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-2,6piperazinedione.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 which 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.
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 the 25 mL vial of 0.167 Molar (M/6) Sodium Lactate Injection, USP diluent provided, each mL contains: 10 mg dexrazoxane. The pH of the resultant solution is 3.5 to 5.5.
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 the 50 mL vial of 0.167 Molar (M/6) Sodium Lactate Injection, USP diluent provided, each mL contains: 10 mg dexrazoxane. The pH of the resultant solution is 3.5 to 5.5.
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 the following table.

SUMMARY OF MEAN (%CV 1) DEXRAZOXANE PHARMACOKINETIC PARAMETERS AT A DOSAGE RATIO OF 10:1 OF ZINECARD: DOXORUBICIN
 

1 Coefficient of variation
2 Steady-state volume of distribution
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 subjects with renal dysfunction. Compared with controls, the mean AUC0–inf value was twofold greater in subjects with moderate (CLCR 30–50 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) (see PRECAUTIONS, DOSAGE AND ADMINISTRATION).
Hepatic insufficiency
The pharmacokinetics of ZINECARD have not been eva luated in patients with hepatic impairment. The ZINECARD dose is dependent upon the dose of doxorubicin (see DOSAGE AND ADMINISTRATION). Since a doxorubicin dose reduction is recommended in the presence of hyperbilirubinemia, the ZINECARD 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.
Clinical Studies
The ability of ZINECARD to prevent/reduce the incidence and severity of doxorubicin-induced cardiomyopathy was demonstrated in three prospectively randomized placebo-controlled studies. In these studies, patients were treated with a doxorubicin-containing regimen and either ZINECARD or placebo starting with the first course of chemotherapy. There was no restriction on the cumulative dose of doxorubicin. Cardiac function was assessed by measurement of the left ventricular ejection fraction (LVEF), utilizing resting multigated nuclear medicine (MUGA) scans, and by clinical eva luations. Patients receiving ZINECARD had significantly smaller mean decreases from baseline in LVEF and lower incidences of congestive heart failure than the control group. The difference in decline from baseline in LVEF was evident beginning with a cumulative doxorubicin dose of 150 mg/m2 and reached statistical significance in patients who received ≥400 mg/m2 of doxorubicin. In addition to eva luating the effect of ZINECARD on cardiac function, the studies also assessed the effect of the addition of ZINECARD on the antitumor efficacy of the chemotherapy regimens. In one study (the largest of three breast cancer studies) patients with advanced breast cancer receiving fluorouracil, doxorubicin and cyclophosphamide (FAC) with ZINECARD had a lower response rate (48% vs 63%; p=0.007) and a shorter time to progression than patients who received FAC + placebo, although the survival of patients who did or did not receive ZINECARD with FAC was similar.

Two of the randomized breast cancer studies eva luating the efficacy and safety of FAC with either ZINECARD or placebo were amended to allow patients on the placebo arm who had attained a cumulative dose of doxorubicin of 300 mg/m2 (six courses of FAC) to receive FAC with open-label ZINECARD for each subsequent course. This change in design allowed examination of whether there was a cardioprotective effect of ZINECARD even when it was started after substantial exposure to doxorubicin.

Retrospective historical analyses were then performed to compare the likelihood of heart failure in patients to whom ZINECARD was added to the FAC regimen after they had received six (6) courses of FAC (and who then continued treatment with FAC therapy) with the heart failure rate in patients who had received six (6) courses of FAC and continued to receive this regimen without added ZINECARD. These analyses showed that the risk of experiencing a cardiac event (see Table 1 for definition) at a given cumulative dose of doxorubicin above 300 mg/m2 was substantially greater in the 99 patients who did not receive ZINECARD beginning with their seventh course of FAC than in the 102 patients who did receive ZINECARD (See Figure 1).

Table 1 The development of cardiac events is shown by:

1. Development of congestive heart failure, defined as having two or more of the following:
   a.Cardiomegaly by X-ray
   • b.Basilar Rales
   • c.S3 Gallop
   • d.Paroxysmal nocturnal dyspnea and/or orthopnea and/or significant dyspnea on exertion.

Figure 1 displays the risk of developing congestive heart failure by cumulative dose of doxorubicin in patients who received ZINECARD starting with their seventh course of FAC compared to patients who did not. Patients unprotected by ZINECARD had a 13 times greater risk of developing congestive heart failure. Overall, 3% of patients treated with ZINECARD developed CHF compared with 22% of patients not receiving ZINECARD.

Because of its cardioprotective effect, ZINECARD permitted a greater percentage of patients to be treated with extended doxorubicin therapy. Figure 2 shows the number of patients still on treatment at increasing cumulative doses.
Figure 2 Cumulative Number of Patients On Treatment FAC vs. FAC/ZINECARD Patients Patients Receiving at Least Seven Courses of Treatment

In addition to eva luating the cardioprotective efficacy of ZINECARD in this setting, the time to tumor progression and survival of these two groups of patients were also compared. There was a similar time to progression in the two groups and survival was at least as long for the group of patients that received ZINECARD starting with their seventh course, i.e., starting after a cumulative dose of doxorubicin of 300 mg/m2. These time to progression and survival data should be interpreted with caution, however, because they are based on comparisons of groups entered sequentially in the studies and are not comparisons of prospectively randomized patients.