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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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