Zinecard

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 firstorder 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 doseindependent, 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:

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

Following a rapid distributive phase (~0.2 to 0.3 hours), dexrazoxane reaches postdistributive 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.

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

Special Populations

The pharmacokinetics of ZINECARD have not been evaluated in pediatric patients.

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.

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 and DOSAGE AND ADMINISTRATION).

The pharmacokinetics of ZINECARD have not been evaluated 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 evaluations. 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 evaluating 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 versus placebo, although the survival of patients who did or did not receive ZINECARD with FAC was similar.

Two of the randomized breast cancer studies evaluating 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 2 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 2

The development of cardiac events is shown by:

1. Development of congestive heart failure, defined as having two or more of the following:
   1. Cardiomegaly by X-ray
   2. Basilar Rales
   3. S3 Gallop
   4. Paroxysmal nocturnal dyspnea and/or orthopnea and/or significant dyspnea on exertion.
2. Decline from baseline in LVEF by ≥ 10% and to below the lower limit of normal for the institution.
3. Decline in LVEF by ≥ 20% from baseline value.
4. Decline in LVEF to ≥ 5% below lower limit of normal for the institution.

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.

Figure 1 : Doxorubicin Dose at Congestive Heart Failure (CHF)
FAC Vs. FAC/ZINECARD Patients
Patients Receiving At Least Seven Courses of Treatment

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 evaluating 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.

Dexrazoxane is used to protect the heart and other tissues from harmful side effects caused by certain cancer medications.

The Zinecard brand of dexrazoxane is used in women who are receiving doxorubicin for metastatic breast cancer.

The Totect brand of dexrazoxane is used in men or women to treat a condition called extravasation (es-TRA-va-ZAY-shun). Extravasation happens when an injected medicine escapes from the blood vessels and circulates into tissues in the body. Serious tissue damage can occur when extravasation happens during injection of certain cancer medications.

Dexrazoxane may also be used for purposes not listed in this medication guide.

• Pfizer U.S. Pharmaceuticals Group

• Pharmacia and Upjohn Company

Dexrazoxane is used to protect the heart and other tissues from harmful side effects caused by certain cancer medications.

The Zinecard brand of dexrazoxane is used in women who are receiving doxorubicin for metastatic breast cancer.

The Totect brand of dexrazoxane is used in men or women to treat a condition called extravasation (es-TRA-va-ZAY-shun). Extravasation happens when an injected medicine escapes from the blood vessels and circulates into tissues in the body. Serious tissue damage can occur when extravasation happens during injection of certain cancer medications.

Dexrazoxane may also be used for purposes not listed in this medication guide.

Since dexrazoxane is given by a healthcare professional as part of your chemotherapy treatment, you are not likely to miss a dose.

Call your doctor if you miss a chemotherapy appointment.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

General

• Consult specialized references for procedures for proper handling and disposal of antineoplastics.1

Administration

IV Administration

Administer by slow IV injection or by rapid IV infusion.1 2 3 4 6 7 8 9 13

Handle cautiously; use protective equipment (e.g., latex gloves).1

Administer dexrazoxane ≤30 minutes prior to initiating doxorubicin therapy; administer doxorubicin no later than 30 minutes after the start of dexrazoxane administration.1 2 3 4 5 6 7 8 9 10 11 46 Do not administer doxorubicin prior to dexrazoxane.a

Reconstitute vial containing 250 or 500 mg of dexrazoxane powder with 25 or 50 mL of (1/6) M sodium lactate injection (provided by manufacturer), respectively, to provide a solution containing 10 mg/mL.1

May be further diluted with 0.9% sodium chloride injection or 5% dextrose injection to a concentration of 1.3–5 mg/mL.a 1

Administer by slow IV push or rapid IV infusion over 5–15 minutes.a 1 2 3 4 6 7 8 9 13

Dosage

Available as dexrazoxane hydrochloride; dosage expressed in terms of dexrazoxane.a 1

Administer in a dosage ratio relative to the IV dose of doxorubicin hydrochloride.1

Adults

Recommended dosage ratio of dexrazoxane to doxorubicin is 10:1 (e.g., 500 mg/m2 dexrazoxane should be administered with 50 mg/m2 doxorubicin).1 2 4 5 8 9 13 44

Prescribing Limits

Adults

Maximum 1000 mg/m2 every 3 weeks was administered during clinical trials.a

Special Populations

Hepatic Impairment

Reduced doxorubicin dose recommended in patients with hyperbilirubinemia; proportionally reduce dexrazoxane dosage maintaining 10:1 dexrazoxane to doxorubicin ratio.a

Renal Impairment

Moderate to severe renal impairment (Clcr <40 mL/min): Reduce dosage ratio to 5:1 dexrazoxane to doxorubicin (e.g., 250 mg/m2 dexrazoxane if 50 mg/m2 doxorubicin is administered).a

Not studied in those undergoing dialysis.a

Geriatric Patients

No dosage adjustments except those related to renal impairment.a (See Renal Impairment under Dosage and Administration.)

Distribution

Extent

Distributed primarily in total body water.a

Plasma Protein Binding

Not bound to plasma proteins.a

Elimination

Metabolism

Metabolized to a diacid-diamide cleavage product and two monoacid-monoamide ring products.a

Elimination Route

Excreted principally in urine as unchanged drug (42%), a diacid-diamide cleavage product, and two monoacid-monoamide ring products.a

Half-life

2.1–2.5 hours.a

• Cardioprotective agent that readily penetrates cell membranes; however, exact mechanism of cardioprotective effect not clearly established.a

• Converts intracellularly to a ring-opened bidentate chelating agent that may prevent anthracycline-induced cardiotoxicity, at least in part, by chelating free iron and thus preventing the formation of the anthracycline-iron complex and resultant free radical generation.a 1 2 3 4 5 7 11 13 16 38 40 42

Using this medicine while you are pregnant can harm your unborn baby. If you think you have become pregnant while using this medicine, tell your doctor right away .

Dexrazoxane can temporarily lower the number of white blood cells in your blood, increasing the chance of getting an infection. It can also lower the number of platelets, which are necessary for proper blood clotting. If this occurs, there are certain precautions you can take, especially when your blood count is low, to reduce the risk of infection or bleeding:

• If you can, avoid people with infections. Check with your doctor immediately if you think you are getting an infection or if you get a fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination.
• Check with your doctor immediately if you notice any unusual bleeding or bruising; black, tarry stools; blood in urine or stools; or pinpoint red spots on your skin.
• Be careful when using a regular toothbrush, dental floss, or toothpick. Your medical doctor, dentist, or nurse may recommend other ways to clean your teeth and gums. Check with your medical doctor before having any dental work done.
• Do not touch your eyes or the inside of your nose unless you have just washed your hands and have not touched anything else in the meantime.
• Be careful not to cut yourself when you are using sharp objects such as a safety razor or fingernail or toenail cutters.
• Avoid situations where bruising or injury could occur .

• It is used to lower the side effects of doxorubicin.
• It is used to treat tissue damage caused by some drugs if they leak from the vein while they are being given.
• It may be given to you for other reasons. Talk with the doctor.

• If you need to store this medicine at home, talk with your doctor, nurse, or pharmacist about how to store it.

The ability of Zinecard to prevent/reduce the incidence and severity of doxorubicin-induced cardiomyopathy was evaluated 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 LVEF, utilizing resting multigated nuclear medicine (MUGA) scans, and by clinical evaluations. Patients receiving Zinecard had significantly smaller mean decreases from baseline in LVEF and lower incidences of congestive heart failure than the control group; however, in the largest study, patients with advanced breast cancer receiving FAC with Zinecard had a lower response rate (48% vs. 63%) and a shorter time to progression than patients who received FAC versus placebo.

In the clinical trials, patients who were initially randomized to receive placebo were allowed to receive Zinecard after a cumulative dose of doxorubicin above 300 mg/m2. Retrospective historical analyses showed that the risk of experiencing a cardiac event (see Table 3 for definition) at a cumulative dose of doxorubicin above 300 mg/m2 was greater in the patients who did not receive Zinecard beginning with their seventh course of FAC than in the patients who did receive Zinecard (HR=13.08; 95% CI: 3.72, 46.03; p<0.001). Overall, 3% of patients treated with Zinecard developed CHF compared with 22% of patients not receiving Zinecard.

Figure 1 shows the number of patients still on treatment at increasing cumulative doses.