Pharmaceutical particulars : מידע רוקחי

6       PHARMACEUTICAL PARTICULARS


6.1     LIST OF EXCIPIENTS

The excipients are polyethylene glycol 400 (macrogol 400) and dimethylacetamide (DMA).
The drug product Busulfex is intended for dilution with 0.9% sodium chloride solution for injection or 5% dextrose solution for injection.

6.2     INCOMPATIBILITIES

In the absence of compatibility studies, Busulfex must not be mixed with other medicinal products except those mentioned in Section 4.2 DOSE AND METHOD OF
ADMINISTRATION.

6.3     SHELF LIFE

The expiry date of the product is indicated on the packaging materials.
6.4     SPECIAL PRECAUTIONS FOR STORAGE

Unopened vials of Busulfex Injection must be stored at 2°-8°C in a refrigerator (Do not freeze).

Busulfex diluted in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP is stable at room temperature (25°C) for up to 8 hours but the infusion must be completed within that time.
Busulfex diluted in 0.9% Sodium Chloride Injection, USP is stable at refrigerated conditions (2°-8°C) for up to 12 hours but the infusion must be completed within that time.

Freezing of diluted preparations of Busulfex is not recommended.

6.5     NATURE AND CONTENTS OF CONTAINER
Busulfex (busulfan) Injection is supplied as a sterile solution in 10 mL single-use clear glass vials each containing 60 mg of busulfan at a concentration of 6 mg/mL for intravenous use.
Busulfex is provided in packages of one or eight clear Type I glass vials.
Not all pack sizes may be marketed.

6.6    SPECIAL PRECAUTIONS FOR DISPOSAL AND OTHER HANDLING OF THE PRODUCT 
Any unused product or waste should be disposed of in accordance with local requirements for cytotoxic drugs.


Instruction for handling and disposal
Procedures for proper handling and disposal of anticancer drugs 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 Busulfex solution:

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

Calculation of the quantity of Busulfex to be diluted and of the diluent 
Busulfex must be diluted prior to use with either sodium chloride (0.9%) solution for injection or dextrose (5%) solution for injection. The quantity of the diluent must be 10 times the volume of Busulfex ensuring the final concentration of busulfan remains at approximately 0.5 mg/mL.

For example, the amount of Busulfex and diluent to be administered would be calculated as follows for a patient with a Y kg body weight receiving Z mg/kg busulfan: • Quantity of Busulfex:

Y (kg) x Z (mg/kg)
6 (mg/mL)                = A mL of Busulfex to be diluted

Y: body weight of the patient in kg
Z: dose on a mg/kg basis
•   Quantity of diluent:

(A mL Busulfex) x (10) = B mL of diluent

To prepare the final solution for infusion, add (A) mL of Busulfex to (B) mL of diluent (sodium chloride 9 mg/mL (0.9%) solution for injection or dextrose solution for injection 5%).

Intravenous Injection

1) 0.9% Sodium Chloride Injection USP
Vial Size Volume of Diluent to             Approximate Available        Nominal (mL)     be Added (mL) (for a            Volume (mL) (for a 70   Concentration per mL 70 kg patient)                   kg patient)
10                93                            102                     0.5 mg 
2) 5% Dextrose Injection, USP
Vial Size Volume of Diluent to             Approximate Available         Nominal (mL)       be Added (mL) (for a          Volume (mL) (for a 70    Concentration per mL 70 kg patient)                 kg patient)
10                 93                           102                     0.5 mg 
By way of example, for a 70 kg patient, the amount of drug to be administered would be calculated as follows:

(70 kg patient) × (0.8 mg/kg) / (6 mg/mL) = 9.3 mL Busulfex (56 mg total dose).
To prepare the final solution for infusion, add 9.3 mL of Busulfex to 93 mL of diluent (normal saline or D5W) as calculated below:
(9.3 mL Busulfex) × (10) = 93 mL of either diluent plus the 9.3 mL of Busulfex to yield a final concentration of busulfan of 0.54 mg/mL (9.3 mL × 6 mg/mL / 102.3 mL = 0.54 mg/mL).

Preparation of the solution for infusion

Due to incompatibility, do not use any infusion components containing polycarbonate with Busulfex.
Using a non polycarbonate syringe fitted with a needle:
- Remove the calculated volume of Busulfex from the vial.
- Dispense the contents of the syringe into an intravenous bag (or syringe) which already contains the calculated amount of the selected diluent. Always add Busulfex to the diluent, not the diluent to Busulfex. Do not put Busulfex into an intravenous bag that does not contain sodium chloride (0.9%) solution for injection or dextrose (5%) solution for injection.
- Mix thoroughly by inverting several times.

After dilution, 1 mL of solution for infusion contains 0.5 mg of busulfan. Diluted Busulfex 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 (0.9%) solution for injection or dextrose(5%) solution for injection.

Do not flush residual drug in the administration tubing as rapid infusion of Busulfex has not been tested and is not recommended.

The entire prescribed Busulfex 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 drug solution prior to beginning the actual Busulfex infusion and then flushed with sodium chloride (0.9%) solution for injection or dextrose (5%) solution for injection.

A nylon or polyester filter should be used if Busulfex is administered via an in-line filter or a filter fitted with an infusion set.

Do not infuse concomitantly with another intravenous solution.

Busulfex contains no antimicrobial agent. Product is for single use in one patient only. Only a clear solution without any particles should be used. Opened vials should be used immediately to assure sterility. Discard any residue.

Busulfex should not be given by rapid intravenous, bolus or peripheral injection.

6.7    PHYSICOCHEMICAL PROPERTIES

Busulfan, 1,4-butanediol dimethanesulfonate

Molecular Formula:       C6H14O6S2
Molecular Weight:    246.31
Chemical structure



CAS number

CAS Registry Number: 55-98-1
7     MARKETING AUTHORISATION HOLDER


Tzamal Bio-Pharma LTD., 20 Hamagshimim st., Petah-Tikva, Israel