KELOMPOK I Dexrazoxane (SHINee Farma)

8/2/2019 KELOMPOK I Dexrazoxane (SHINee Farma)

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FORMULATION

Dexrazoxan infusion

Diluted Infusion Solution:

a. Ringer Laktatb. NaCl

c. Glukosa

d. Ringer Dextrose


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DEXRAZOXANE


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Dexrazoxane is a cyclic derivative of EDTA

that was initially evaluated as an

antineoplastic agent.

For the treatment of extravasation

resulting from intravenous (IV)

anthracycline chemotherapy

For reducing the incidence andseverity of cardiomyopathy

associated with doxorubin

therapy in women with metastatic

breast cancer.

indications


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Mechanism of action

Dexrazoxane has two major mechanisms of action:1. Prevention of anthracycline cardiotoxicity: chelation of

iron especially through its ring-opened metabolitereduces the iron-dependant free radical oxidative

stress associated with anthracyclineinducedcardiotoxicity.

2. Antineoplastic effect: inhibition of topoisomerase II.

It is not known to which extent each of these

mechanisms contributes to the protective effect oftissue destruction following anthracyclineextravasation.


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The Reason for

Using Hydrochloride Salt

Dexrazoxane is the S-enantiomer of theracemic mixture of Razoxane. Due to its lowsolubility, Razoxane cannot be formulated for

parenteral use and is erratically absorbed whenadministered orally. Dexrazoxane is more solublein water than Razoxane, which allows parenteraladministration. Dexrazoxane is poorly soluble in

its base form, and in order to obtain a moresoluble form, the drug substance is convertedinto its hydrochloride salt.


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The reason for Dry Powder

Due to the limited stability

of dexrazoxane in aqueoussolutions a liquid or

solution dosage form of

Savene was not feasible,

therefore a solid dosage

form was developed.


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The desired efficacy of dexrazoxane in clinicalpractice is achieved when administered in a three-day schedule with 1000 mg/m2 administered for thefirst 2 days and 500 mg/m2 administered the third

day. Hence, the standard dose (based upon a 70 kgperson with a 1.8 m2 body surface area) will be1800 mg/patient per treatment day 1 and 2 and900mg/patient day 3. Consequently, the

formulation of 500 mg dexrazoxane/vial wasconsidered optimal, since lower dexrazoxanecontent would require too many vials per treatmentwhile a higher content would complicate themanufacturing process

500mg


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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


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Dexrazoxane hydrochloride is administered IV byslow direct injection or by continuous infusionover 5-15 minutes

Dexrazoxane hydrochloride powder for injectionshould be reconstituted by adding 25 or 50 mL of1/6 M sodium lactate injection (provided by themanufacturer) to a vial labeledas containing 250

or 500 mg of dexrazoxane, respectively; theresultant solutions contain 10 mg of dexrazoxaneper mL.1 For IV infusion, the reconstitutedsolution of the drug may be further diluted to thedesired concentration (usually 1.3-5 mg/mL) in acompatible IV solution such as 0.9% sodiumchloride or 5% dextrose injection. (AHFS: 19682)


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Formula I


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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 closedwith rubber stoppers

and either an

aluminium cap with a

polypropylene disc ontop


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Each kit contains twenty 50 mL Type I glass vials.Ten vials each contains dexrazoxane

hydrochloride equivalent to 500 mg dexrazoxaneand 10 vials each contains diluent (0.167MSodium Lactate Injection, USP).

When reconstituted as directed, the admixture

contains dexrazoxane and the followingexcipients: hydrochloric acid, sodium lactate,water for injection, sodium hydroxide and lacticacid. 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.

h il l hili i li d i i l


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The sterile lyophilizate is supplied in 50 mL vials(containing dexrazoxane hydrochloride 589 mgequivalent to dexrazoxane 500 mg) provided in cartonscontaining 10 vials of dexrazoxane and 10 vials of

diluent. Upon reconstitution, the resulting admixture contains

dexrazoxane, hydrochloric acid, sodium lactate, waterfor injection, sodium hydroxide, and lactic acid.

The reconstituted solution should be further diluted insodium chloride 0.9% prior to administration topatients.The reconstituted solution contains noantibacterial preservative and should be used

immediately after mixing and diluting; the product isphysically stable for 4 hours after mixing and dilutingwhen stored below 25C


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Incompatibilities Dexrazoxane:

In the absence of compatibility

studies, this medicinal product

must not be mixed with othermedicinal

products.Shelf life

Vials and bags: 3 years.

After reconstitution and dilution:

Chemical and physical in-use stability has beendemonstrated 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


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Formula II


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Vial I:

Dexrazoxane HCl 589 mg ~ 500 mg

Vial II (reconstituted) :

WFIad 50 ml

Diluent (Infusion bag) :Ringer Lactate 500 ml

Contains : -Sodium Lactate 1, 56 g

- Sodium Chloride 3,0 g

-Potassium Chloride 0,15 g- Calsium Chloride 0,1 g

-WFI ad 500 ml

Type I glass vial closed

with rubber stoppers

and either an

aluminium cap with a

polypropylene disc on

top


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Dexrazoxane is known as acardioprotective agent used before bolusinjections of anthracyclines such asdoxorubicin and epirubicin. In France, therecommended solvent for infusion isRingers lactate solution (RL). According tothe manufacturer, the stability of the

infusion is four hours.

Dexrazoxane 8 mg/mL solutions diluted in RLwere stable for eight hours stored at roomtemperature under normal ambient light,except 4 mg/mL solutions in PE containerswhich were stable for four hours.

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


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The reconstituted solution when furtherdiluted with Lactated Ringers Injection MUSTbe given by rapid drip intravenous infusion.DO NOT ADMINISTER VIA IV PUSH. This

should be given as a single administration, atany point, within a time period of 30 minutesbefore to 15 minutes after the start ofdoxorubicin administration


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Methode preparation of Dexrazoxane

preparation of the bulksolution

aseptic filling

sterilisation by filtration

Lyophilisation

washing of the outside ofthe vials

Visual inspection


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Freeze drying

The main advantage of freeze dryingover dry powder filling is that sterilesolution can be metered into final

container and solvent removed bysublimation after freezing thecontents.


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Freeze

drying asappliedto a dry

powder fill oran in situ

lyophilization


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KELOMPOK I Dexrazoxane (SHINee Farma)

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