Busulfan Fresenius Kabi

1 

 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 

 

SUMMARY OF PRODUCT CHARACTERISTICS 



2 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Busulfan Fresenius Kabi 6 mg/ml concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

One ml of concentrate contains 6 mg of busulfan (60 mg in 10 ml). 

After dilution: 1 ml of solution contains 0.5 mg of busulfan 

 

For the full list of excipients, see section 6.1 
 
 
3. PHARMACEUTICAL FORM 

 

Concentrate for solution for infusion (sterile concentrate). 

Clear, colourless viscous solution. 
 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

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. 

 

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: 

 

 



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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. 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 FB in pediatric population has not been established. 

 

Elderly patients 

The administration of FB regimen has not been specifically investigated in elderly patients. However, 

more than 500 patients aged ≥ 55 years were reported in publications with FB 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). 

 

In paediatric population 

The medicinal product is not recommended in obese children and adolescents with 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 



4 

 

 

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 

 

Busulfan is for intravenous use. 

 

Precautions to be taken before handling or administering the medicinal product 

This medicinal product 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 

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, 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 



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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, 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 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 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 



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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 

 

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 > 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. 

 

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 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 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. 



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

or granisetron. 

 

4.6 Fertility, pregnancy and lactation 

 

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). 

 

4.7 Effects on ability to drive and use machines 

 

Not relevant 

 

4.8 Undesirable effects 

 

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 



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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 reactions 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. 

 

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 reactions 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%]. 

 

 



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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 post-

transplant 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. 

 

Tabulated lists 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 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 reactions 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   



10 

 

 

System organ 

class 

Very common Common Uncommon Not known 

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** 

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 

Oligurea 

Haematuria 

Moderate renal 

insufficiency 

  



11 

 

 

System organ 

class 

Very common Common Uncommon Not known 

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 reactions presented in the following table 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.   

 

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 

 



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System organ class Very common Common 

 

Not known*  

Psychiatric disorders   Agitation 

Confusional state 

Hallucination 

Nervous system 

disorders 

 Headache 

Nervous system 

disorders [Not 

Elsewhere 

Classified] 

 

Cerebral 

haemorrhage 

Encephalo-pathy 

 

Cardiac disorders   Atrial fibrillation 

 

Vascular disorders  Hyper-tension  

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 national reporting 

system listed in Appendix V. 

 

4.9 Overdose 

 

The principal toxic effect is profound myeloablation and pancytopenia but the central nervous system, 



13 

 

 

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. 
 
 
5 PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, alkylating agents, alkyl sulfonates, ATC code: 

L01AB01.  
 
Mechanism of action 

Busulfan is a potent cytotoxic agent and a bifunctional alkylating agent. In aqueous media, release of 
the methanesulphonate groups produces carbonium ions which can alkylate DNA, thought to be an 

important biological mechanism for its cytotoxic effect. 
 
Clinical efficacy and safety 

Busulfan in combination with cyclophosphamide 

In adults 

Documentation on the safety and efficacy of busulfan in combination with cyclophosphamide in the 

BuCy2 regimen prior to conventional allogeneic and/or autologous HPCT derives from two clinical 

trials (OMC-BUS-4 and OMC-BUS-3). 

 

Two prospective, single arm, open-label, uncontrolled phase II studies were conducted in patients with 

haematological disease, the majority of whom had advanced disease. 

 

Diseases included were acute leukaemia past first remission, in first or subsequent relapse, in first 

remission (high risk), or induction failures; chronic melogenous leukaemia in chronic or advanced 

phase; primary refractory or resistant relapsed Hodgkin’s disease or non-Hodgkin’s lymphoma, and 

myelodysplastic syndrome. 

 

Patients received doses of 0.8 mg/kg busulfan every 6 hours infusion for a total 16 doses followed by 

cyclophosphamide at 60 mg/kg once per day for two days (BuCy2 regimen). 

The primary efficacy parameters in these studies were myeloablation, engraftment, relapse, and 

survival. 

In both studies, all patients received a 16/16 dose regimen of busulfan. No patients were discontinued 

from treatment due to adverse reactions related to busulfan. 

 

All patients experienced a profound myelosuppression. The time to Absolute Neutrophil Count (ANC) 

greater than 0.5x109 /l was 13 days (range 9-29 days) in allogenic patients (OMC-BUS 4), and 10 days 

(range 8-19 days) in autologous patients (OMC-BUS 3). All evaluable patients engrafted. There is no 

primary nor secondary graft rejection. Overall mortality and non-relapse mortality at more than 

100 days post-transplant was (8/61) 13% and (6/61) 10% in allotransplanted patients, respectively. 

During the same period there was no death in autologous recipients. 

 

 



14 

 

 

Paediatric population 

Documentation of the safety and efficacy of busulfan in combination with cyclophosphamide in the 

BuCy4 or with melphalan in the BuMel regimen prior to conventional allogeneic and/or autologous 

HPCT derives from clinical trial F60002 IN 101 G0. 

The patients received the dosing mentioned in section 4.2. 

All patients experienced a profound myelosuppression. The time to Absolute Neutrophil Count (ANC) 

greater than 0.5x109/l was 21 days (range 12-47 days) in allogenic patients, and 11 days (range 10-15 

days) in autologous patients. All children engrafted. There is no primary or secondary graft rejection. 

93% of allogeneic patients showed complete chimerism. There was no regimen-related death through 

the first 100-day post-transplant and up to one year post-transplant. 

 

Busulfan in combination with fludarabine (FB)  

In adults 

Documentation on the safety and efficacy of busulfan in combination with fludarabine (FB) prior to 

allogeneic HPCT derives from the literature review of 7 published studies involving 731 patients with 

myeloid and lymphoid malignancies reporting the use of intravenous busulfan infused once daily 

instead of four doses per day.  

 

Patients received a conditioning regimen based on the administration of fludarabine immediately 

followed by single daily dose of 3.2 mg/kg busulfan over 2 or 3 consecutive days. Total dose of 

busulfan per patient was between 6.4 mg/kg and 9.6 mg/kg. 

The FB combination allowed sufficient myeloablation modulated by the intensity of conditioning 

regimen through the variation of number of days of busulfan infusion. Fast and complete engraftment 

rates in 80-100% of patients were reported in the majority of studies. A majority of publications 

reported a complete donor chimerism at day+30 for 90-100% of patients. The long-term outcomes 

confirmed that the efficacy was maintained without unexpected effects.  

 

Data from a recently completed prospective multicentre phase 2 study including 80 patients, aged 18 to 

65 years old, diagnosed with different hematologic malignancies who underwent allo-HCT with an FB 

(3 days of busulfan) reduced intensity conditioning regimen became available. In this study, all, but one, 

patients engrafted, at a median of 15 (range, 10-23) days after allo-HCT. The cumulative incidence of 

neutrophil recovery at day 28 was 98.8% (95%CI, 85.7-99.9%). Platelet engraftment occurred at a 

median of 9 (range, 1-16) days after allo-HCT.  

The 2-year OS rate was 61.9% (95%CI, 51.1-72.7%)]. At 2 years, the cumulative incidence of NRM 

was 11.3% (95%CI, 5.5-19.3%), and that of relapse or progression from allo-HCT was 43.8% (95CI, 

31.1-55.7%). The Kaplan-Meier estimate of DFS at 2 years was 49.9% (95%CI, 32.6-72.7). 

 

5.2 Pharmacokinetic properties 

 

The pharmacokinetics of busulfan has been investigated. The information presented on 

biotransformation and elimination is based on oral busulfan. 

 

Pharmacokinetics in adults 

Absorption 

The pharmacokinetics of intravenous busulfan was studied in 124 evaluable patients following a 

2-hour intravenous infusion for a total of 16 doses over four days. Immediate and complete 

availability of the dose is obtained after intravenous infusion of busulfan. Similar blood exposure 

was observed when comparing plasma concentrations in adult patients receiving oral and intravenous 

busulfan at 1 mg/kg and 0.8 mg/kg respectively. Low inter (CV=21%) and intra (CV=12%) patient 

variability on busulfan exposure was demonstrated through a population pharmacokinetic analysis, 

performed on 102 patients. 

 

Distribution 

Terminal volume of distribution Vz ranged between 0.62 and 0.85 l/kg. 

Busulfan concentrations in the cerebrospinal fluid are comparable to those in plasma although these 
concentrations are probably insufficient for anti-neoplastic activity. 

Reversible binding to plasma proteins was around 7% while irreversible binding, primarily to albumin, 



15 

 

 

was about 32%. 

 

Biotransformation 

Busulfan is metabolised mainly through conjugation with glutathione (spontaneous and 

glutathione-S-transferase mediated). The glutathione conjugate is then further metabolised in the liver 

by oxidation. None of the metabolites is thought to contribute significantly to either efficacy or 

toxicity. 

 

Elimination 

Total clearance in plasma ranged 2.25 - 2.74 ml/minute/kg. The terminal half-life ranged from 2.8 to 

3.9 hours. 

Approximately 30% of the administered dose is excreted into the urine over 48 hours with 1% as 

unchanged busulfan. Elimination in faeces is negligible. Irreversible protein binding may explain the 

incomplete recovery. Contribution of long-lasting metabolites is not excluded. 

 

Linearity 

The dose proportional increase of busulfan exposure was demonstrated following intravenous busulfan 

up to 1 mg/kg. 

Compared to the four times a day regimen, the once-daily regimen is characterized by a higher peak 

concentration, no drug accumulation and a wash out period (without circulating busulfan 

concentration) between consecutive administrations. The review of the literature allows a comparison 

of PK series performed either within the same study or between studies and demonstrated unchanged 

dose-independent PK parameters regardless the dosage or the schedule of administration. It seems that 

the recommended intravenous busulfan dose administered either as an individual infusion (3.2 mg/kg) 

or into 4 divided infusions (0.8 mg/kg) provided equivalent daily plasma exposure with similar both 

inter-and intrapatient variability. As a result, the control of intravenous busulfan AUC within the 

therapeutic windows is not modified and a similar targeting performance between the two schedules 

was illustrated. 

 

Pharmacokinetic/pharmacodynamic relationships 

The literature on busulfan suggests a therapeutic AUC window between 900 and 1500 µmol/L.minute 

per administration (equivalent to a daily exposure between 3600 and 6000 µmol/L.minute). During 

clinical trials with intravenous busulfan administered as 0.80 mg/kg four-times daily, 90% of patients 

AUCs were below the upper AUC limit (1500 µmol/L.minute) and at least 80% were within the 

targeted therapeutic window (900 - 1500 µmol/L.minute). Similar targeting rate is achieved within the 

daily exposure of 3600 - 6000 µmol/L.minute following the administration of intravenous busulfan 

3.2 mg/kg once daily. 

 

Special populations 

Hepatic or renal impairment 

The effects of renal dysfunction on intravenous busulfan disposition have not been assessed. 

The effects of hepatic dysfunction on intravenous busulfan disposition have not been assessed. 

Nevertheless the risk of liver toxicity may be increased in this population. 

No age effect on busulfan clearance was evidenced from available intravenous busulfan data in 

patients over 60 years. 

 

Paediatric population 

A continuous variation of clearance ranging from 2.49 to 3.92 ml/minute/kg has been established in 

children from < 6 months up to 17 years old. The terminal half life ranged from 2.26 to 2.52 h. 

Inter and intra patient variabilities in plasma exposure were lower than 20% and 10%, respectively. 

A population pharmacokinetic analysis has been performed in a cohort of 205 children adequately 

distributed with respect to bodyweight (3.5 to 62.5 kg), biological and diseases (malignant and 

non-malignant) characteristics, thus representative of the high heterogeneity of children undergoing 

HPCT. This study demonstrated that bodyweight was the predominant covariate to explain the busulfan 

pharmacokinetic variability in children over body surface area or age. 

The recommended posology for children as detailed in section 4.2 enabled over 70% up to 90% of 

children ≥ 9kg in achieving the therapeutic window (900 - 1500 µmol/L.minute). However a higher 



16 

 

 

variability was observed in children < 9 kg leading to 60% of children achieving the therapeutic 

window (900 - 1500 µmol/L.minute). For the 40% of children < 9 kg outside the target, the AUC 

was evenly distributed either below or above the targeted limits; i.e. 20% each < 900 and 

> 1500 µmol/L.min following 1 mg/kg. In this regard, for children < 9 kg, a monitoring of the 

plasma concentrations of busulfan (therapeutic drug monitoring) for dose-adjustment may improve 

the busulfan targeting performance, especially in extremely young children and neonates. 

 

Pharmacokinetic/pharmacodynamic relationships: 

The successful engraftment achieved in all patients during phase II trials suggests the appropriateness 

of the targeted AUCs. Occurrence of VOD was not related to overexposure. PK/PD relationship was 

observed between stomatitis and AUCs in autologous patients and between bilirubin increase and 

AUCs in a combined autologous and allogeneic patient analysis. 

 

5.3 Preclinical safety data 

 

Busulfan is mutagenic and clastogenic. Busulfan was mutagenic in Salmonella typhimurium, 

Drosophila melanogaster and barley. Busulfan induced chromosomal aberrations in vitro (rodent and 

human cell) and in vivo (rodents and humans). Various chromosome aberrations have been observed in 

cells from patients receiving oral busulfan. 

 

Busulfan belongs to a class of substances which are potentially carcinogenic based on their mechanism 

of action. On the basis of human data, busulfan has been classified by the IARC as a human 

carcinogen. WHO has concluded that there is a causal relationship between busulfan exposure and 

cancer. The available data in animals support the carcinogenic potential of busulfan. Intravenous 

administration of busulfan to mice significantly increased the incidences of thymic and ovarian 

tumours. 

 

Busulfan is a teratogen in rats, mice and rabbits. Malformations and anomalies included significant 

alterations in the musculoskeletal system, body weight gain, and size. In pregnant rats, busulfan 

produced sterility in both male and female offspring due to the absence of germinal cells in testes and 

ovaries. Busulfan was shown to cause sterility in rodents. Busulfan depleted oocytes of female rats, 

and induced sterility in male rats and hamster. 

 

Repeated doses of DMA produced signs of liver toxicity, the first being increases in serum clinical 

enzymes followed by histopatological changes in the hepatocytes. Higher doses can produce hepatic 

necrosis and liver damage can be seen following single high exposures. 

 

DMA is teratogenic in rats. Doses of 400 mg/kg/day DMA administered during organogenesis caused 

significant developmental anomalies. The malformations included serious heart and/or major vessels 

anomalies: a common truncus arteriosis and no ductus arteriosis, coarctation of the pulmonary trunk 

and the pulmonary arteries, intraventricular defects of the heart. Other frequent anomalies included 

cleft palate, anasarca and skeletal anomalies of the vertebrae and ribs. DMA decreases fertility in male 

and female rodents. A single s.c. dose of 2.2 g/kg administered on gestation day 4 terminated 

pregnancy in 100% of tested hamster. In rats, a DMA daily dose of 450 mg/kg given to rats for nine 

days caused inactive spermatogenesis. 
 
 

6 PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Dimethylacetamide 

Macrogol 400 

 

6.2 Incompatibilities 

 

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 



17 

 

 

products except those mentioned in section 6.6. 

 

Polycarbonate syringes must not be used with busulfan. 

 

 

6.3 Shelf life 

 

Vials 
 2 years. 

 
Diluted solution 
 

Chemical and physical in-use stability after dilution in glucose 5% or sodium chloride 9 mg/ml (0.9%) 

solution for injection has been demonstrated for: 

 

- 8 hours (including infusion time) after dilution when stored at 25°C ± 2°C 

 

- 12 hours after dilution when stored at 2°C-8°C followed by 3 hours stored at 25°C ± 2°C 

(including infusion time). 

 

From a microbiological point of view, the product should be used immediately after dilution. 

If not used immediately, in-use storage times and conditions prior to use are the responsibility of the 

user and would normally not be longer than the above-mentioned conditions when dilution has taken 

place in controlled and validated aseptic conditions. 

 

6.4 Special precautions for storage 

 

Store in a refrigerator (2°C-8°C). 

Do not freeze the diluted solution. 

For storage conditions after dilution of the medicinal product see section 6.3. 

 

6.5 Nature and contents of container 

 

10 ml of concentrate for solution for infusion in clear colourless glass vials (type I) with teflon faced 

rubber stopper and sealed with aluminium flip-off seal. Each vial is sleeved with shrinkable plastic 

film. 

 

Pack size 

1 pack containing 8 vials (8 cartons of 1 vial). 

 

6.6 Special precautions for disposal and other handling 

 

Preparation of Busulfan Fresenius Kabi 

Procedures for proper handling and disposal of anticancer medicinal products should be considered. 

 

All transfer procedures require strict adherence to aseptic techniques, preferably employing a vertical 
laminar flow safety hood. 

 

As with other cytotoxic compounds, caution should be exercised in handling and preparing the busulfan 
solution: 
- The use of gloves and protective clothing is recommended. 
- If the concentrate or diluted busulfan solution contacts the skin or mucosa, wash them thoroughly 

with water immediately. 

 

Calculation of the quantity of Busulfan Fresenius Kabi to be diluted and of the diluent 

 

Busulfan Fresenius Kabi must be diluted prior to use with either sodium chloride 9 mg/ml (0.9%) 



18 

 

 

solution for injection or glucose solution for injection 5%. 

 

The quantity of the diluent must be 10 times the volume of the Busulfan Fresenius Kabi ensuring the 
final concentration of busulfan remains at approximately 0.5 mg/ml. By example: 

 

The amount of Busulfan Fresenius Kabi and diluent to be administered would be calculated as follows: 

for a patient with a Y kg body weight: 

 
• Quantity of Busulfan Fresenius Kabi: 

 

Y (kg) x D (mg/kg)  

   = A ml of Busulfan Fresenius Kabi to be diluted 

 

6 (mg/ml) 

 

Y: body weight of the patient in kg 

D: dose of busulfan (see section 4.2) 

 
• Quantity of diluent: 

 

(A ml Busulfan Fresenius Kabi) x (10) = B ml of diluent 

 

To prepare the final solution for infusion, add (A) ml of Busulfan Fresenius Kabi to (B) ml of diluent 
(sodium chloride 9 mg/ml (0.9%) solution for injection or glucose solution for injection 5%)  

 

Preparation of the solution for infusion 

 
• Busulfan Fresenius Kabi must be prepared by a healthcare professional using sterile transfer 

techniques. Using a non polycarbonate syringe fitted with a needle: 

 
- the calculated volume of Busulfan Fresenius Kabi must be removed from the vial. 

 
- the contents of the syringe must be dispensed into an intravenous bag (or syringe) which 

already contains the calculated amount of the selected diluent. Busulfan Fresenius Kabi 
must always be added to the diluent, not the diluent to the Busulfan Fresenius Kabi. 
Busulfan Fresenius Kabi must not be put into an intravenous bag that does not contain 
sodium chloride 9 mg/ml (0.9%) solution for injection or glucose solution for injection 5%. 

• The diluted solution must be mixed thoroughly by inverting several times.  

 

After dilution, 1 ml of solution for infusion contains 0.5 mg of busulfan. 

 

Diluted Busulfan Fresenius Kabi is a clear colourless solution. 

 

Instructions for use 

Prior to and following each infusion, flush the indwelling catheter line with approximately 5 ml of 
sodium chloride 9 mg/ml (0.9%) solution for injection or glucose (5%) solution for injection. 

 

The residual medicinal product must not be flushed in the administration tubing as rapid infusion of 
busulfan has not been tested and is not recommended. 

 

The entire prescribed busulfan dose should be delivered over two or three hours depending of the 
conditioning regimen. 

 

Small volumes may be administered over 2 hours using electric syringes. In this case infusion sets with 
minimal priming space should be used (i.e 0.3-0.6 ml), primed with medicinal product solution prior to 
beginning the actual busulfan infusion and then flushed with sodium chloride 9 mg/ml (0.9%) solution 
for injection or glucose (5%) solution for injection. 



19 

 

 

Busulfan must not be infused concomitantly with another intravenous solution.  

 

Polycarbonate syringes must not be used with busulfan. 

 

Only a clear solution without any particles should be used. 

 

Busulfan is for single use only. Any unused medicinal product or waste material should be disposed of 
in accordance with local requirements for cytotoxic medicinal products. 

 

 

7 MARKETING AUTHORISATION HOLDER 

 

Fresenius Kabi Deutschland GmbH 

Else-Kröner-Straße 1, 

61352 Bad Homburg v.d.Höhe 

Germany 

 

 

8 MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/14/951/001 

 

 

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 22 September 2014 

Date of latest renewal: 20 June 2019 

 

 

10 DATE OF REVISION OF THE TEXT 

 

 

Detailed information on this medicinal product is available on the website of European Medicinal 
Agency http://www.ema/europa.eu 



20 

 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 

 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE  

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 



21 

 

 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturer(s) responsible for batch release 

Fresenius Kabi Deutschland GmbH 

Pfingstweide 53 

61169 Friedberg 

Germany  

 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

Medicinal product subject to restricted medical prescription (see Annex I: Summary of 

Product Characteristics, section 4.2). 

 

 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
 AUTHORISATION  

 

• Periodic safety update reports  

 

The requirements for submission of periodic safety update reports for this medicinal 

product are set out in the list of Union reference dates (EURD list) provided for under 

Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the 

European medicines web-portal. 

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
 EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

• Risk Management Plan (RMP) 

 

The MAH shall perform the required pharmacovigilance activities and interventions 

detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation 

and any agreed subsequent updates of the RMP. 

 

An updated RMP should be submitted: 

 

• At the request of the European Medicines Agency; 

• Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk 

profile or as the result of an important (pharmacovigilance or risk minimisation) 

milestone being reached.  

 

If the submission of a PSUR and the update of a RMP coincide, they can be submitted at 

the same time. 



22 

 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 



23 

 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



24 

 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

 

OUTER CARTON containing 8 vials  
 
 

1. NAME OF THE MEDICINAL PRODUCT 

 

Busulfan Fresenius Kabi 6 mg/ml concentrate for solution for infusion  

busulfan 
 
 

2. STATEMENT OF ACTIVE SUBSTANCE 

 

One ml of concentrate contains 6 mg of busulfan and provides 0.5 mg/ml of busulfan after dilution 
 
 

3. LIST OF EXCIPIENTS 

 

Excipients: Dimethylacetamide and Macrogol 400 
 
 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Concentrate for solution for infusion 

 

 8 vials of 10 ml 

 

60 mg per vial 
 
 

5. METHOD AND ROUTE OF ADMINISTRATION 

 

Read the package leaflet before use 
Intravenous use after dilution. 
 
 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 
Keep out of the sight and reach of children. 
 
 

7. OTHER SPECIAL WARNING IF NECESSARY 

 

Cytotoxic 
 
 

8. EXPIRY DATE 

 

EXP: 

 

 

9. SPECIAL STORAGE CONDITIONS 

 



25 

 

 

Store in a refrigerator. 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Fresenius Kabi Deutschland GmbH 

Else-Kröner-Straße 1, 

61352 Bad Homburg v.d.Höhe 

Germany 
 
 

12. MARKETING AUTHORISATION NUMBER(S) 

 
EU/1/14/951/001 
 
 

13. BATCH NUMBER 

 

Lot 
 
 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to restricted medical prescription. 
 
 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Justification for not including Braille accepted. 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE  

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA  

 

PC: 

SN: 

NN: 



26 

 

 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 

 

 

CARTON containing 1 vial  
 
 

1. NAME OF THE MEDICINAL PRODUCT 

 

Busulfan Fresenius Kabi 6 mg/ml concentrate for solution for infusion  

busulfan 
 
 

2. STATEMENT OF ACTIVE SUBSTANCE 

 

One ml of concentrate contains 6 mg of busulfan and provides 0.5 mg/ml of busulfan after dilution 
 
 

3. LIST OF EXCIPIENTS 

 

Excipients: Dimethylacetamide and Macrogol 400 
 
 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Concentrate for solution for infusion 

 

1 vial of 10 ml.  

 

60 mg per vial 
 
 

5. METHOD AND ROUTE OF ADMINISTRATION 

 

Read the package leaflet before use 

Intravenous use after dilution. 
 
 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 
Keep out of the sight and reach of children. 
 
 

7. OTHER SPECIAL WARNING IF NECESSARY 

 

Cytotoxic 
 
 

8. EXPIRY DATE 

 

EXP: 

 

 

9. SPECIAL STORAGE CONDITIONS 

 



27 

 

 

Store in a refrigerator. 
 
 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 
 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Fresenius Kabi Deutschland GmbH 

Else-Kröner-Straße 1, 

61352 Bad Homburg v.d.Höhe 

Germany 
 
 

12. MARKETING AUTHORISATION NUMBER(S) 

 
EU/1/14/951/001 
 
 

13. BATCH NUMBER 

 

Lot 
 
 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to restricted medical prescription. 
 
 

15. INSTRUCTIONS ON USE 

 

 

 

16. INFORMATION IN BRAILLE 

 

Justification for not including Braille accepted. 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE  

 

  

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA  

 

 

 

 

 

 

 

 

 

 

 

 



28 

 

 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS  

 

VIAL 

 
 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 

 

Busulfan Fresenius Kabi 6 mg/ml sterile concentrate 

busulfan 

IV after dilution 
 
 

2. METHOD OF ADMINISTRATION 
 
 

3. EXPIRY DATE 

 

EXP 
 
 

4. BATCH NUMBER 

 

Lot 
 
 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

 

60 mg/10 ml 
 
 

6. OTHER 
 
Cytotoxic 



29 

 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 

 

 

B. PACKAGE LEAFLET 



30 

 

 

Package leaflet: Information for the user 

 

Busulfan Fresenius Kabi 6 mg/ml concentrate for solution for infusion 

busulfan 
 
 

Read all of this leaflet carefully before you start using this medicine because it contains 

important information for you. 

- Keep this leaflet. You may need to read it again. 

- If you have any further questions, ask your doctor. 

- If you get any side effects, talk to your doctor. This includes any possible side effects not listed in 

this leaflet. See section 4. 

 

What is in this leaflet: 

 

1. What Busulfan Fresenius Kabi is and what it is used for 

2. What you need to know before you use Busulfan Fresenius Kabi 

3. How to use Busulfan Fresenius Kabi  

4. Possible side effects 

5 How to store Busulfan Fresenius Kabi 

6. Contents of the pack and other information 
 
 
1. What Busulfan Fresenius Kabi is and what it is used for 

 

This medicine contains the active substance busulfan, which belongs to a group of medicines called 

alkylating agents. Busulfan Fresenius Kabi destroys the original bone marrow before the transplant. 

 

Busulfan Fresenius Kabi is used in adults, new-born infants, children and adolescents as a treatment 

prior to transplantation. 

 

In adults Busulfan Fresenius Kabi is used in combination with cyclophosphamide or fludarabine. 

 

In new-born infants, children and adolescents, this medicine is used in combination with 

cyclophosphamide or melphalan. 

 

You will receive this preparative medicine before receiving a transplant of either bone marrow or 

haematopoietic progenitor cell. 
 
 
2. What you need to know before you use Busulfan Fresenius Kabi 

 

Do not use Busulfan Fresenius Kabi: 

- if you are allergic to busulfan or any of the other ingredients of this medicine listed in section 6. 

- if you are pregnant, or think you may be pregnant. 

 

Warnings and precautions 

Busulfan Fresenius Kabi is a potent cytotoxic medicine that results in profound decrease of blood cells. 

At the recommended dose, this is the desired effect. Therefore careful monitoring will be performed.  

 

It is possible that use of Busulfan Fresenius Kabi may increase the risk of suffering another 

malignancy in the future. You should tell your doctor: 

- if you have a liver, kidney, heart or lung problem, 

- if you have a history of seizures, 

- if you are currently taking other medicines. 

 

Cases of formation of blood clots in the small blood vessels may appear after hematopoietic cell 

transplantation (HCT) with high-dose of your treatment in combination with other medicines. 



31 

 

 

Other medicines and Busulfan Fresenius Kabi 

Tell your doctor if you are taking or have recently taken or might take any other medicines, including 
medicines obtained without a prescription. Busulfan Fresenius Kabi may interact with other medicines 
such as Deferasirox (a medicine used to remove excess iron from your body). 

 

Particular caution should be taken if you use itraconazol and metronidazole (used for certain 

types of infections) or ketobemidone (used to treat pain), because this may increase the 

side-effects. 

 

The use of paracetamol during the 72 hours prior to or with Busulfan Fresenius Kabi administration 

should be used with caution. 

 

Pregnancy, breast-feeding and fertility 

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 

your doctor before you receive treatment with Busulfan Fresenius Kabi. Women must not be 

pregnant during treatment with Busulfan Fresenius Kabi and up to 6 months after treatment. 

Women must stop breast-feeding before starting their treatment with Busulfan Fresenius Kabi. 

 

Adequate contraceptive precautions should be used when either partner is receiving Busulfan Fresenius 

Kabi. 

 

It may no longer be possible for you to achieve a pregnancy (infertility) after treatment with Busulfan 

Fresenius Kabi. If you are concerned about having children, you should discuss this with your doctor 

before treatment. Busulfan Fresenius Kabi can also produce symptoms of menopause and in 

pre-adolescent girls it can prevent the onset of puberty. 

 

Men treated with Busulfan Fresenius Kabi are advised not to father child during and up to 6 months after 

treatment. 
 
 
3. How to use Busulfan Fresenius Kabi 

 

Dose and administration 

The dose of busulfan will be calculated according to your body weight. 

 

In adults: 

Busulfan Fresenius Kabi in combination with cyclophosphamide: 

- The recommended dose of Busulfan Fresenius Kabi is 0.8 mg/kg  

− Each infusion will last 2 hours 

− Busulfan will be administered every 6 hours during 4 consecutive days prior to transplant. 

 

Busulfan Fresenius Kabi in combination with fludarabine 

− The recommended dose of busulfan is 3.2 mg/kg 

− Each infusion will last 3 hours 

− Busulfan will be administered once daily during 2 or 3 consecutive days prior to transplant. 

 

In new-born infants, children and adolescents (0 to 17 years): 

The recommended dose of Busulfan Fresenius Kabi in combination with cyclophosphamide or 

melphalan is based on your body weight varying between 0.8 and 1.2 mg/kg. 

 

 

Medicines before you receive Busulfan Fresenius Kabi: 

Before receiving Busulfan Fresenius Kabi, you will be medicated with 

- anticonvulsive medicines to prevent seizures (phenytoin or benzodiazepines) and 

- antiemetic medicines to prevent vomiting. 

 

 



32 

 

 

4. Possible side effects 

 

Like all medicines, Busulfan Fresenius Kabi can cause side effects, although not everybody gets them. 

 

Serious side effects: 

The most serious side effects of busulfan therapy or the transplant procedure may include decrease in 

circulating blood cell counts (intended effect of the medicine to prepare you for your transplant 

infusion), infection, liver disorders including blocking of a liver vein, graft versus host disease (the graft 

attacks your body) and pulmonary complications. Contact your doctor immediately if you get any of the 

following symptoms. Your doctor will monitor your blood counts and liver enzymes regularly to detect 

and manage these events. 

 

Other side effects may include: 

Very common (may affect more than 1 in 10 people): 

Blood: decrease of blood circulating cells (red and white) and platelets. Infections.  Nervous system: 

insomnia, anxiety, dizziness, and depression. Nutrition: loss of appetite, decrease in magnesium, 

calcium, potassium, phosphate, albumine in blood, and increase in blood sugar. Cardiac: increase in 

heart rate, increase or decrease of blood pressure, vasodilatation (a state of increased calibre of the 

blood vessels), and blood clots. Respiratory: shortness of breath, nasal secretion (rhinitis), sore throat, 

cough, hiccup, nosebleeds, abnormal breath sounds. Gastro-intestinal: nausea, inflammation of the 

mucosa of the mouth, vomiting, abdominal pain, diarrhoea, constipation, heart burn, anus discomfort, 

liquid in the abdomen. Hepatic: enlarged liver, jaundice, blocking of a liver vein. Skin: rash, itching, 

loss of hairs. Muscle and bone: back, muscle and joint pain. Renal: increase in creatinine elimination, 

discomfort in urination, and decrease in urine output and bloody urine. General: fever, headache, 

weakness, chills, pain, allergic reaction, oedema, general pain or inflammation at injection site, chest 

pain, inflammation of the mucosa. Investigations: elevated liver enzymes and weight increased. 

 

Common (may affect up to 1 in 10 people): 

Nervous system: confusion, nervous system disorders. Nutrition: low blood sodium. Cardiac: 

changes and abnormalities in heart rhythm, fluid retention or inflammation around the heart, decrease 

heart output. Respiratory: increase in breath rhythm, respiratory failure, alveolar haemorrhages, 

asthma, collapse of small portions of the lung, fluid around the lung. Gastro-intestinal: inflammation 

of the mucosa of oesophagus, paralysis of the gut, vomiting blood. Skin: Skin colour disorder, redness 

of the skin, skin desquamation. Renal: increase in the amount of nitrogen components in the blood 

stream, moderate renal insufficiency, renal disorder. 

 

Uncommon (may affect up to 1 in 100 people): 

Nervous system: delirium, nervousness, hallucination, agitation, abnormal brain function, cerebral 

haemorrhage, and seizure. Cardiac: clotting of femoral artery, extra heart beats, decrease in heart rate, 

diffuse leak of fluid from the capillaries (small blood vessels). Respiratory: decrease in blood oxygen. 

Gastro-intestinal: bleeding in the stomach and/or the gut. 

 

Not known (frequency cannot be estimated from the available data) 

Sex glands dysfunction 

Lens disorders including clouding of the lens of the eye (cataract), and blurred vision (corneal 

thinning) 

Menopausal symptoms and female infertility. 

Brain abscess, Inflammation of the skin, generalised infection. 

Liver disorders. 

Increase of lactate dehydrogenase in the blood. 

Increase of uric acid and urea in the blood. 

Incomplete development of teeth 

 

Reporting of side effects 

If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this 

leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. 



33 

 

 

By reporting side effects you can help provide more information on the safety of this medicine. 

 

 
5. How to store Busulfan Fresenius Kabi 
 

Keep this medicine out of the sight and reach of children. 

Do not use this medicine after the expiry date which is stated on the vial label and the carton after EXP. 

 

Unopened vials: 

Store in a refrigerator (2°C - 8°C). 

Diluted solution: 

Chemical and physical in-use stability after dilution in glucose 5% or sodium chloride 9 mg/ml (0.9%) 

solution for injection has been demonstrated for 8 hours (including infusion time) after dilution when 

stored at 25°C ± 2°C or 12 hours after dilution when stored at 2°C-8°C followed by 3 hours stored at 

25°C ± 2°C (including infusion time). Do not freeze. 

 

Do not throw away any medicine via wastewater or household waste. Ask your pharmacist how 

to throw away medicine you no longer use. These measures will help protect environment. 
 
 
6. Contents of the pack and other information 

 

What Busulfan Fresenius Kabi contains 

- The active substance is busulfan. One ml of concentrate contains 6 mg busulfan (60 mg in the 

vial). After dilution: one ml of solution contains approximately 0.5 mg of busulfan. 

- The other ingredients are dimethylacetamide and macrogol 400. 
 
What Busulfan Fresenius Kabi looks like and contents of the pack 

Busulfan Fresenius Kabi consists of a concentrate for solution for infusion. When diluted Busulfan 

Fresenius Kabi is a clear colourless viscous solution.  

 

Busulfan Fresenius Kabi is supplied in colourless glass vials, each vial containing 60 mg of busulfan. 

Each vial is sleeved with shrinkable plastic film. 

 

Each vial contains 10 ml of concentrate. 

 

Pack size 

1 pack containing 8 vials (8 cartons of 1 vial). 

 

Marketing Authorisation Holder  

 

Fresenius Kabi Deutschland GmbH 

Else-Kröner-Straße 1, 

61352 Bad Homburg v.d.Höhe 

Germany 

 

Manufacturer 

Fresenius Kabi Deutschland GmbH 

Pfingstweide 53 

61169 Friedberg 

Germany  

 

 

For any information about this medicine, please contact the Marketing Authorisation Holder 

 

This leaflet was last revised in {MM/YYYY} 

 



34 

 

 

Other sources of information 

Detailed information on this product is available on the website of European Medicinal 

Agency http://www.ema/europa.eu 



35 

 

 

---------------------------------------------------------------------------------------------------------------- 

The following information is intended for healthcare professionals only 

 

PREPARATION GUIDE 

 

 

Busulfan Fresenius Kabi 6 mg/ml concentrate for solution for infusion 

Busulfan 

 

Read this guide prior to the preparation and administration of Busulfan Fresenius Kabi. 

 

 

1. PRESENTATION 

 

Busulfan Fresenius Kabi is supplied as a clear colourless viscous solution in 10 ml clear, colourless 

glass vials (type I). Busulfan Fresenius Kabi must be diluted prior to administration. 

 

 

2. RECOMMENDATION FOR SAFE HANDLING 

 

Procedures for proper handling and disposal of anticancer medicinal products should be considered. 

 

All transfer procedures require strict adherence to aseptic techniques, preferably employing a vertical 

laminar flow safety hood. 

 

As with other cytotoxic compounds, caution should be exercised in handling and preparing the busulfan 

solution: 

- The use of gloves and protective clothing is recommended. 

- If the concentrate or diluted busulfan solution contacts the skin or mucosa, wash them thoroughly 

with water immediately. 

 

Calculation of the quantity of Busulfan Fresenius Kabi to be diluted and of the diluent 

 

Busulfan Fresenius Kabi must be diluted prior to use with either sodium chloride 9 mg/ml (0.9%) 

solution for injection or glucose solution for injection 5%. 

 

The quantity of the diluent must be 10 times the volume of Busulfan Fresenius Kabi ensuring the final 

concentration of busulfan remains at approximately 0.5 mg/ml. 

 

The amount of Busulfan Fresenius Kabi and diluent to be administered would be calculated as follows: 

for a patient with a Y kg body weight: 

 

• Quantity of Busulfan Fresenius Kabi: 

 

Y (kg) x D (mg/kg)  

   = A ml of Busulfan Fresenius Kabi to be diluted 

 

6 (mg/ml) 

 

Y: body weight of the patient in kg 

D: dose of busulfan (see SPC section 4.2) 

 

• Quantity of diluent: 

 

(A ml Busulfan Fresenius Kabi) x (10) = B ml of diluent 

 

To prepare the final solution for infusion, add (A) ml of Busulfan Fresenius Kabi to (B) ml of diluent 



36 

 

 

(sodium chloride 9 mg/ml (0.9%) solution for injection or glucose solution for injection 5%). 

 

Preparation of the solution for infusion 

 

Busulfan Fresenius Kabi must be prepared by a healthcare professional using sterile transfer techniques.  

• Using a non polycarbonate syringe fitted with a needle: 

 

- the calculated volume of Busulfan Fresenius Kabi must be removed from the vial. 

 

- the contents of the syringe must be dispensed into an intravenous bag (or syringe) which 

already contains the calculated amount of the selected diluent. Busulfan Fresenius Kabi must 

always be added to the diluent, not the diluent to the Busulfan Fresenius Kabi. Busulfan 

Fresenius Kabi must not be put into an intravenous bag that does not contain sodium chloride 

9 mg/ml (0.9%) solution for injection or glucose solution for injection 5%. 

 

• The diluted solution must be mixed thoroughly by inverting several times. 

 

After dilution, 1 ml of solution for infusion contains 0.5 mg of busulfan. 

 

Diluted Busulfan Fresenius Kabi is a clear colourless solution 

 

Instructions for use 

Prior to and following each infusion, flush the indwelling catheter line with approximately 5 ml of 

sodium chloride 9 mg/ml (0.9%) solution for injection or glucose (5%) solution for injection. 

 

The residual medicinal product must not be flushed in the administration tubing as rapid infusion of 

busulfan has not been tested and is not recommended. 

 

The entire prescribed busulfan dose should be delivered over two or three hours depending on the 

conditioning regimen. 

 

Small volumes may be administered over 2 hours using electric syringes. In that case infusion sets with 

minimal priming space should be used (i.e 0.3-0.6 ml), primed with medicinal product solution prior to 

beginning the actual busulfan infusion and then flushed with sodium chloride 9 mg/ml (0.9%) solution 

for injection or glucose (5%) solution for injection. 

 

Busulfan must not be infused concomitantly with another intravenous solution.  

 

Polycarbonate syringes must not be used with busulfan. 

 

For single use only. Only a clear solution without particles should be used. 

 

Storage conditions 

Unopened vials: 

Store in a refrigerator (2°C – 8°C). 

 

Diluted solution: 

Chemical and physical in-use stability after dilution in glucose 5% or sodium chloride 9 mg/ml (0.9%) 

solution for injection has been demonstrated for 8 hours (including infusion time) after dilution when 

stored at 25°C ± 2°C or 12 hours after dilution when stored at 2°C-8°C followed by 3 hours stored at 

25°C ± 2°C (including infusion time). 

 

From a microbiological point of view, the product should be used immediately after dilution. 

If not used immediately, in-use storage times and conditions are the responsibility of the user and would 

normally not be longer than the above-mentioned conditions when dilution has taken place in controlled 

and validated aseptic conditions. 

 



37 

 

 

Do not freeze the diluted solution. 

 

 

3. PROCEDURE FOR PROPER DISPOSAL 

 

Any unused medicinal product or waste should be disposed of in accordance with local requirements for 

cytotoxic medicinal products. 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET