DESCRIPTION

ZINECARD® (dexrazoxane for injection) is a sterile, pyrogen-free lyophilizate intended for intravenous administration. It is a cardioprotective agent for use in conjunction with doxorubicin.

Chemically, dexrazoxane is (S)-4,4'-(1-methyl-1,2-ethanediyl)bis-2,6-piperazinedione. The structural formula is as follows:

C11H16N4O4     M.W. 268.28

Dexrazoxane, a potent intracellular chelating agent is a derivative of EDTA. Dexrazoxane is a whitish crystalline powder that melts at 191° to 197°C. It is sparingly soluble in water and 0.1 N HCl, slightly soluble in ethanol and methanol, and practically insoluble in nonpolar organic solvents. The pKa is 2.1. Dexrazoxane has an octanol/water partition coefficient of 0.025 and degrades rapidly above a pH of 7.0.

ZINECARD is available in 250 mg and 500 mg single use only vials. ZINECARD must be reconstituted with Sterile Water for Injection, USP.

Each 250 mg vial contains dexrazoxane hydrochloride equivalent to 250 mg dexrazoxane. Hydrochloric Acid, NF is added for pH adjustment. When reconstituted as directed with 25 mL of Sterile Water for Injection, USP, each mL contains: 10 mg dexrazoxane. The pH of the resultant solution is 1.0 to 3.0.

Each 500 mg vial contains dexrazoxane hydrochloride equivalent to 500 mg dexrazoxane. Hydrochloric Acid, NF is added for pH adjustment. When reconstituted as directed with 50 mL of Sterile Water for Injection, USP, each mL contains: 10 mg dexrazoxane. The pH of the resultant solution is 1.0 to 3.0.

The reconstituted ZINECARD solutions prepared from Sterile Water for Injection, USP, is intended for further dilution with Lactated Ringer's Injection, USP, for rapid intravenous drip infusion. DO NOT ADMINISTER VIA IV PUSH (see DOSAGE AND ADMINISTRATION).

CLINICAL PHARMACOLOGY

Mechanism of Action

The mechanism by which ZINECARD 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 µg/mL at the end of the 15 minute infusion of a 500 mg/m2 dose of ZINECARD administered 15 to 30 minutes prior to the 50 mg/m2 doxorubicin dose. The important pharmacokinetic parameters of dexrazoxane are summarized in Table 1:

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 ZINECARD 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 ZINECARD was excreted in the urine.

Protein Binding

In vitro studies have shown that ZINECARD is not bound to plasma proteins.

Special Populations

Pediatric

The pharmacokinetics of ZINECARD have not been eva luated 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 ZINECARD 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