Busilvex 6 mg/ml concentrate for solution for infusion

Changes made to update the MAH address (section 7) and revision date (Section 10) 

Changes to Section 6 MAH address, manufacturer address and updated revision date

Section 2 - What you need to know before you use Busilvex

Updated to include interactions with Deferasirox

Section 4 - Possible side effects

Updated to reflect the current template

Section 6 - Contents of the pack and other information

Date of Revision of the Text

Section 4.5 - Interaction with other medicinal products and other forms of interaction

Updated to include interactions with Deferasirox

Section 4.8 - Reporting of suspected adverse reactions

Updated to reflect the current template

Section 5.2 - Pharmacokinetic properties

Minor update to values in the Paediatric population

Section 6.2 – Incompatibilities and Section 6.6 - Special precautions for disposal and other handling

Updates to incompatibility concerning polycarbonate infusion components

Section 10 – Date of Revision of the Text

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

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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.

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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.

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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.

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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.  

* 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).

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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).

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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'.

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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:

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.

*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.