BUSULFAN FRESENIUS KABI 6mg / ml perfusive solution concentrate medication leaflet

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

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

Concentrate for solution for infusion (sterile concentrate).

Clear, colourless viscous solution.

Busulfan followed by cyclophosphamide (BuCy2) is indicated as conditioning treatment prior toconventional haematopoietic progenitor cell transplantation (HPCT) in adult patients when thecombination is considered the best available option.

Busulfan following fludarabine (FB) is indicated as conditioning treatment prior to haematopoieticprogenitor cell transplantation (HPCT) in adult patients who are candidates for a reduced-intensityconditioning (RIC) regimen.

Busulfan followed by cyclophosphamide (BuCy4) or melphalan (BuMel) is indicated as conditioningtreatment prior to conventional haematopoietic progenitor cell transplantation in paediatric patients.

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

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

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 consecutivedays for a total of 16 doses,

- followed by cyclophosphamide at 60 mg/kg/day over 2 days initiated for at least 24 hoursfollowing 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 1.09 to < 16 1.216 to 23 1.1> 23 to 34 0.95> 34 0.8followed 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 of16 doses prior to cyclophosphamide or melphalan and haematopoietic progenitor cell transplantation(HPCT).

Patients older than 50 years of age (n=23) have been successfully treated with busulfan withoutdose-adjustment. However, for the safe use of busulfan in patients older than 60 years only limitedinformation 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 consecutivedays or 40 mg/m² for 4 consecutive days.

- Busulfan will be administered at 3.2 mg/kg as a single daily three-hour infusion immediatelyafter 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.

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.

Studies in renally impaired patients have not been conducted, however, as busulfan is moderatelyexcreted in the urine, dose modification is not recommended in these patients.

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

Busulfan has not been studied in patients with hepatic impairment.

Caution is recommended, particularly in those patients with severe hepatic impairment (see section4.4).

Busulfan is for intravenous use.

This medicinal product must be diluted prior to administration. A final concentration of approximately0.5 mg/ml busulfan should be achieved. Busulfan should be administered by intravenous infusion viacentral 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 seizuresreported 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 ofbusulfan.

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

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

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

Pregnancy (see section 4.6).

The consequence of treatment with busulfan at the recommended dose and schedule is profoundmyelosuppression, occurring in all patients. Severe granulocytopenia, thrombocytopenia, anaemia, orany combination thereof may develop. Frequent complete blood counts, including differential whiteblood cell counts, and platelet counts should be monitored during the treatment and until recovery isachieved.

Prophylactic or empiric use of anti-infectives (bacterial, fungal, viral) should be considered for theprevention and management of infections during the neutropenic period. Platelet and red blood cellsupport, 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 transplantrespectively (median neutropenic period of 6 and 9 days respectively).

Thrombocytopenia (< 25x109/l or requiring platelet transfusion) occurred at a median of 5-6 days in98% 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 transplantoccurred in 100% of patients and lasted 5 and 18.5 days in autologous and allogeneic transplantrespectively. In children, thrombocytopenia (< 25x109/l or requiring platelet transfusion) occurred in100% 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 particularin extremely young children and neonates (see section 5.2).

The Fanconi anaemia cells have hypersensitivity to cross-linking agents. There is limited clinicalexperience of the use of busulfan as a component of a conditioning regimen prior to HSCT in childrenwith Fanconi’s anaemia. Therefore busulfan should be used with caution in this type of patients.

Busulfan has not been studied in patients with hepatic impairment. Since busulfan is mainlymetabolized through the liver, caution should be observed when busulfan is used in patients withpre-existing impairment of liver function, especially in those with severe hepatic impairment.

It is recommended when treating these patients that serum transaminase, alkaline phosphatase, andbilirubin should be monitored regularly 28 days following transplant for early detection ofhepatotoxicity.

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 ofchemotherapy, 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 withbusulfan 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 specificcardiac toxicities related to busulfan. However cardiac function should be monitored regularly inpatients receiving busulfan (see section 4.8).

Occurrence of acute respiratory distress syndrome with subsequent respiratory failure associated withinterstitial pulmonary fibrosis was reported in busulfan studies in one patient who died, although, noclear aetiology was identified. In addition, busulfan might induce pulmonary toxicity that may beadditive to the effects produced by other cytotoxic agents. Therefore, attention should be paid to thispulmonary 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 section4.8).

Seizures have been reported with high dose busulfan treatment. Special caution should be exercisedwhen administering the recommended dose of busulfan to patients with a history of seizures. Patientsshould receive adequate anticonvulsant prophylaxis. In adults and children studies, data with busulfanwere obtained when using concomitant administration of either phenytoin or benzodiazepines forseizure prophylaxis. The effect of those anticonvulsant agents on busulfan pharmacokinetics wasinvestigated 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 humandata, busulfan has been classified by the International Agency for Research on Cancer (IARC) as ahuman carcinogen. The World Health Organisation has concluded that there is a causal relationshipbetween busulfan exposure and cancer. Leukaemia patients treated with busulfan developed manydifferent cytological abnormalities, and some developed carcinomas. Busulfan is thought to beleukemogenic.

Busulfan can impair fertility. Therefore, men treated with busulfan are advised not to father a childduring and up to 6 months after treatment and to seek advice on cryo-conservation of sperm prior totreatment because of the possibility of irreversible infertility due to therapy with busulfan.

Ovarian suppression and amenorrhoea with menopausal symptoms commonly occur inpre-menopausal patients. Busulfan treatment in a pre-adolescent girl prevented the onset of pubertydue to ovarian failure. Impotence, sterility, azoospermia, and testicular atrophy have been reported inmale patients. The solvent dimethylacetamide (DMA) may also impair fertility. DMA decreasesfertility in male and female rodents (see sections 4.6 and 5.3).

Cases of thrombotic microangiopathy after hematopoietic cell transplantation (HCT), including fatalcases, have been reported in high-dose conditioning regimens in which busulfan was administered incombination with another conditioning treatment.

No specific clinical trial was carried out to assess drug-drug interaction between intravenous busulfanand itraconazole or metronidazole. From published studies in adults, administration of itraconazole topatients receiving high-dose busulfan may result in reduced busulfan clearance. Also, there arepublished case reports of increased plasma levels of busulfan after administration of metronidazole.

Patients who are concurrently treated with busulfan and itraconazole or metronidazole should beclosely 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 highlevels of plasma busulfan. Therefore special care is recommended when combining these twocompounds.

In adults, for the BuCy2 regimen it has been reported that the time interval between the last oralbusulfan administration and the first cyclophosphamide administration may influence the developmentof toxicities. A reduced incidence of Hepatic Veno Occlusive Disease (HVOD) and otherregimen-related toxicity have been observed in patients when the lag time between the last dose of oralbusulfan 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 interactionbetween intravenous busulfan and fludarabine.

In paediatric population, for the BuMel regimen it has been reported that the administration ofmelphalan less than 24 hours after the last oral busulfan administration may influence the developmentof toxicities.

Increases in busulfan exposure have been observed at concomitant administration of busulfan anddeferasirox. The mechanism behind the interaction is not fully elucidated. It is recommended toregularly monitor busulfan plasma concentrations and, if necessary, adjust the busulfan dose in patientswho are or have recently been treated with deferasirox.

Paracetamol is described to decrease glutathione levels in blood and tissues, and may therefore decreasebusulfan clearance when used in combination (see section 4.4).

Either phenytoin or benzodiazepines were administered for seizure prophylaxis in patientsparticipating 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 busulfanhas been reported to increase busulfan clearance, due to induction of glutathion-S-transferase whereasno interaction has been reported when benzodiazepines such as diazepam, clonazepam or lorazepamhave 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 onintravenous 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 thesepatients were compared to historical data collected in patients treated with phenytoin. The analysis ofdata through a population pharmacokinetic method indicated no difference on intravenous busulfanclearance between phenytoin and clonazepam based therapy and therefore similar busulfan plasmaexposures were achieved whatever the type of seizure prophylaxis.

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

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

HPCT is contraindicated in pregnant women; therefore, busulfan is contraindicated during pregnancy.

Studies in animals have shown reproductive toxicity (embryo-foetal lethality and malformations) (seesection 5.3)

There are no or limited amount of data from the use of busulfan or DMA in pregnant women. A fewcases of congenital abnormalities have been reported with low-dose oral busulfan, not necessarilyattributable to the active substance, and third trimester exposure may be associated with impairedintrauterine growth.

It is unknown whether busulfan and DMA are excreted in human milk. Because of the potential fortumorigenicity shown for busulfan in human and animal studies, breast-feeding should bediscontinued during treatment with busulfan.

Busulfan and DMA can impair fertility in man or woman. Therefore it is advised not to father childduring the treatment and up to 6 months after treatment and to seek advice on cryo-conservation ofsperm prior to treatment because of the possibility of irreversible infertility (see section 4.4).

Not relevant

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 asexpected 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 ofmorbidity and mortality, especially in allogeneic HPCT.

Myelo-suppression and immuno-suppression were the desired therapeutic effects of the conditioningregimen. Therefore all patients experienced profound cytopenia: leucopenia 96%, thrombocytopenia94%, and anemia 88%. The median time to neutropenia was 4 days for both autologous and allogeneicpatients. The median duration of neutropenia was 6 days and 9 days for autologous and allogeneicpatients.

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-GVHDgrades I-II was 13% (8/61), while the incidence of grade III-IV was 5% (3/61). Acute GVHD was ratedas serious in 3 patients. Chronic GVHD (c-GVHD) was reported if serious or the cause of death, andwas reported as the cause of death in 3 patients.

Infections and infestations39% of patients (40/103) experienced one or more episodes of infection, of which 83% (33/40) wererated 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 andgraded as mild/moderate in 84% and severe in 3%. 47% of patients experienced chills which weremild/moderate in 46% and severe in 1%.

Hepato-biliary disorders15% of SAEs involved liver toxicity. HVOD is a recognized potential complication of conditioningtherapy 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 serumhepatotoxicity were among patients with diagnosed HVOD.

One patient experienced a fatal case of acute respiratory distress syndrome with subsequent respiratoryfailure associated with interstitial pulmonary fibrosis in the busulfan studies.

Adverse reactions information are derived from the clinical study in paediatrics (n=55). Serioustoxicities involving the hepatic and respiratory systems were considered as expected consequences ofthe conditioning regimen and transplant process.

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 was46.4% (13/28), while the incidence of grade III-IV was 3.6% (1/28). Chronic GVHD was reported onlyif it is the cause of death: one patient died 13 months post-transplant.

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 andallogenic 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 ofadverse reactions reported in published data from clinical trials in RIC regimen. In these studies, a totalof 1574 patients received FB as a reduced intensity conditioning (RIC) regimen prior to haematopoieticprogenitor cell transplantation.

Myelo-suppression and immuno-suppression were the desired therapeutic effects of the conditioningregimen and consequently were not considered undesirable effects.

The occurrence of infectious episodes or reactivation of opportunistic infectious agents mainly reflectsthe 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%].

The highest frequency of nausea and vomiting was 59.1% and the highest frequency of stomatitis was11%.

It has been suggested that conditioning regimens containing fludarabine were associated with higherincidence of opportunistic infections after transplantation because of the immunosuppressive effect offludarabine. Late haemorrhagic cystitis occurring 2 weeks post-transplant are likely related to viralinfection/reactivation. Haemorrhagic cystitis including haemorrhagic cystitis induced by viralinfection 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 wasconsidered as deaths that could be attributable to secondary side effects after HPCT and not related tothe relapse/progression of the underlying haematological malignancies.

The most frequent causes of reported TRM/NRMs were infection/sepsis, GVHD, pulmonary disordersand 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 frompost-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 listedbelow, by system organ class and by frequency. Within each frequency grouping, adverse reactions arepresented in order of decreasing seriousness.

System organ Very common Common Uncommon Not knownclass

Infections and Rhinitisinfestations Pharyngitis

Blood and Neutropenialymphatic system Thrombocytopeniadisorders Febrile neutropenia

Pancytopenia

Immune system Allergic reactiondisorders

Endocrine Hypogonadism**disorders

Metabolism and Anorexia Hyponatraemianutrition Hyperglycaemiadisorders Hypocalcaemia

Hypomagnesaemia

Hypophosphatemia

System organ Very common Common Uncommon Not knownclass

Psychiatric Anxiety Confusion Deliriumdisorders Depression Nervousness

Insomnia Hallucination

Agitation

Nervous system Headache Seizuredisorders Dizziness Encephalopathy

Cerebralhaemorrhage

Eye disorders Cataract Cornealthinning

Lensdisorders***

Cardiac-disorders Tachycardia Arrhythmia Ventricular

Atrial fibrillation Extrasystoles

Cardiomegaly Bradycardia

Pericardialeffusion

Pericarditis

Vascular Hypertension Femoraldisorders Hypotension artery

Thrombosis thrombosis

Vasodilatation Capillary leak

Respiratory Dyspnoea Hyperventilation sHyynpdorxomia e Interstitial lungthoracic and Epistaxis Respiratory disease**mediastinal Cough failuredisorders Hiccup Alveolarhaemorrhages

Asthma

Atelectasis

Pleural effusion

Gastrointestinal Stomatitis Haematemesis Gastrointestinal Toothdisorders Diarrhoea Ileus haemorrhage hypoplasia**

Abdominal pain Oesophagitis

Nausea

Dyspepsia

Ascites

Anus discomfort

Hepato-biliary Hepatomegaly Veno occlusivedisorders Jaundice liver disease *

Skin and Rash Skinsubcutaneous Pruritis desquamationtissue disorders Alopecia Erythema

Pigmentationdisorder

Musculoskeletal Myalgiaand connective Back paintissue disorders Arthralgia

Renal and urinary Dysuria Haematuriadisorders Oligurea Moderate renalinsufficiency

System organ Very common Common Uncommon Not knownclass

Reproductive Prematuresystem and breast menopausedisorders Ovarian failure**

General disorders Astheniaand Chillsadministration Feversite conditions Chest pain

Oedema

Oedema general

Pain orinflammation atinjection site

Mucositis

Investigations Transaminases Bun increaseincreased Decrease ejection

Bilirubin increased fraction

GGT increased

Alkalinephosphatasesincreased

Weight increased

Abnormal breathsounds

Creatinine elevated

*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 tothe highest incidence observed in published clinical trials in RIC regimen for which the populationtreated with FB was clearly identified, whatever the schedules of busulfan administrations andendpoints. Adverse reactions reported as more than an isolated case are listed below, by system organclass and by frequency.

System organ class Very common Common Not known*

Infections and Viral infection Invasive fungal Brain abscessinfestations CMV reactivation infection Cellulitis

EBV reactivation Pulmonary infection Sepsis

Bacterial infection

Blood and lymphatic Febrile neutropeniasystem disorders

Metabolism and Hypoalbuminaemia Anorexianutrition disorders Electrolyte disturbance

System organ class Very common Common Not known*

Psychiatric disorders Agitation

Confusional state

Hallucination

Nervous system Headache Cerebraldisorders Nervous system haemorrhagedisorders [Not Encephalo-pathy

Elsewhere

Classified]

Cardiac disorders Atrial fibrillation

Vascular disorders Hyper-tension

Respiratory thoracic Pulmonary Respiratory failureand mediastinal haemorrhagedisorders

Gastro-intestinal Nausea Gastro-intestinaldisorders Vomiting haemorrhage

Diarrhoea Tooth hypoplasia*

Stomatitis

Hepato-biliary Veno occlusive liver disease Jaundicedisorders Liver disorders

Skin and subcutaneous Rashtissue disorders

Renal and urinary Haemorrhagic cystitis** Renal disorder Oliguriadisorders

General disorders and Astheniaadministration site Mucositis Oedemaconditions Pain

Investigations Transaminases increased Creatinine elevated Blood lactate

Bilirubine increased dehydrogenase

Alkaline phosphatases increased increased

Blood uric acidincreased

Blood urea increased

GGT increased

Weight increased

* reported in post-marketing experience

** include haemorrhagic cystitis induced by viral infection

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 reportingsystem listed in Appendix V.

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 busulfanwould constitute an overdose of busulfan. The haematologic status should be closely monitored andvigorous supportive measures instituted as medically indicated.

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

It must be considered that overdose of busulfan will also increase exposure to DMA. In human theprincipal toxic effects were hepatotoxicity and central nervous system (CNS) effects. CNS changesprecede 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

Pharmacotherapeutic group: Antineoplastic agents, alkylating agents, alkyl sulfonates, ATC code:

L01AB01.

Busulfan is a potent cytotoxic agent and a bifunctional alkylating agent. In aqueous media, release ofthe methanesulphonate groups produces carbonium ions which can alkylate DNA, thought to be animportant biological mechanism for its cytotoxic effect.

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

Two prospective, single arm, open-label, uncontrolled phase II studies were conducted in patients withhaematological disease, the majority of whom had advanced disease.

Diseases included were acute leukaemia past first remission, in first or subsequent relapse, in firstremission (high risk), or induction failures; chronic melogenous leukaemia in chronic or advancedphase; primary refractory or resistant relapsed Hodgkin’s disease or non-Hodgkin’s lymphoma, andmyelodysplastic syndrome.

Patients received doses of 0.8 mg/kg busulfan every 6 hours infusion for a total 16 doses followed bycyclophosphamide at 60 mg/kg once per day for two days (BuCy2 regimen).

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

In both studies, all patients received a 16/16 dose regimen of busulfan. No patients were discontinuedfrom 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 noprimary nor secondary graft rejection. Overall mortality and non-relapse mortality at more than100 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.

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 10-15days) 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 throughthe 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 toallogeneic HPCT derives from the literature review of 7 published studies involving 731 patients withmyeloid and lymphoid malignancies reporting the use of intravenous busulfan infused once dailyinstead of four doses per day.

Patients received a conditioning regimen based on the administration of fludarabine immediatelyfollowed by single daily dose of 3.2 mg/kg busulfan over 2 or 3 consecutive days. Total dose ofbusulfan per patient was between 6.4 mg/kg and 9.6 mg/kg.

The FB combination allowed sufficient myeloablation modulated by the intensity of conditioningregimen through the variation of number of days of busulfan infusion. Fast and complete engraftmentrates in 80-100% of patients were reported in the majority of studies. A majority of publicationsreported a complete donor chimerism at day+30 for 90-100% of patients. The long-term outcomesconfirmed that the efficacy was maintained without unexpected effects.

Data from a recently completed prospective multicentre phase 2 study including 80 patients, aged 18 to65 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 ofneutrophil recovery at day 28 was 98.8% (95%CI, 85.7-99.9%). Platelet engraftment occurred at amedian 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 NRMwas 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).

The pharmacokinetics of busulfan has been investigated. The information presented onbiotransformation and elimination is based on oral busulfan.

Pharmacokinetics in adults

The pharmacokinetics of intravenous busulfan was studied in 124 evaluable patients following a2-hour intravenous infusion for a total of 16 doses over four days. Immediate and completeavailability of the dose is obtained after intravenous infusion of busulfan. Similar blood exposurewas observed when comparing plasma concentrations in adult patients receiving oral and intravenousbusulfan at 1 mg/kg and 0.8 mg/kg respectively. Low inter (CV=21%) and intra (CV=12%) patientvariability on busulfan exposure was demonstrated through a population pharmacokinetic analysis,performed on 102 patients.

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 theseconcentrations are probably insufficient for anti-neoplastic activity.

Reversible binding to plasma proteins was around 7% while irreversible binding, primarily to albumin,was about 32%.

Busulfan is metabolised mainly through conjugation with glutathione (spontaneous andglutathione-S-transferase mediated). The glutathione conjugate is then further metabolised in the liverby oxidation. None of the metabolites is thought to contribute significantly to either efficacy ortoxicity.

Total clearance in plasma ranged 2.25 - 2.74 ml/minute/kg. The terminal half-life ranged from 2.8 to3.9 hours.

Approximately 30% of the administered dose is excreted into the urine over 48 hours with 1% asunchanged busulfan. Elimination in faeces is negligible. Irreversible protein binding may explain theincomplete recovery. Contribution of long-lasting metabolites is not excluded.

The dose proportional increase of busulfan exposure was demonstrated following intravenous busulfanup to 1 mg/kg.

Compared to the four times a day regimen, the once-daily regimen is characterized by a higher peakconcentration, no drug accumulation and a wash out period (without circulating busulfanconcentration) between consecutive administrations. The review of the literature allows a comparisonof PK series performed either within the same study or between studies and demonstrated unchangeddose-independent PK parameters regardless the dosage or the schedule of administration. It seems thatthe 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 bothinter-and intrapatient variability. As a result, the control of intravenous busulfan AUC within thetherapeutic windows is not modified and a similar targeting performance between the two scheduleswas illustrated.

The literature on busulfan suggests a therapeutic AUC window between 900 and 1500 µmol/L.minuteper administration (equivalent to a daily exposure between 3600 and 6000 µmol/L.minute). Duringclinical 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 thetargeted therapeutic window (900 - 1500 µmol/L.minute). Similar targeting rate is achieved within thedaily exposure of 3600 - 6000 µmol/L.minute following the administration of intravenous busulfan3.2 mg/kg once daily.

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 inpatients over 60 years.

A continuous variation of clearance ranging from 2.52 to 3.97 ml/minute/kg has been established inchildren from < 6 months up to 17 years old. The terminal half life ranged from 2.24 to 2.5 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 adequatelydistributed with respect to bodyweight (3.5 to 62.5 kg), biological and diseases (malignant andnon-malignant) characteristics, thus representative of the high heterogeneity of children undergoing

HPCT. This study demonstrated that bodyweight was the predominant covariate to explain the busulfanpharmacokinetic 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% ofchildren ≥ 9kg in achieving the therapeutic window (900 - 1500 µmol/L.minute). However a highervariability was observed in children < 9 kg leading to 60% of children achieving the therapeuticwindow (900 - 1500 µmol/L.minute). For the 40% of children < 9 kg outside the target, the AUCwas 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 theplasma concentrations of busulfan (therapeutic drug monitoring) for dose-adjustment may improvethe busulfan targeting performance, especially in extremely young children and neonates.

The successful engraftment achieved in all patients during phase II trials suggests the appropriatenessof the targeted AUCs. Occurrence of VOD was not related to overexposure. PK/PD relationship wasobserved between stomatitis and AUCs in autologous patients and between bilirubin increase and

AUCs in a combined autologous and allogeneic patient analysis.

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

Drosophila melanogaster and barley. Busulfan induced chromosomal aberrations in vitro (rodent andhuman cell) and in vivo (rodents and humans). Various chromosome aberrations have been observed incells from patients receiving oral busulfan.

Busulfan belongs to a class of substances which are potentially carcinogenic based on their mechanismof action. On the basis of human data, busulfan has been classified by the IARC as a humancarcinogen. WHO has concluded that there is a causal relationship between busulfan exposure andcancer. The available data in animals support the carcinogenic potential of busulfan. Intravenousadministration of busulfan to mice significantly increased the incidences of thymic and ovariantumours.

Busulfan is a teratogen in rats, mice and rabbits. Malformations and anomalies included significantalterations in the musculoskeletal system, body weight gain, and size. In pregnant rats, busulfanproduced sterility in both male and female offspring due to the absence of germinal cells in testes andovaries. 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 clinicalenzymes followed by histopatological changes in the hepatocytes. Higher doses can produce hepaticnecrosis 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 causedsignificant developmental anomalies. The malformations included serious heart and/or major vesselsanomalies: a common truncus arteriosis and no ductus arteriosis, coarctation of the pulmonary trunkand the pulmonary arteries, intraventricular defects of the heart. Other frequent anomalies includedcleft palate, anasarca and skeletal anomalies of the vertebrae and ribs. DMA decreases fertility in maleand female rodents. A single s.c. dose of 2.2 g/kg administered on gestation day 4 terminatedpregnancy in 100% of tested hamster. In rats, a DMA daily dose of 450 mg/kg given to rats for ninedays caused inactive spermatogenesis.

6 PHARMACEUTICAL PARTICULARS

Dimethylacetamide

Macrogol 400

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts except those mentioned in section 6.6.

Due to incompatibility, do not use any infusion components containing polycarbonate with busulfan.

Vials2 years.

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 theuser and would normally not be longer than the above-mentioned conditions when dilution has takenplace in controlled and validated aseptic conditions.

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.

10 ml of concentrate for solution for infusion in clear colourless glass vials (type I) with teflon facedrubber stopper and sealed with aluminium flip-off seal. Each vial is sleeved with shrinkable plasticfilm.

Pack size1 pack containing 8 vials (8 cartons of 1 vial).

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 verticallaminar flow safety hood.

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

- The use of gloves and protective clothing is recommended.

- If the concentrate or diluted busulfan solution contacts the skin or mucosa, wash them thoroughlywith 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 the Busulfan Fresenius Kabi ensuring thefinal 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 diluted6 (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 transfertechniques. 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) whichalready contains the calculated amount of the selected diluent. Busulfan Fresenius Kabimust 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 containsodium 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.

Prior to and following each infusion, flush the indwelling catheter line with approximately 5 ml ofsodium 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 ofbusulfan has not been tested and is not recommended.

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

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

Busulfan must not be infused concomitantly with another intravenous solution.

No infusion components containing polycarbonate must 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 ofin accordance with local requirements for cytotoxic medicinal products.

Fresenius Kabi Deutschland GmbH

Else-Kröner-Straße 1,61352 Bad Homburg v.d.Höhe

Germany

EU/1/14/951/001

Date of first authorisation: 22 September 2014

Date of latest renewal: 20 June 2019

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

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