Pierre Fabre Limited

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.

Busilvex is administered prior the conventional haematopoietic progenitor cell transplantation (HPCT) to above 'Dosage in adults'
Change of text in section relating to obese patients:  

In paediatric patients

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.
Section 4.3 - Removal of word: lactation
Section 4.4 - Clarification of abbreviation: (G-CSF)
Section 4.5 - Change of wording: Published studies in adults described that ketobemidone (analgesic) might be associated with high levels of plasma busulfan. Therefore special care is recommended when combining these two compounds.
Section 4.6 - Change of wording:  There are no adequate data from the use of either busulfan or DMA in pregnant woman. 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.
Removal of text: Patient who are taking Busilvex would not breast feeding.
Addition of section on Fertility: 
Fertility

Busulfan and DMA can impair fertility in man or woman. Therefore it is advised not to father child during the treament and up to 6 months after treatment and to seek advice on cryo-conservation of sperm prior to treatment because of the possibility of irreversible infertility (see section 4.4).
Section 4.8 - Change of wording from Undesirable effects in adults to Adverse events
Change of wording from new born infants, children and adolescents to paediatric patients
Addition of wording:

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. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100,< 1/10), uncommon (≥ 1/1,000, < 1/100).
A number of changes made to table:

Section 6.4 - Change to storage information: Storein a refrigerator (2 ° C-8 °C).
Section 6.6 - Change to wording: 

Preparation of Busilvex

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

Change to wording:

Preparation of the solution for infusion

 Busilvex must  be prepared by a healthcare professional using sterile transfer techniques.Using a non polycarbonate syringe fitted with a needle:
-          the calculated volume of Busilvex must be removed from the vial.

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

The diluted solution must be mixed thoroughly by inverting several times

Change to wording:

Instructions for use

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

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

The entire prescribed Busilvex dose should be delivered over two hours.

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

Busilvex must not be infused concomitantly with another intravenous solution.

Polycarbonate syringes must not be used with Busilvex.

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

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

Sections 9 and 10:  Change of date