Zinecard (Dexrazoxane)

ZINECARD™

Pharmacia & Upjohn

Dexrazoxane

Cardioprotective Agent

Action And Clinical Pharmacology: Dexrazoxane is a cyclic derivative of EDTA which, unlike EDTA, readily penetrates cell membranes. Dexrazoxane was shown to be able to protect the myocardium from anthracycline-induced cardiotoxicity. The mechanism by which dexrazoxane exerts its cardioprotective activity is not fully understood. Results of laboratory studies suggest that dexrazoxane is converted intracellularly to an open-ringed chelating agent which interferes with iron-mediated free radical generation thought to be responsible, in part, for anthracycline-induced cardiotoxicity.

The efficacy of dexrazoxane in preventing/reducing the incidence and severity of doxorubicin-induced cardiomyopathy was demonstrated in a series of prospective studies. In these studies, patients were treated with a doxorubicin-containing regimen and either dexrazoxane or placebo starting with the first course of chemotherapy. 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 dexrazoxane 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/mand reached statistical significance in patients who received 400 mg/mof doxorubicin. The studies also assessed the effect of the addition of dexrazoxane on the antitumor efficacy of the chemotherapy regimens. In one of the studies (the largest of the breast cancer studies) patients with advanced breast cancer receiving fluorouracil, Adriamycin and cyclophosphamide (FAC) with dexrazoxane had a lower response rate and a shorter time to progression than patients on the control arm although the survival of the patients who did or did not receive dexrazoxane with FAC was similar. It appears that dexrazoxane may potentiate doxorubicin toxicity in some patients, thus causing increased early dropout rate or decreased dose-intensity. More nonresponders dropped out by course 3 in the dexrazoxane arm. The nonresponders correlated to dose delays due to additive myelotoxicity.

Two of the randomized breast cancer studies evaluating the efficacy and safety of FAC with either dexrazoxane or placebo were amended to allow patients on the placebo arm who had attained a cumulative dose of doxorubicin of 300 mg/m(6 courses of FAC) to receive FAC with open-label dexrazoxane for each subsequent course.

Most of these patients had already experienced a partial or complete response or have stable disease. Analyses of these amended studies indicate that significant though not complete cardioprotection can be obtained with the administration of dexrazoxane even after an accumulated dose of 300 mg/mof doxorubicin. In addition, the time to tumor progression and survival of these 2 groups of patients were also compared. Results demonstrate significantly longer overall survival for the group of patients who received dexrazoxane starting with the seventh course of FAC treatment.

Indications And Clinical Uses: For reducing (preventing) the incidence and severity of cardiotoxicity associated with doxorubicin administration for the treatment of breast cancer in patients who have already experienced a partial response or at least maintain stable disease.

Dexrazoxane should be used only with chemotherapy regimens containing doxorubicin.

Dexrazoxane should be used only after tolerance to a full dose doxorubicin has been established (see Precautions).

Contra-Indications: Dexrazoxane should not be used as a chemotherapeutic agent.

Manufacturers’ Warnings In Clinical States: Caution: Dexrazoxane is a potent drug and should be used only by physicians experienced with cancer chemotherapy drugs (see Warnings and Precautions). Blood counts and hepatic function tests should be performed regularly due to the possibility of additive myelosuppressive effects. Dexrazoxane should not be administered in a dose that exceeds 500 mg/m

Dexrazoxane may add to the myelosuppression caused by chemotherapeutic agents.

Dexrazoxane may interfere with the antitumor activity of chemotherapeutic agents.

Pregnancy: Dexrazoxane should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

There is no conclusive information about dexrazoxane adversely affecting human fertility, or causing teratogenesis; however, in rats and rabbits, it is teratogenic and embryotoxic. Therefore, women of childbearing potential should be advised to practice effective contraception.

Lactation: Mothers should be advised not to breast-feed while undergoing therapy with dexrazoxane (see Precautions).

Children: Safety and effectiveness in children have not been established.

Precautions: General: As dexrazoxane will always be used with cytotoxic drugs, patients should be monitored closely. While the myelosuppressive effects of dexrazoxane at the recommended dose are considered to be mild, additive effects upon the myelosuppressive activity of chemotherapeutic agents may occur. In controlled studies, a slightly higher incidence of infection associated with granulocytopenia occurred in patients receiving dexrazoxane.

Dexrazoxane should be administered only after the tolerance of the patient to the full dose of doxorubicin-containing chemotherapeutic regimen has been determined. Dexrazoxane should be given only when there is no need for dose reduction or dose delay, of the chemotherapeutic regimen due to myelosuppression or other toxicities, in 2 consecutive courses.

Currently, the only clinical experience with late administration is in patients who were crossed-over from placebo and received dexrazoxane after 6 courses of chemotherapy. Dexrazoxane was found to retain its cardioprotective effect in these patients. However, an incidence of up to 20% of cardiovascular events was seen prior to the initiation of dexrazoxane administration. Therefore, the administration of dexrazoxane should not be delayed beyond the 7th course of therapy.

Laboratory Tests: As dexrazoxane may add to the myelosuppressive effects of cytotoxic drugs, frequent complete blood counts, including one prior to each treatment, are recommended (see Adverse Effects).

Drug Interactions: Based on a kinetic study, dexrazoxane does not appear to influence the pharmacokinetics of doxorubicin.

Lactation: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from dexrazoxane, it is recommended that nursing be discontinued during treatment.

Pharmacokinetic studies with dexrazoxane have not been conducted in patients with hepatic or renal insufficiency.

Adverse Reactions: Dexrazoxane at a dose of 500 mg/mhas been administered in combination with fluorouracil, doxorubicin, and cyclophosphamide (FAC) or cyclophosphamide, doxorubicin and vincristine (CAV) in randomized placebo controlled double-blind studies to patients with either metastatic breast cancer (FAC) or extensive disease small cell lung cancer (CAV). The dose of doxorubicin was 50 mg/min each of the trials. Courses were repeated every 3 weeks provided recovery from toxicity had occurred.

The only adverse experience that was observed in 5% more patients on FAC+dexrazoxane than on FAC+placebo was pain on injection.

However, the early drop-out rate for patients receiving dexrazoxane was higher than for patients receiving placebo.

Myelosuppression: Eight-eight percent (88%) of breast cancer patients receiving FAC+500 mg/mdexrazoxane and 85% of patients receiving FAC+placebo experienced Grade 3 or 4 granulocytopenia. Ten percent (10%) of patients receiving FAC+dexrazoxane and 9% of patients receiving FAC+placebo experienced Grade 3 or 4 thrombocytopenia at some time while on study.

The median decline in hemoglobin levels from baseline was 2.6 g/dL for patients receiving FAC+dexrazoxane or FAC+ placebo.

Hepatic and Renal: Very few patients receiving FAC+ dexrazoxane or FAC+placebo experienced marked abnormalities in hepatic or renal function tests; the frequency and severity of abnormalities in bilirubin, alkaline phosphatase, LDH, BUN, and creatinine levels were similar.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There have been no instances of drug overdose in the clinical studies sponsored by either Adria Laboratories or the National Cancer Institute, U.S. The maximum dose administered during the cardioprotection trials was 1 000 mg/mevery 3 weeks.

Disposition studies with dexrazoxane have not been conducted in cancer patients undergoing dialysis. However, 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 its toxicity and efficacy would be altered by its removal using conventional peritoneal or hemodialysis.

There is no known antidote. 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: Dexrazoxane should be reconstituted with 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 i.v. infusion from an empty i.v. bag to which the solution has been added. No further dilution is necessary. Dexrazoxane should be given as a single administration, at any point, within a time period of 30 minutes before to 15 minutes after the start of doxorubicin administration.

The recommended dosage of dexrazoxane is 500 mg/m (see Precautions).

Dexrazoxane should be administered only after the tolerance of the patient to the full dose of doxorubicin-containing chemotherapeutic regimen has been determined. Dexrazoxane should be given only when there is no need for dose reduction or dose delay, of the chemotherapeutic regimen due to myelosuppression or other toxicities, in 2 consecutive courses.

Dexrazoxane should be given only to patients who have already experienced partial response or at least maintained stable disease.

Recommended Diluent for Reconstitution: M/6 Sodium Lactate Injection, USP (supplied in the carton with dexrazoxane).

Storage: The reconstituted solution should be stored for a maximum of 6 hours under refrigeration, 2 to 8°C. Unused solutions should be discarded.

Incompatibility: Unless specific compatibility data are available, dexrazoxane should not be mixed with other drugs.

Guidelines for Safe Preparation and Handling: Caution in the handling and preparation of the reconstituted solution must be exercised and the use of gloves is recommended. If dexrazoxane powder or solution contacts the skin or mucosae, immediately wash thoroughly with soap and water.

Procedures normally used for proper handling and disposal of anticancer drugs should be considered for use with dexrazoxane. However, there is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

Preparation and Handling: 1. Preparation of the reconstituted solutions should be done in a vertical laminar flow hood (Biological Safety Cabinet – Class II).

2. Personnel handling dexrazoxane solutions should wear PVC gloves, safety glasses and protective clothing such as disposable gowns and masks. If dexrazoxane solutions contact the skin or mucosa, the area should be washed with soap and water immediately.

3. Personnel regularly involved in the preparation and handling of antineoplastics should have blood examinations on a regular basis.

Disposal: 1. Avoid contact with skin and inhalation of airborne particles by use of PVC gloves and disposable gowns and masks.

2. All needles, syringes, vials and other materials which have come in contact with dexrazoxane should be segregated in plastic bags, sealed, and marked as hazardous waste. Incinerate at 1 000°C or higher. Sealed containers may explode if a tight seal exists.

3. If incineration is not available, dexrazoxane may be detoxified by adding sodium hypochlorite solution (household bleach) to the vial, in sufficient quantity to decolorize the dexrazoxane, care being taken to vent the vial to avoid a pressure build-up of the chlorine gas which is generated. Dispose of detoxified vials in a safe manner.

Needles, Syringes, Disposable and Nondisposable Equipment: Rinse equipment with an appropriate quantity of sodium hypochlorite solution. Discard the solution in the sewer system with running water and discard disposable equipment in a safe manner. Thoroughly wash nondisposable equipment in soap and water.

Spillage/Contamination: Wear gloves, mask, protective clothing. Treat spilled liquid with sodium hypochlorite solution. Carefully absorb solution with gauze pads or towels, wash area with water and absorb with gauze or towels again and place in polyethylene bag; seal, double bag and mark as hazardous waste. Disposal of waste by incineration or by other methods approved for hazardous materials. Personnel involved in clean-up should wash with soap and water.

Availability And Storage: 250 mg: Each single dose vial contains: dexrazoxane 250 mg. pH is adjusted with hydrochloric acid, NF. Also contains a 25 mL vial of M/6 sodium lactate injection USP. Each mL contains: anhydrous sodium lactate 18.6 mg in Water for Injection. pH is adjusted with sodium hydroxide NF and/or hydrochloric acid NF.

500 mg: Each single dose vial contains: dexrazoxane 500 mg. pH is adjusted with hydrochloric acid, NF. Also contains a 50 mL vial of M/6 sodium lactate injection USP. Each mL contains: anhydrous sodium lactate 18.6 mg in Water for Injection. pH is adjusted with sodium hydroxide NF and/or hydrochloric acid NF.

Store at controlled room temperature, 15 to 30°C.

ZINECARD™ Pharmacia & Upjohn Dexrazoxane Cardioprotective Agent

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