BUSILVEX Concentrate for solution Ref.[6718] Active ingredients: Busulfan

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

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

Posology

Busilvex in combination with cyclophosphamide or melphalan

In adults

The recommended dose and schedule of administration is:

• 0.8 mg/kg body weight (BW) of busulfan as a two-hour infusion every 6 hours over 4 consecutive days for a total of 16 doses,
• followed by cyclophosphamide at 60 mg/kg/day over 2 days initiated for at least 24 hours following the 16th dose of Busilvex (see section 4.5).

Paediatric population (0 to 17 years)

The recommended dose of Busilvex is as follows:

followed by:

• 4 cycles of 50 mg/kg body weight (BW) cyclophosphamide (BuCy4) or
• one administration of 140 mg/m² melphalan (BuMel) initiated for at least 24 hours following the 16th dose of Busilvex.(see section 4.5).

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 haematopoietic progenitor cell transplantation (HPCT).

Elderly patients

Patients older than 50 years of age (n=23) have been successfully treated with Busilvex without doseadjustment. However, for the safe use of Busilvex in patients older than 60 years only limited information is available. Same dose (see section 5.2) for elderly patients as for adults (<50 years old) should be used.

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.

Obese patients

In adults

For obese patients, dosing based on adjusted ideal body weight (AIBW) should be considered.

Ideal body weight (IBW) is calculated as follows:

IBW men (kg) = 50 + 0.91x (height in cm-152);

IBW women (kg) = 45 + 0.91x (height in cm-152).

Adjusted ideal body weight (AIBW) is calculated as follows:

AIBW= IBW+0.25x (actual body weight – IBW).

In paediatric population

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

Patients with renal impairment

Studies in renally impaired patients have not been conducted, however, as busulfan is moderately excreted in the urine, dose modification is not recommended in these patients. However, caution is recommended (see sections 4.8 and 5.2).

Patients with hepatic impairment

Busilvex as well as busulfan has not been studied in patients with hepatic impairment. Caution is recommended, particularly in those patients with severe hepatic impairment (see section 4.4).

Method of administration

Precautions to be taken before handling or administering the medicinal product

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

For instructions on dilution of the medicinal product before administration, see section 6.6.

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 paediatric studies, patients received either phenytoin or benzodiazepines as seizure prophylaxis treatment. (see sections 4.4 and 4.5).

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

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 Busilvex other than haematopoietic progenitor cell transplantation. In the absence of haematopoietic progenitor cell transplantation, the recommended dose 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.

It must be considered that overdose of Busilvex will also increase exposure to DMA. In human the principal toxic effects were hepatotoxicity and central nervous system (CNS) effects. CNS changes precede any of the more severe side effects. No specific antidote for DMA overdose is known. In case of overdose, management would include general supportive care.

Vials: 3 years.

Diluted solution: Chemical and physical in-use stability after dilution in glucose 5% or sodium chloride 9 mg/ml (0.9%) solution for injection has been demonstrated for:

• 8 hours (including infusion time) after dilution when stored at 20°C-5°C
• 12 hours after dilution when stored at 2°C-8°C followed by 3 hours stored at 20°C-5°C (including infusion time).

From a microbiological point of view, the product should be used immediately after dilution. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than the above mentioned conditions when dilution has taken place in controlled and validated aseptic conditions.

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 glass vials (type I) with a butyl rubber stopper covered by a purple flip-off aluminium seal cap.

Multipack containing 8 (2 packs of 4) vials.

Preparation of Busilvex

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

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

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

• The use of gloves and protective clothing is recommended.
• If Busilvex or diluted Busilvex solution contacts the skin or mucosa, wash them thoroughly with water immediately.

Calculation of the quantity of Busilvex to be diluted and of the diluent

Busilvex 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 Busilvex ensuring the final concentration of busulfan remains at approximately 0.5 mg/ml. By example:

The amount of Busilvex and diluent to be administered would be calculated as follows: for a patient with a Y kg body weight:

Quantity of Busilvex:

Y (kg) x D (mg/kg) / 6 (mg/ml) = A ml of Busilvex to be diluted

Y: body weight of the patient in kg
D: dose of Busilvex (see section 4.2)

Quantity of diluent:

(A ml Busilvex) x (10) = B ml of diluent

To prepare the final solution for infusion, add (A) ml of Busilvex 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

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.

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

Diluted Busilvex is a clear colourless solution.

Instructions for use

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

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

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

Small volumes may be administered over 2 hours using electric syringes. In this case infusion sets with minimal priming space should be used (i.e. 0.3-0.6 ml), primed with medicinal product solution prior to beginning the actual 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 medicinal product or waste material should be disposed of in accordance with local requirements for cytotoxic medicinal products.