Dexrazoxane

Dexrazoxane hydrochloride (Zinecard [Pfizer for USA & Canada]; Cardioxane [Novartis for EU & ROW]) is a medication used to protect the heart against the cardiotoxic side effects of anthracycline chemotherapy. As a derivative of EDTA, dexrazoxane chelates iron, but the precise mechanism by which it protects the heart is not known.

FDA has also approved a dexrazoxane hydrochloride drug, brand name Totect, for use as a treatment of extravasation resulting from IV anthracycline chemotherapy. Extravasation is an adverse event in which chemotherapies containing anthracylines leak out of the blood vessel and necrotize the surrounding tissue.

Mechanism of Action
The mechanism by which Dexrazoxane exerts its cardioprotective activity is not fully understood. Dexrazoxane is a cyclic derivative of EDTA that readily penetrates cell membranes. Results of 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.

Pharmacokinetics
The pharmacokinetics of Dexrazoxane have been studied in advanced cancer patients with normal renal and hepatic function. Generally, the pharmacokinetics of Dexrazoxane can be adequately described by a two-compartment open model with first-order elimination. Dexrazoxane has been administered as a 15 minute infusion over a dose-range of 60 to 900 mg/m2 with 60 mg/m2 of doxorubicin, and at a fixed dose of 500 mg/m2 with 50 mg/m2 doxorubicin. The disposition kinetics of Dexrazoxane are dose-independent, as shown by linear relationship between the area under plasma concentration-time curves and administered doses ranging from 60 to 900 mg/m2. The mean peak plasma concentration of Dexrazoxane was 36.5 mcg/mL at the end of the 15 minute infusion of a 500 mg/m2 dose of Dexrazoxane administered 15 to 30 minutes prior to the 50 mg/m2 doxorubicin dose

Following a rapid distributive phase (~0.2 to 0.3 hours), Dexrazoxane reaches post-distributive equilibrium within two to four hours. The estimated steady-state volume of distribution of Dexrazoxane suggests its distribution primarily in the total body water (25 L/m2). The mean systemic clearance and steady-state volume of distribution of Dexrazoxane in two Asian female patients at 500 mg/m2 Dexrazoxane along with 50 mg/m2 doxorubicin were 15.15 L/h/m2 and 36.27 L/m2, respectively, but their elimination half-life and renal clearance of Dexrazoxane were similar to those of the ten Caucasian patients from the same study. Qualitative metabolism studies with Dexrazoxane have confirmed the presence of unchanged drug, a diacid-diamide cleavage product, and two monoacid-monoamide ring products in the urine of animals and man. The metabolite levels were not measured in the pharmacokinetic studies.

Urinary excretion plays an important role in the elimination of Dexrazoxane. Forty-two percent of the 500 mg/m2 dose of Dexrazoxane was excreted in the urine.

Protein Binding: In vitro studies have shown that Dexrazoxane is not bound to plasma proteins.

Indications and Usage
Dexrazoxane is indicated for reducing the incidence and severity of cardiomyopathy associated with doxorubicin administration in women with metastatic breast cancer who have received a cumulative doxorubicin dose of 300 mg/m2 and who will continue to receive doxorubicin therapy to maintain tumor control. lt is not recommended for use with the initiation of doxorubicin therapy.

Contraindications
Dexrazoxane should not be used with chemotherapy regimens that do not contain an anthracycline.

Overdosage
There have been no instances of drug overdose in the clinical studies sponsored by either Pharmacia & Upjohn Company or the National Cancer Institute. The maximum dose administered during the cardioprotective trials was 1000 mg/m2 every three weeks.

Disposition studies with Dexrazoxane have not been conducted in cancer patients undergoing dialysis, but retention of a significant dose fraction (>0.4) of the unchanged drug in the plasma pool, minimal tissue partitioning or binding, and availability of greater than 90% of the systemic drug levels in the unbound form suggest that it could be removed using conventional peritoneal or hemodialysis.

There is no known antidote for Dexrazoxane. Instances of suspected overdose should be managed with good supportive care until resolution of myelosuppression and related conditions is complete. Management of overdose should include treatment of infections, fluid regulation, and maintenance of nutritional requirements.

Dosage and Administration
The recommended dosage ratio of Dexrazoxane:doxorubicin is 10:1 (e.g., 500 mg/m2 Dexrazoxane:50 mg/m2 doxorubicin). In patients with moderate to severe renal dysfunction (creatinine clearance values <40 mL/min), the recommended dosage ratio of Dexrazoxane:doxorubicin is 5:1 (e.g., 250 mg/m2 Dexrazoxane:50 mg/m2 doxorubicin). Creatinine clearance can be determined from a 24 hour urinary creatinine collection or estimated using the Crockroft-Gault equation (assuming stable renal function):

CLCR=[140-age (years)] x weight (kg) {x 0.85 for female patients} ———————————————————————————   72 x serum creatinine (mg/dL)

Since a doxorubicin dose reduction is recommended in the presence of hyperbilirubinemia, the Dexrazoxane dosage should be proportionately reduced (maintaining the 10:1 ratio) in patients with hepatic impairment. Dexrazoxane must be reconstituted with 0.167 Molar (M/6) Sodium Lactate Injection USP to give a concentration of 10 mg Dexrazoxane for each mL of sodium lactate. The reconstituted solution should be given by slow I.V. push or rapid drip intravenous infusion from a bag. After completing the infusion of Dexrazoxane, and prior to a total elapsed time of 30 minutes (from the beginning of the Dexrazoxane infusion), the intravenous injection of doxorubicin should be given.

Reconstituted Dexrazoxane, when transferred to an empty infusion bag, is stable for 6 hours from the time of reconstitution when stored at 20° to 25°C (68° to 77°F), see USP controlled room temperature, or under refrigeration, 2° to 8°C (36° to 46°F). DISCARD UNUSED SOLUTIONS.

The reconstituted Dexrazoxane solution may be diluted with either 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a concentration range of 1.3 to 5 mg/mL in intravenous infusion bags. The resultant solutions are stable for 6 hours when stored at 20° to 25°C (68° to 77°F), see USP controlled room temperature, or under refrigeration, 2° to 8°C (36° to 46°F). DISCARD UNUSED SOLUTIONS.

Pediatric
The pharmacokinetics of Dexrazoxane have not been evaluated in pediatric patients.

Gender
Analysis of pooled data from two pharmacokinetic studies indicate that male patients have a lower mean clearance value than female patients (110 mL/min/m2 versus 133 mL/min/m2). This gender effect is not clinically relevant.

Renal Insufficiency
The pharmacokinetics of Dexrazoxane were assessed following a single 15 minute IV infusion of 150 mg/m2 of Dexrazoxane in male and female subjects with varying degrees of renal dysfunction as determined by creatinine clearance (CLCR) based on a 24 hour urinary creatinine collection. Dexrazoxane clearance was reduced in subjects with renal dysfunction. Compared with controls, the mean AUC0-inf value was twofold greater in subjects with moderate (CLCR 30 to 50 mL/min) to severe (CLCR <30 mL/min) renal dysfunction. Modeling demonstrated that equivalent exposure (AUC0-inf) could be achieved if dosing were reduced by 50% in subjects with creatinine clearance values <40 mL/min compared with control subjects (CLCR >80 mL/min).

Hepatic Insufficiency
The pharmacokinetics of Dexrazoxane have not been evaluated in patients with hepatic impairment. The Dexrazoxane dose is dependent upon the dose of doxorubicin. Since a doxorubicin dose reduction is recommended in the presence of hyperbilirubinemia, the dexrazone dosage is proportionately reduced in patients with hepatic impairment.

Drug Interactions
There was no significant change in the pharmacokinetics of doxorubicin (50 mg/m2) and its predominant metabolite, doxorubicinol, in the presence of Dexrazoxane (500 mg/m2) in a crossover study in cancer patients.

Incompatibility
Dexrazoxane should not be mixed with other drugs.

Additional Resources

 * ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh,PA; Oncology Nursing Society; 1999:32-41.
 * Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH Publication No. 83-2621. For sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402.
 * AMA Council Report. Guidelines for Handling Parenteral Antineoplastics JAMA. 1985 March 15.
 * National Study Commission on Cytotoxic Exposure-Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, Sc.D., Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115.
 * Clinical Oncological Society of Australia. Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia. 1983; 1:426-428.
 * Jones RB. et al. Safe handling of Chemotherapeutic Agents: A report from the Mount Sinai Medical Center. CA - A Cancer Journal for Clinicians. 1983; (Sept/Oct) 258-263.
 * American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm. 1990; 47:1033-1049.
 * Controlling Occupational Exposure to Hazardous Drugs. (OSHA WORK-PRACTICE GUIDELINES). Am J Health-Syst Pharm 1996; 53:1669-1685.