OTECT- dexrazoxane
TopoTarget USA
1 INDICATIONS AND USAGE
Totect� is indicated for the treatment of extravasation resulting from intravenous anthracycline chemotherapy.
2 DOSAGE AND ADMINISTRATION
Vial contents must be mixed and diluted before use.
2.1 Recommended Dose
Totect� should be given once daily for 3 consecutive days. The first infusion should be initiated as soon as possible and within the first six hours after extravasation.
The individual dosage is based on calculation of the Body Surface Area (BSA) up to a maximum dose of 2000 mg (each on Day 1 and 2) and 1000 mg (Day 3), corresponding to a BSA of 2 m2.
The recommended dose is: Maximum daily dose:
Day one: 1000 mg/m2 2000 mg
Day two: 1000 mg/m2 2000 mg
Day three: 500 mg/m2 1000 mg
2.2 Dose Modifications
The Totect� dose should be reduced by 50% in patients with creatinine clearance values < 40 mL/min.
2.3 Directions for Mixing and Final Dilution
Read this entire section carefully before mixing and diluting.
Aseptic technique should be used during preparation.
Caution must be exercised when handling Totect� and preparing the mixed solution. [see How Supplied/Storage and Handling (16)]
Totect� should not be mixed or administered with any other drug during the infusion.
Preparation of Totect �
Step 1. Each vial of Totect� (dexrazoxane for injection) (500 mg) must first be mixed with 50 mL of the enclosed diluent. The resultant solution contains 10 mg/mL. This resultant solution should be used immediately (within 2 hours) after preparation. It contains no antibacterial preservative.
Step 2. Withdraw the recommended dose from the solution containing 10 mg/mL as prepared in Step 1 and further dilute into an infusion bag containing 1000 mL 0.9% Sodium Chloride. In order to obtain the required dose more than one vial may be needed. Totect� must not be mixed with any other drugs.
The infusion bag should be used immediately after preparation. The product is stable for 4 hours from the time of preparation when stored below 25�C (77�F).
The solution of Totect� is slightly yellow.
Parenteral drug products should be inspected visually for particulate matter prior to administration, whenever solution and container permit. Solutions containing a precipitate should be discarded. Vials are for single use only. Unused solution should be discarded.
2.4 Administration
Totect� should not be mixed or administered with any other drug during the infusion. Administer as an intravenous infusion over 1 to 2 hours at room temperature and normal light conditions in a large caliber vein in an extremity/area other than the one affected by the extravasation. Cooling procedures such as ice packs, if used, should be removed from the extravasation area at least 15 minutes before Totect� administration in order to allow sufficient blood flow to the area of extravasation. Treatment on Day 2 and Day 3 should start at the same hour (+/- 3 hours) as on the first day.
3 DOSAGE FORMS AND STRENGTHS
Totect� is packaged as an urgent treatment kit for single patient use. Each kit contains 10 vials of Totect� (dexrazoxane for injection) 500 mg and 10 vials of 50 mL diluent, which provides a complete three day treatment.
DESCRIPTION
Totect� (dexrazoxane for injection) is a sterile, pyrogen-free lyophilizate intended for intravenous (IV) administration. Totect� is packaged as a kit for single patient use. Each kit contains 10 vials of Totect� (dexrazoxane for injection) 500 mg and 10 vials of 50 mL diluent, which provides a complete three day treatment.
Chemically, dexrazoxane is 2,6-piperazinedione,4,4′-(1-methyl-1,2-ethanediyl)bis-,(S)- or (S)-(+)-1,2-bis(3,5-dioxopiperazin-1-yl)propane. The following diagram shows the chemical structure:
chemical structure
The molecular formula is C11 H16 N4 O4 ; the molecular weight is 268.3. Dexrazoxane is a white to off-white powder, with a melting point of 194 � 3 �C. It is soluble in dioxane and 0.1 N HCl, sparingly soluble in water, tetrahydrofuran, citrate buffer at pH 4.0, phosphate buffer at pH 7.0, and borate-potassium chloride sodium hydroxide buffer at pH 9.0. The acid dissociation constants, pKa, are 2.5 (for the tertiary piperazine nitrogen) and 9.7 (for the nitrogen imide). Log P is -2.135.
The finished product is supplied in a sterile form for intravenous infusion only following mixing and diluting.
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). Each vial of dexrazoxane for injection is closed with an aluminum flip-off cap covered with a dark red overcap. Each vial of diluent is closed with an aluminum flip-off cap covered with a white overcap.
When reconstituted as directed, the admixture contains dexrazoxane and the following excipients: hydrochloric acid, sodium lactate, water for injection, sodium hydroxide and lactic acid [see Dosage and Administration (2.4)]. The admixture should be further diluted in 0.9 % NaCl prior to administration to patients.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The mechanism by which Totect� diminishes tissue damage resulting from the extravasation of anthracycline drugs is unknown. Some evidence suggests that dexrazoxane inhibits topoisomerase II reversibly.
