FORMULATION

Dexrazoxan infusion Diluted Infusion Solution: a. Ringer Laktat b. NaCl c. Glukosa d. Ringer Dextrose

DEXRAZOXANE

exrazoxane is a cyclic derivative of EDTA

that was initially evaluated as an antineoplastic agent.

indications

For the treatment of extravasation resulting from intravenous (IV) anthracycline chemotherapy For reducing the incidence and severity of cardiomyopathy associated with doxorubin therapy in women with metastatic breast cancer.

Mechanism of action
Dexrazoxane has two major mechanisms of action: 1. Prevention of anthracycline cardiotoxicity: chelation of iron especially through its ring-opened metabolite reduces the iron-dependant free radical oxidative stress associated with anthracyclineinduced cardiotoxicity. 2. Antineoplastic effect: inhibition of topoisomerase II. It is not known to which extent each of these mechanisms contributes to the protective effect of tissue destruction following anthracycline extravasation.

The Reason for Using Hydrochloride Salt

Dexrazoxane is the S-enantiomer of the racemic mixture of Razoxane. Due to its low solubility, Razoxane cannot be formulated for parenteral use and is erratically absorbed when administered orally. Dexrazoxane is more soluble in water than Razoxane, which allows parenteral administration. Dexrazoxane is poorly soluble in its base form, and in order to obtain a more soluble form, the drug substance is converted into its hydrochloride salt.

The reason for Dry Powder

Due to the limited stability of dexrazoxane in aqueous solutions a liquid or solution dosage form of Savene was not feasible, therefore a solid dosage form was developed.

500mg

The desired efficacy of dexrazoxane in clinical practice is achieved when administered in a threeday schedule with 1000 mg/m2 administered for the first 2 days and 500 mg/m2 administered the third day. Hence, the standard dose (based upon a 70 kg person with a 1.8 m2 body surface area) will be 1800 mg/patient per treatment day 1 and 2 and 900mg/patient day 3. Consequently, the formulation of 500 mg dexrazoxane/vial was considered optimal, since lower dexrazoxane content would require too many vials per treatment while a higher content would complicate the manufacturing process

The recommended dose

The recommended dose is: Day one: 1000 mg/m2 Day two: 1000 mg/m2 Day three: 500 mg/m2 The maximum dose is: Day one: 1000 mg/m2 Day two: 1000 mg/m2 Day three: 500 mg/m2

 Dexrazoxane hydrochloride is administered IV by slow direct injection or by continuous infusion over 5-15 minutes Dexrazoxane hydrochloride powder for injection should be reconstituted by adding 25 or 50 mL of 1/6 M sodium lactate injection (provided by the manufacturer) to a vial labeled as containing 250 or 500 mg of dexrazoxane, respectively; the resultant solutions contain 10 mg of dexrazoxane per mL.1 For IV infusion, the reconstituted solution of the drug may be further diluted to the desired concentration (usually 1.3-5 mg/mL) in a compatible IV solution such as 0.9% sodium chloride or 5% dextrose injection. (AHFS: 19682)

Formula I

Vial I: Dexrazoxane HCl 589 mg ~ 500 mg Vial II (reconstituted) : Sodium Lactate Injection USP 50 ml Contains: - Sodium Lactate 0,16M (1g) - Lactate Acid -NaOH/HCl q.s (pH 6-7,3) -SWFI ad 50 ml Diluent (Infusion bag) : NaCl 0,9 % Contains : NaCl 4,5 gram WFI 500ml
Type I glass vial closed with rubber stoppers and either an aluminium cap with a polypropylene disc on top

 Each kit contains twenty 50 mL Type I glass vials. Ten vials each contains dexrazoxane hydrochloride equivalent to 500 mg dexrazoxane and 10 vials each contains diluent (0.167M Sodium Lactate Injection, USP). When reconstituted as directed, the admixture contains dexrazoxane and the following excipients: hydrochloric acid, sodium lactate, water for injection, sodium hydroxide and lactic acid. The pH of the resultant solution is 3.5 to 5.5. The admixture should be further diluted in 0.9 % NaCl prior to administration to patients.

 The sterile lyophilizate is supplied in 50 mL vials (containing dexrazoxane hydrochloride 589 mg equivalent to dexrazoxane 500 mg) provided in cartons containing 10 vials of dexrazoxane and 10 vials of diluent. Upon reconstitution, the resulting admixture contains dexrazoxane, hydrochloric acid, sodium lactate, water for injection, sodium hydroxide, and lactic acid. The reconstituted solution should be further diluted in sodium chloride 0.9% prior to administration to patients.The reconstituted solution contains no antibacterial preservative and should be used immediately after mixing and diluting; the product is physically stable for 4 hours after mixing and diluting when stored below 25C

Incompatibilities Dexrazoxane: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Shelf life

Vials and bags: 3 years. After reconstitution and dilution: Chemical and physical in-use stability has been demonstrated for 4 hours when stored at 2 to 8C. From a microbiological point of view the product should be used immediately. 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 4 hours at 2 to 8C.

Not contains preservative

Formula II

Vial I: Dexrazoxane HCl 589 mg ~ 500 mg

Vial II (reconstituted) : WFI ad 50 ml Diluent (Infusion bag) : Ringer Lactate 500 ml Contains : -Sodium Lactate - Sodium Chloride -Potassium Chloride Type I glass vial closed with rubber stoppers - Calsium Chloride and either an -WFI aluminium cap with a
polypropylene disc on top

1, 56 g 3,0 g 0,15 g 0,1 g ad 500 ml

Dexrazoxane is known as a cardioprotective agent used before bolus injections of anthracyclines such as doxorubicin and epirubicin. In France, the recommended solvent for infusion is Ringers lactate solution (RL). According to the manufacturer, the stability of the infusion is four hours. Dexrazoxane 8 mg/mL solutions diluted in RL were stable for eight hours stored at room temperature under normal ambient light, except 4 mg/mL solutions in PE containers which were stable for four hours.

Source: Chemical and physical stability of dexrazoxane, diluted with Ringers lactate solution in polyvinyl and polyethylene containers. Europeaan journal of Hospital Pharmacy

The reconstituted solution when further diluted with Lactated Ringers Injection MUST be given by rapid drip intravenous infusion. DO NOT ADMINISTER VIA IV PUSH. This should be given as a single administration, at any point, within a time period of 30 minutes before to 15 minutes after the start of doxorubicin administration

Methode preparation of Dexrazoxane

preparation of the bulk solution

Visual inspection

sterilisation by filtration washing of the outside of the vials

aseptic filling

Lyophilisation

Freeze drying
The main advantage of freeze drying over dry powder filling is that sterile solution can be metered into final container and solvent removed by sublimation after freezing the contents.

Freeze drying as applied to a dry powder fill or an in situ lyophilizatio n