$0Section 4.4: Special warnings and precautions for use$0 $0$0 $0Addition of “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.”$0 $0$0 $0Section 4.5: Interaction with other medicinal products and other forms of interaction$0 $0$0 $0Addition of the interaction with Metronidazole.$0 $0$0 $0Section 4.8:  Undesirable effects$0 $0$0 $0Addition of Tooth hypoplasia in the Gastrointestinal disorders with the frequency of “Not known.”$0

The address has been updated to:

 

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie

Text inserted is highlighted in blue, text deleted is highlighted in red.

 

New indication added in section:

 

4.1        Therapeutic indications

 

Busilvex 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.

 

Busilvex 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.

 

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

 

 

Updated text in section:

 

4.2        Posology and method of administration

 

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

 

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

 

Posology

Busilvex in combination with cyclophosphamide or melphalan

 

Updated text:

 

Busilvex 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 conventional haematopoietic progenitor cell transplantation (HPCT).

 

 

Busilvex 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.

-    Busilvex 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.

 

 

Text inserted in section:

 

4.5   Interaction with other medicinal products and other forms of interaction

 

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.

 

Updated section:

 

4.8   Undesirable effects

 

Summary of the safety profile

 

Busilvex in combination with cyclophosphamide or melphalan

 

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: leucopenialeukopenia 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.

 

Busilvex in combination with fludarabine (FB)

In adults

The safety profile of Busilvex combined with fludarabine (FB) has been examined through a review of adverse events reported in published data from clinical trials in RIC regimen. In these studies, a total of 1574 patients received FB as a reduced intensity conditioning (RIC) regimen prior to haematopoietic progenitor cell transplantation.

 

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

 

Infections and infestations:

The occurrence of infectious episodes or reactivation of opportunistic infectious agents mainly reflects the immune status of the patient receiving a conditioning regimen.

The most frequent infectious adverse reactions were Cytomegalovirus (CMV) reactivation [range: 30.7% - 80.0%], Epstein-Barr Virus (EBV) reactivation [range: 2.3% - 61%], bacterial infections [range: 32.0% - 38.9%] and viral infections [range: 1.3% - 17.2%].

 

Gastrointestinal disorders:

The highest frequency of nausea and vomiting was 59.1% and  the highest frequency of stomatitis was 11%.

 

Renal and urinary disorders:

It has been suggested that conditioning regimens containing fludarabine were associated with higher incidence of opportunistic infections after transplantation because of the immunosuppressive effect of fludarabine. Late haemorrhagic cystitis occurring 2 weeks post-transplant are likely related to viral infection / reactivation. Haemorrhagic cystitis including haemorrhagic cystitis induced by viral infection was reported in a range between 16% and 18.1%.

 

Hepato-biliary disorders:

VOD was reported with a range between 3.9% and 15.4%.

 

The treatment-related mortality/non-relapse mortality (TRM/NRM) reported until day+100 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 summaries of adverse reactions

Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100) or not known (cannot be estimated from the available data). Undesirable effects coming from post-marketing survey have been implemented in the tables with the incidence “not known”.

 

Busilvex in combination with cyclophosphamide or melphalan

Adverse reactions reported both in adults and paediatric patients as more than an isolated case are listed below, by system organ class and by frequency. Within each frequency grouping, adverse events are presented in order of decreasing seriousness.

 

Text and table inserted below existing table:

 

Busilvex 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
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
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

 

 

Updated section:

 

5.1   Pharmacodynamic properties

 

Clinical efficacy and safety

Busilvex in combination with cyclophosphamide

In adults

Documentation on of the safety and efficacy of Busilvex 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).

 

Inserted text:

 

Paediatric population

Documentation of the safety and efficacy of Busilvex 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.

 

Busilvex in combination with fludarabine (FB)

In adults

Documentation on the safety and efficacy of Busilvex 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.

 

Updated text:

 

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 Busilvex) 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).

 

Updated section:

 

5.2    Pharmacokinetic properties

 

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

 

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).for AUC. 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.

 

 

Updated section:

 

6.6  Special precautions for disposal and other handling

 

Instructions for use

 

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

 

 

Updated section:

 

10        DATE OF REVISION OF THE TEXT

 

08/2014

 

4.1   Therapeutic indications
'Busilvex 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'.

Has been removed

4.1: Therapeutic indication :

“Busilvex 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.”

The text above has been added to the section 4.1 Therapeutic indication.

In section 4.8 (Undesirable effects) the table has been updated in system organ class -  Respiratory thoracic and mediastinal disorders, Interstitial lung disease** has been added in the not known column.
(** reported in post marketing with IV busulfan)

In section 4.8 (Undesirable effects - how to report a side effect)
Added:
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
United Kingdom
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard
Ireland
IMB Pharmacovigilance
Earlsfort Terrace
IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.imb.ie
e-mail: imbpharmacovigilance@imb.ie

In section 10
Date of revision of the text has been updated to 05/2014

The shelf life has been extended from 2 years to 3 years.

In section 4.8 (undesirable effects), hypogonadism has been added to the endocrine disorders section.

$02.QUALITATIVE AND QUANTITATIVE COMPOSITION$0$0 $0$0One ml of concentrate contains6 mg of busulfan (60 mg in 10 ml).$0$0After dilution: 1 ml ofsolution contains 0.5 mg of busulfan$0$0For a the fulllist of excipients see section 6.1$0$0 $0$03.PHARMACEUTICALFORM$0$04.CLINICALPARTICULARS$0$04.1Therapeutic indications$0$04.2Posology and method of administration$0$0 $0$0Renallyimpaired patient: Patientswith renal impairment$0$0Studies in renally impairedpatients have not been conducted, however, as busulfan is moderately excretedin the urine, dose modification is not recommended in these patients.$0$0However, caution is recommended(see sections 4.8 and 5.2).$0$0 $0$0Patientswith hepatic impairment$0$0Hepaticallyimpaired patient:$0$0Busilvex as well as busulfan hasnot been studied in patients with hepatic impairment.$0$0Caution is recommended,particularly in those patients with severe hepatic impairment (see section4.4).$0$0 $0$0Elderly patients:$0$0Patients older than 50 years ofage (n=23) have been successfully treated with Busilvex without dose-adjustment. However, for the safe use of Busilvexin patients older than 60 years only limited information is available. Samedose (see section 5.2) for elderly as for adults (< 50 years old)should be used.$0$0 $0$0Method of administration$0$0Precautions to be taken before handling oradministering the medicinal product$0$0Busilvex must be diluted prior toadministration (see section 6.6). A finalconcentration of approximately 0.5 mg/ml busulfan should be achieved.Busilvex should be administered by intravenous infusion via central venouscatheter.$0$0 $0$0For instructions on dilution ofthe medicinal product before administration, see section 6.6.$0$0 $0$0In adult and paediatricstudies, patients received either phenytoin or benzodiazepines as seizureprophylaxis treatment. (see sections 4.4 and 4.5).$0$0 $0$04.3Contraindications$0$0 $0$0Hypersensitivity to the activesubstance or to any of the excipients listed in section 6.1.$0$0Pregnancy(see section 4.6). $0$0 $0$04.4Special warnings and precautions for use$0$0 $0$0Inchildren < 9 kg,a therapeutic drug monitoring may be justified on a case by case basis, inparticular in extremely young children and neonates (see section 5.2).$0$0 $0$0Hepatic impairment $0$0Busilvex as well as busulfan hasnot been studied in patients with hepatic impairment. Since busulfan is mainlymetabolized through the liver, caution should be observed when Busilvex is usedin patients with pre-existing impairment of liver function, especially in thosewith severe hepatic impairment. It is recommended when treating these patientsthat serum transaminase, alkaline phosphatase, and bilirubin should bemonitored regularly 28 days following transplant for early detection ofhepatotoxicity.$0$0 $0$0Fertility$0$0BFertility: busulfancan impair fertility. Therefore, men treated with Busilvex are advised not tofather a child during and up to 6 months after treatment and to seek advice oncryo-conservation of sperm prior to treatment because of the possibility ofirreversible infertility due to therapy with Busilvex. Ovarian suppression andamenorrhoea with menopausal symptoms commonly occur in pre-menopausal patients.Busulfan treatment in a pre-adolescent girl prevented the onset of puberty dueto ovarian failure. Impotence, sterility, azoospermia, and testicular atrophyhave been reported in male patients. The solvent dimethylacetamide (DMA) mayalso impair fertility. DMA decreases fertility in male and female rodents (seesections 4.6 and 5.3).$0$0 $0$04.5Interaction with other medicinal products andother forms of interaction$0$0 $0$0In paediatric patientspopulation, forthe BuMel regimen it has been reported that the administration of melphalanless than 24 hours after the last oral busulfan administration may influencethe development of toxicities.$0$0 $0$04.6Fertility, pregnancy and lactation$0$04.7Effects on ability to drive and use machines$0$04.8Undesirable effects$0$0 $0$0Respiratory, thoracic andmediastinal disorders :$0$0One patient experienced a fatalcase of acute respiratory distress syndrome with subsequent respiratory failureassociated with interstitial pulmonary fibrosis in the Busilvex studies.$0$0 $0$0Inaddition the literature review reports alterations of cornea and lens of the eye withoral busulfan.$0$0 $0$0Adversereactions reported both in adults and paediatric patients as more than anisolated case are listed below, by system organ class and by frequency. Withineach frequency grouping, adverse events are presented in order of decreasingseriousness. Frequencies are defined as: very common (≥ 1/10), common(≥ 1/100, < 1/10), uncommon(≥ 1/1,000, < 1/100) or notknown (cannotbe estimated from the available data).$0$0 $0$0$0$0$0$0Systemorgan class$0$0$0$0Verycommon$0$0$0$0Common$0$0$0$0Uncommon$0$0$0$0Not known$0$0$0$0$0$0Eye disorders$0$0$0$0 $0$0$0$0 $0$0$0$0 $0$0$0$0Cataract$0$0Cornealthinning $0$0Lensdisorders$0$0***$0$0$0$0$0$0Reproductivesystem and breast disorders$0$0$0$0 $0$0$0$0 $0$0$0$0 $0$0$0$0Prematuremenopause$0$0Ovarianfailure**$0$0$0$0$0$0*venoocclusive liverdisease is more frequent in paediatric population. $0$0**reported in postmarketing with IVbusulfan $0$0***reported in postmarketing with oralbusulfan $0$0 $0$04.9Overdose$0$05PHARMACOLOGICALPROPERTIES$0$05.1Pharmacodynamic properties$0$0 $0$0Mechanismof action$0$0Busulfan is apotent cytotoxic agent and a bifunctional alkylating agent .In aqueous media, release of the methanesulphonate groups produces carboniumions which can alkylate DNA, thought to be an important biological mechanismfor its cytotoxic effect.$0$0 $0$0Clinical trials in adultsefficacyand safety$0$0Documentation of the safety andefficacy of Busilvex in combination with cyclophosphamide in the BuCy2 regimenprior to conventional allogeneic and/or autologous HPCT derive from twoclinical trials (OMC-BUS-4 and OMC-BUS-3).$0$0 $0$0Clinicaltrials in paediatric populationPaediatricpopulation$0$05.2Pharmacokinetic properties$0$0 $0$0MetabolismBiotransformation$0$0Busulfan is metabolised mainlythrough conjugation with glutathione (spontaneous and glutathione-S-transferasemediated). The glutathione conjugate is then further metabolised in the liverby oxidation. None of the metabolites is thought to contribute significantly toeither efficacy or toxicity.$0$0 $0$0PharmacokineticlinearityLinearity  $0$0The dose proportional increase ofbusulfan exposure was demonstrated following intravenous busulfan up to1 mg/kg.$0$0 $0$0Pharmacokinetic/pharmacodynamicrelationships$0$0The literature on busulfansuggests a therapeutic window between 900 and 1500 µmol/LµMol.minute for AUC. During clinicaltrials with intravenous busulfan, 90% of patients AUCs were below the upper AUClimit (1500 µmol/LµMol.minute)and at least 80% were within the targeted therapeutic window (900-1500 µmol/LµMol.minute).$0$0 $0$0Special populations$0$0Hepatic or renal impairment$0$0The effects of renal dysfunctionon intravenous. busulfan disposition have not been assessed.$0$0The effects of hepaticdysfunction on intravenous busulfan disposition have not been assessed.Nevertheless the risk of liver toxicity may be increased in this population.$0$0No age effect on busulfanclearance was evidenced from available intravenous busulfan data in patientsover 60 years.$0$0 $0$0Pharmacokinetics inP paediatric population $0$0A continuousvariation of clearance ranging from 2.49 to 3.92 ml/minute/kg has beenestablished in children from < 6 months up to 17 years old. Theterminal half life ranged from 2.26 to 2.52 h.$0$0Thedosing recommended in section 4.2. allows to achieve a similar AUC whatever thechildren's age, the targeted range of AUCs being the one used for adults.  Interand intra patient variabilities in plasma exposure were lower than 20% and 10%,respectively.$0$0A population pharmacokinetic analysis has been performed in acohort of 205 children adequately distributed with respect to bodyweight (3.5to 62.5 kg), biological and diseases (malignant and non-malignant)characteristics, thus representative of the high heterogeneity of childrenundergoing HPCT. This study demonstrated that bodyweight was the predominantcovariate to explain the busulfan pharmacokinetic variability in children overbody surface area or age. $0$0Therecommended posology for children as detailed in section 4.2 enabled over 70%up to 90% of children ≥ 9 kg in achieving the therapeutic window (900-1500µmol/L.minute). Howevera higher variability was observed in children < 9kg leading to 60% ofchildren achieving the therapeutic window(900-1500 µmol/L.minute). Forthe 40% of children < 9 kg outside the target, the AUC was evenlydistributed either below or above the targeted limits; i.e. 20% each < 900 and > 1500 µmol/L.min following 1mg/kg. In this regard, for children < 9 kg, a monitoring of the plasmaconcentrations of busulfan (therapeutic drug monitoring) for dose-adjustmentmay improve the busulfan targeting performance, especially in extremely youngchildren and neonates. $0$0 $0$05.3Preclinical safety data$0$06PHARMACEUTICALPARTICULARS$0$06.1List of excipients$0$06.2Incompatibilities$0$06.3Shelf life$0$06.4Special precautions for storage$0$0 $0$0Store in a refrigerator (2°C –8°C).$0$0Do not freeze the dilutedsolution.$0$0Forstorage conditions after dilution of the diluted medicinalproduct see section 6.3.$0$0 $0$06.5Nature and contents of container$0$0 $0$010 ml of concentrate forsolution for infusion in clear glass vials (type I) with a butyl rubber stoppercovered by a purple flip-off aluminium seal cap.$0$0Pack size: 8vials per box.Multipack containing 8 (2 packs of 4)vials.$0$0 $0$06.6Special precautions for disposal and otherhandling$0$0 $0$0Any unused medicinal productor waste material should be disposed of in accordance with local requirementsfor cytotoxic medicinal products.$0

SUMMARY OF PRODUCT CHARACTERISTICS

 

4.2         Posology and method of administration

 

DosagePosology in adults

The recommended dosagedose and schedule of administration is:

 

DosagePosology in paediatric patientspopulation  (0 to 17 years)

The recommended dose of Busilvex is as follows:

Actual body weight (kg)	BusulfexBusilvex dose (mg/kg)
< 9	1.0
9 to < 16	1.2
16 to 23	1.1
> 23 to 34	0.95
> 34	0.8

 

Administration

Busilvex must be diluted prior to administration (see section 6.6). A final concentration of approximately 0.5 mg/ml busulfan should be achieved. Busilvex should be administered by intravenous infusion via central venous catheter.

 

Busilvex 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 Busilvex to 24 h after the last dose of Busilvex.

 

In adults all studied patients received phenytoin. There is no experience with other anticonvulsant agents such as benzodiazepines (see sections 4.4 and 4.5).

In children studied patients received either phenytoin or benzodiazepines.

 

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

 

In paediatric patientspopulation

The medicinal product is not recommended  in obese children and adolescents with body mass index Weight (kg)/(m)² > 30 kg/m² until further data become available.

 

Method of administration

Busilvex must be diluted prior to administration (see section 6.6). A final concentration of approximately 0.5 mg/ml busulfan should be achieved. Busilvex should be administered by intravenous infusion via central venous catheter.

 

Busilvex 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 Busilvex to 24 h after the last dose of Busilvex.

 

In adult and pediatric 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 Busilvex and continued on a fixed schedule according to local practice through its administration.

 

4.4  Special warnings and precautions for use

 

In paediatric patientspopulation, absolute neutrophil counts < 0.5x10⁹/l at a median of 3 days post transplant occurred in 100% of patients and lasted 5 and 18.5 days in autologous and allogeneic transplant respectively. In children, thrombocytopenia (< 25x10⁹/l or requiring platelet transfusion) occurred in 100% of patients. Anaemia (haemoglobin< 8.0 g/dl) occurred in 100% of patients.

 

Seizures have been reported with high dose busulfan treatment. Special caution should be exercised when administering the recommended dose of Busilvex to patients with a history of seizures. Patients should receive adequate anti-convulsant prophylaxis. In adults, all and children studies, data with Busilvex were obtained when using concomitant administration of either phenytoin. There are no data available on the use of other anticonvulsant agents such as  or benzodiazepines. Thus, the for seizure prophylaxis. The effect of those anticonvulsant agents (other than phenytoin) on busulfan pharmacokinetics is not known.was investigated in a phase II study. (see sections 4.2 and section 4.5 ).).

In paediatric patients, data with Busilvex were obtained using benzodiazepines or phenytoin.

 

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 AssociationOrganisation 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.

 

4.5  Interaction with other medicinal products and other forms of interaction

 

Phenytoin Either phenytoin or benzodiazepines were administered for seizure prophylaxis in all patients in 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 Busilvex data. A phase II clinical trial was performed to evaluate the influence of seizure prophylaxis treatment on intravenous busulfan pharmacokinetics. In this study, 24 adult patients received clonazepam (0.025-0.03 mg/kg/day as IV continuous infusions) as anticonvulsant therapy and the PK data of these patients were compared to historical data collected in patients treated with phenytoin. The analysis of data through a population pharmacokinetic method indicated no difference on intravenous busulfan clearance between phenytoin and clonazepam based therapy and therefore similar busulfan plasma exposures were achieved whatever the type of seizure prophylaxis.

 

 

4.6  PregnancyFertility, pregnancy and lactation

 

Pregnancy

HPCT is contraindicated in pregnant women ; therefore, Busilvex is contraindicated during pregnancy. Busulfan has caused Studies in animals have shown reproductive toxicity (embryofoetal lethality and malformationsin pre-clinical studies.). (see section 5.3)

 

There are no adequate or limited amount of data from the use of either busulfan or DMA in pregnant woman.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.

 

Lactation

Breastfeeding

It is not 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 at the start of therapyduring treatment with Busulfan.

 

4.8  Undesirable effects

 

Averse events Adverse reactions in adults

Adverse events information is derived from two clinical trials (n=103) of Busilvex.

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 the lymphatic system disorders:

Myelo-suppression and immuno-suppression were the desired therapeutic effects of the conditioning regimen. Therefore all patients experienced profound cytopenia: leukopenia 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.

 

Adverse eventsreactions in paediatric patientspopulation

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

 

 

 

System organ class	Very common	Common	Uncommon
Hepato-biliary disorders	Hepatomegaly Jaundice	Veno occlusive liver disease *

*venoocclusive liver disease is more frequent in paediatric population.

 

4.9  Overdose

 

There is no known antidote to Busilvex other than haematopoietic progenitor cell transplantation. In the absence of haematopoietic progenitor cell transplantation, the recommended dosagedose of Busilvex 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.

 

 

5.1  Pharmacodynamic properties

 

Clinical trials in paediatric patientspopulation

Documentation of the safety and efficacy of Busilvex 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.

5.2  Pharmacokinetic properties

 

Pharmacokinetics in paediatric patientspopulation

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.

The dosing recommended in section 4.2. allows to achieve a similar AUC whatever the children's age, the targeted range of AUCs being the one used for adults. Inter and intra patient variabilities in plasma exposure were lower than 20% and 10%, respectively.

 

 

6.4  Special precautions for storage

 

StoreStore in a refrigerator (2 ° °C- – 8 °C).

Do not freeze the diluted solution.

For storage conditions of the diluted medicinal product see section 6.3.