Professional Information
Dexrazoxane (Systemic)
VA CLASSIFICATION
Primary: AN700
Commonly used brand name(s): Zinecard.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
Category:
Chelating agent—
Indications
Accepted
Cardiomyopathy (prophylaxis)—Dexrazoxane is indicated for reducing the incidence and severity of cardiomyopathy associated with the administration of doxorubicin in women with metastatic breast cancer who have received a cumulative doxorubicin dose of 300 mg per square meter of body surface (mg/m 2) and who would benefit from continued therapy with doxorubicin {01}.
—Dexrazoxane is not indicated for use at the time of initiation of doxorubicin therapy {01}. Concurrent use of dexrazoxane with the initiation of fluorouracil, doxorubicin, and cyclophosphamide (FAC) therapy is not recommended because of possible interference with the antitumor efficacy of the regimen. {01}
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Molecular weight—
268.28 {01}
pKa—
2.1 {01}
Mechanism of action/Effect:
The mechanism of action of dexrazoxane's cardioprotective activity is not fully understood. Dexrazoxane is a cyclic derivative of ethylenediamine tetra-acetic acid (EDTA) that readily penetrates cell membranes. Laboratory studies suggest that dexrazoxane is converted intracellularly to a ring-opened chelating agent that interferes with iron-mediated free radical generation thought to be responsible, in part, for anthracycline-induced cardiomyopathy {01}. Dexrazoxane does not affect the pharmacokinetics of doxorubicin {01}.
Distribution:
Following a rapid distributive phase (0.2 to 0.3 hours), dexrazoxane reaches post-distributive equilibrium within 2 to 4 hours, primarily in total body water {01}.
Volume of distribution—Steady-state: 25 liters per square meter of body surface {01}.
Protein binding:
Not bound to plasma proteins {01}.
Biotransformation:
Metabolic products include the unchanged drug, a diacid-diamide cleavage product, and two monoacid-monoamide ring products of unknown concentrations {01}.
Half-life:
Elimination—2.5 hours {01}.
Peak concentration
Plasma—After administration of a dose of 500 mg per square meter of body surface (mg/m 2): 36.5 mcg per mL {01}.
Elimination:
Renal—42% {01}.
In dialysis—It is not known whether dexrazoxane is removable by dialysis {01}. However, because a significant dose fraction (greater than 0.4) of unchanged drug is retained in the plasma pool, minimal tissue partitioning or binding occurs, and systemic drug availability in the unbound form is greater than 90%, it is possible that dexrazoxane is removable by conventional peritoneal dialysis or hemodialysis {01}.
Precautions to Consider
Carcinogenicity
Carcinogenicity studies have not been done in animals or humans {01}.
Mutagenicity
Dexrazoxane was not mutagenic in the Ames test but was found to be clastogenic to human lymphocytes in vitro and to mouse bone marrow erythrocytes in vivo (micronucleus test) {01}.
Pregnancy/Reproduction
Fertility—
Dexrazoxane produced testicular atrophy in rats and dogs at doses as low as 30 mg per kg of body weight (mg/kg) weekly for 6 weeks (1/3 the human dose on a mg per square meter of body surface [mg/m 2] basis) and 20 mg/kg weekly for 13 weeks (approximately equal to the human dose on a mg/m 2 basis), respectively {01}.
Pregnancy—
Adequate and well-controlled studies in humans have not been done {01}.
Studies in pregnant rats, at doses of 2 mg/kg (1/40 the human dose on a mg/m 2 basis) given daily during the period of organogenesis, found dexrazoxane to be maternotoxic; dexrazoxane was embryotoxic and teratogenic at doses of 8 mg/kg (1/10 the human dose on a mg/m 2 basis) and also impaired fertility at maturity in both males and females. Teratogenic effects in rats included imperforate anus, microphthalmia, and anophthalmia. Studies in pregnant rabbits, at doses of 5 mg/kg (1/10 the human dose on a mg/m 2 basis), found dexrazoxane to be maternotoxic; dexrazoxane was embryotoxic and teratogenic at doses of 20 mg/kg (1/2 the human dose on a mg/m 2 basis). Teratogenic effects in rabbits included several skeletal malformations such as short tail, rib and thoracic malformations, and soft tissue variations including subcutaneous, eye, and cardiac hemorrhagic areas, as well as agenesis of the gallbladder and of the intermediate lobe of the lung. {01}
FDA Pregnancy Category C {01}.
Breast-feeding
It is not known whether dexrazoxane is distributed into breast milk {01}.
Pediatrics
No information is available on the relationship of age to the effects of dexrazoxane in pediatric patients. Safety and efficacy have not been established {01}.
Geriatrics
No information is available on the relationship of age to the effects of dexrazoxane in geriatric patients.
Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medicine.
» Bone marrow depressants (See Appendix II ){01} (enhanced bone marrow depression may occur)
Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
» Cardiac function tests (recommended at periodic intervals because dexrazoxane reduces, but does not eliminate, the risk of doxorubicin cardiotoxicity, especially in patients who have already received a cumulative doxorubicin dose of 300 mg/m 2)
{01}
» Complete blood count (CBC) (frequent determinations are recommended because of the risk of increased bone marrow depression with concurrent use of cytotoxic medications)
{01}
Side/Adverse Effects
Note: Most adverse experiences encountered with the administration of dexrazoxane are probably the result of the FAC (fluorouracil, doxorubicin, and cyclophosphamide) chemotherapy regimen, with the exception of pain at the injection site.
Severity of leukopenia and thrombocytopenia at nadir with the FAC regimen was greater in patients receiving dexrazoxane, but recovery was similar with or without dexrazoxane {01}.
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence less frequent
Pain at injection site
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Dexrazoxane (Systemic).
Before using this medication
» Conditions affecting use, especially:
Pregnancy—Teratogenic effects in animals
Breast-feeding—Not recommended
Other medications, especially bone marrow depressants
Proper use of this medication
» Proper dosing
Side/adverse effects
Signs of potential side effects, especially pain at injection site
General Dosing Information
Dexrazoxane solution should be given by slow intravenous injection or rapid-drip intravenous infusion from a bag {01}. The intravenous injection of doxorubicin should be administered within 30 minutes after the beginning of the infusion of dexrazoxane {01}. Doxorubicin should not be administered prior to dexrazoxane {01}.
Safety considerations for handling this medication
It is suggested that dexrazoxane be handled with the same caution as antineoplastic agents {01}.
There is limited but increasing evidence and concern that personnel involved in preparation and administration of parenteral antineoplastics may be at some risk because of the potential mutagenicity, teratogenicity, and/or carcinogenicity of these agents, although the actual risk is unknown. USP advisory panels recommend cautious handling both in preparation and disposal of antineoplastic agents. Precautions that have been suggested include: • Use of a biological containment cabinet during reconstitution and dilution of parenteral medications and wearing of disposable surgical gloves and masks.
• Use of proper technique to prevent contamination of the medication, work area, and operator during transfer between containers (including proper training of personnel in this technique).
• Cautious and proper disposal of needles, syringes, vials, ampuls, and unused medication.
A number of medical centers have developed detailed guidelines for handling of antineoplastic agents.
Parenteral Dosage Forms
DEXRAZOXANE FOR INJECTION
Note: Dexrazoxane for injection contains dexrazoxane hydrochloride, but strength and dosage are expressed in terms of dexrazoxane {01}.
Usual adult dose
Cardiomyopathy
Intravenous, in a dosage ratio of 10 parts dexrazoxane to 1 part doxorubicin (10:1), or 500 mg of dexrazoxane per square meter of body surface (mg/m 2) for every 50 mg/m 2 of doxorubicin, repeated every three weeks, providing recovery has occurred {01}.
Note: Administer solution by slow intravenous injection or by rapid-drip intravenous infusion from a bag. Doxorubicin should be administered within thirty minutes after the beginning of the dexrazoxane infusion {01}.
Usual pediatric dose
Safety and efficacy have not been established {01}.
Size(s) usually available:
U.S.—
250 mg (base) (single-dose vial) (Rx) [Zinecard]
500 mg (base) (single-dose vial) (Rx) [Zinecard]
Packaging and storage:
Store at controlled room temperature between 15 and 30 °C (59 and 86 °F) {01}. Store reconstituted solution up to six hours at controlled room temperature or under refrigeration between 2 and 8 °C (36 and 46 °F) {01}.
Preparation of dosage form:
Dexrazoxane for injection is prepared for intravenous administration by adding 25 or 50 mL of 0.167 molar (M/6) sodium lactate injection (provided by the manufacturer) to the 250- or 500-mg vial, respectively, to produce a solution containing 10 mg per mL (mg/mL) {01}.
The reconstituted solution may be further diluted with either 0.9% sodium chloride injection or 5% dextrose injection to a concentration ranging from 1.3 to 5.0 mg/mL in intravenous infusion bags {01}.
Stability:
After reconstitution or further dilution, dexrazoxane solution is stable for 6 hours at controlled room temperature (between 15 and 30 °C [59 and 86 °F]) or under refrigeration (between 2 and 8 °C [36 and 46 °F]) {01}. Any unused solution should be discarded {01}.
Incompatibilities:
Dexrazoxane should not be mixed with other medications {01}.
Auxiliary labeling:
• Discard unused solution.
Note: If accidental contamination of the skin or mucosae with dexrazoxane occurs, the area should be immediately and thoroughly washed with soap and water {01}.
Developed: 09/28/1995
References
- Zinecard package insert (Pharmacia—US), Rev 5/22/95, Rec 6/19/95.
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