renal and urinary disorders

Haemorrhagic cystitis**

Renal disorder

Oliguria

General disorders and administration site conditions

Mucositis

Asthenia

Oedema

Pain

Investigations

Transaminases increased

Bilirubine increased

Alkaline phosphatases increased

Creatinine elevated

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

Reporting of suspected adverse reactions

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.

4.9. Overdose

The principal toxic effect is profound myeloablation and pancytopenia, but the central nervous system, liver, lungs, and gastrointestinal tract may also be affected.

There is no known antidote to busulfan, other than haematopoietic progenitor cell transplantation. In the absence of haematopoietic progenitor cell transplantation, the recommended dose of Busulfan would constitute an overdose of busulfan. The haematologic status should be closely monitored and vigorous supportive measures instituted as medically indicated.

There have been two reports that busulfan is dialyzable, thus dialysis should be considered in the case of an overdose. Since, busulfan is metabolized through conjugation with glutathione, administration of glutathione might be considered.

It must be considered that overdose of busulfan will also increase exposure to DMA. In human the principal toxic effects were hepatotoxicity and central nervous system (CNS) effects. CNS changes precede any of the more severe side effects. No specific antidote for DMA overdose is known. In case of overdose, management would include general supportive care.