Pharmaceutical particulars : מידע רוקחי

6.     PHARMACEUTICAL PARTICULARS

6.1.   LIST OF EXCIPIENTS
Macrogol 400, Citric acid anhydrous, Dimethylacetamide (Purified N,N- Dimethylacetamide).

The drug product BUSULFAN RAZ 6 MG/ML is intended for dilution with 0.9% sodium chloride solution for injection or glucose 5% solution for injection.

6.2.   INCOMPATIBILITIES

In the absence of compatibility studies, BUSULFAN RAZ 6 MG/ML 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

Store in a refrigerator (2°C –8°C). Do not freeze the diluted solution.
Diluted solution: Chemical and physical in-use stability after dilution has been demonstrated for:
8 hours (including infusion time) after dilution in glucose 5% solution for injection or sodium chloride 9 mg/ml (0.9%) solution for injection when stored at 20°C ± 5°C.
6 hours after dilution in sodium chloride 9 mg/ml (0.9%) solution for injection 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, unless the method of dilution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

6.5.   NATURE AND CONTENTS OF CONTAINER

10 ml of concentrate for solution for infusion in clear glass vials (type I) with a chlorobutyl Teflon laminated rubber stopper covered by a flip-off aluminium purple color MT seal. Vials may or may not be sleeved with plastic shrink sleeve/bottom (puck).
This plastic sleeving is not in contact with the drug product and is there to provide additional protection during transportation. This improves the safe handling of the medicinal product by both healthcare professionals and pharmaceutical personnel.
Busulfan RAZ 6mg/ml is available in a package of 1 vial or 8 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 solution of BUSULFAN RAZ 6 MG/ML:
• The use of gloves and protective clothing is recommended.
• If BUSULFAN RAZ 6 MG/ML or diluted BUSULFAN RAZ 6 MG/ML contacts the skin or mucosa, wash them thoroughly with water immediately.

Calculation of the quantity of BUSULFAN RAZ 6 MG/ML to be diluted and of the diluent

BUSULFAN RAZ 6 MG/ML must be diluted prior to use with either sodium chloride (0.9%) solution for injection or glucose (5%) solution for injection. The quantity of the diluent must be 10 times the volume of BUSULFAN RAZ 6 MG/ML ensuring the final concentration of busulfan remains at approximately 0.5 mg/mL.

For example, the amount of BUSULFAN RAZ 6 MG/ML 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 BUSULFAN RAZ 6 MG/ML:

Y (kg) x Z (mg/kg)
6 (mg/mL)              = A mL of BUSULFAN RAZ 6 MG/ML to be diluted 
Y: body weight of the patient in kg
Z: dose on a mg/kg basis

•   Quantity of diluent:
(A mL BUSULFAN RAZ 6 MG/ML) x (10) = B mL of diluent

To prepare the final solution for infusion, add (A) mL of BUSULFAN RAZ 6 MG/ML to (B) mL of diluent (sodium chloride 9 mg/mL (0.9%) solution for injection or glucose 5% solution for injection).

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 BUSULFAN RAZ 6 MG/ML (56 mg total dose).
To prepare the final solution for infusion, add 9.3 mL of BUSULFAN RAZ 6 MG/ML to 93 mL of diluent (sodium chloride 0.9% or glucose 5%) as calculated below: (9.3 mL BUSULFAN RAZ 6 MG/ML) × (10) = 93 mL of either diluent plus the 9.3 mL of BUSULFAN RAZ 6 MG/ML 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).

Parenteral Products:
Intravenous Injection
1) 0.9% Sodium Chloride Solution for Injection
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% Glucose solution for injection
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 

Preparation of the solution for infusion
All transfer procedures require strict adherence to aseptic techniques, preferably employing a vertical laminar flow safety hood while wearing gloves and protective clothing. Using a syringe fitted with a needle, remove the calculated volume of BUSULFAN RAZ 6 MG/ML from the vial and dispense the contents of the syringe into an intravenous bag (or syringe) that already contains the calculated amount of either sodium chloride 9 mg/ml (0.9%) or glucose 5% solution for injection, making sure that the drug flows into and through the solution. DO NOT put BUSULFAN RAZ 6 MG/ML into an intravenous bag that does not contain sodium chloride 9 mg/ml (0.9%) or glucose 5% solution for injection. Always add the BUSULFAN RAZ 6 MG/ML to the diluent, not the diluent to the BUSULFAN RAZ 6 MG/ML. Mix thoroughly by inverting several times.

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 glucose (5%) solution for injection.

Do not flush residual drug in the administration tubing as rapid infusion of BUSULFAN RAZ 6 MG/ML has not been tested and is not recommended.

The entire prescribed BUSULFAN RAZ 6 MG/ML 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 BUSULFAN RAZ 6 MG/ML infusion and then flushed with sodium chloride )0.9%( solution for injection or glucose (5%) solution for injection.

A nylon or polyester filter should be used if BUSULFAN RAZ 6 MG/ML is administered via an in-line filter or a filter fitted with an infusion set.

Do not infuse concomitantly with another intravenous solution.

BUSULFAN RAZ 6 MG/ML 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.

BUSULFAN RAZ 6 MG/ML 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