ZINECARD Solution for injection Ref.[27445] Active ingredients: Dexrazoxane

Dosing Considerations

ZINECARD (dexrazoxane) should be reconstituted with Sterile Water for Injection, USP to a concentration of 10 mg/mL. The reconstituted Zinecard solution is intended for further dilution with Lactated Ringer’s Injection, USP to a concentration range of 1.3 to 3.0 mg/ml before use according to the instructions given in the DOSAGE AND ADMINISTRATION, Reconstitution section.

Recommended Dose and Dosage Adjustment

The recommended dosage ratio of ZINECARD: doxorubicin is 10:1 (e.g. 500 mg/m² ZINECARD: 50mg/m² doxorubicin) (see WARNINGS AND PRECAUTIONS).

Hepatic insufficiency: Since a doxorubicin dose reduction is recommended in the presence of hyperbilirubinemia, the ZINECARD dosage should be proportionately reduced in patients with hepatic impairment to maintain the 10:1 ratio of dexrazoxane:doxorubicin.

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

Males: CLCR = body weight (kg) x (140 – age in years) / 72 x serum creatinine (mg/dL)

Females: CLCR = [ body weight (kg) x (140 – age in years) / 72 x serum creatinine (mg/dL) ] x 0.85

Administration

• The reconstituted solution when further diluted with Lactated Ringer’s Injection MUST be given by rapid drip intravenous infusion. DO NOT ADMINISTER VIA IV PUSH. Administer the final diluted solution of ZINECARD over 15 minutes before the administration of doxorubicin. Administer doxorubicin within 30 minutes after the completion of ZINECARD infusion.
• ZINECARD should be administered only after the tolerance of the patient to the full dose of doxorubicin-containing chemotherapeutic regimen has been determined.
• ZINECARD 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 two consecutive courses.
• ZINECARD should be given only to patients who have already experienced partial response or at least maintained stable disease.

Reconstitution

Recommended Diluent for Reconstitution: The reconstitution diluent Sterile Water for Injection, USP, has been studied for compatibility and stability with Zinecard. Zinecard should only be reconstituted with Water for Injection, USP. No other diluent should be used to reconstitute Zinecard.

The reconstituted ZINECARD solution is intended for further dilution for rapid intravenous drip infusion. DO NOT ADMINISTER VIA IV PUSH.

Reconstitution table:

^* Must be further diluted prior to administration

Reconstitute each vial with Sterile Water for Injection, USP, according to the above table. The reconstituted ZINECARD prepared from Sterile Water for Injection, USP, is stable for 30 minutes at room temperature or if storage is necessary, up to 3 hours from the time of reconstitution when stored under refrigeration, 2 to 8°C. The pH of the resultant solution is 1.0 to 3.0. DISCARD UNUSED SOLUTIONS, (see STORAGE AND STABILITY).

Dilution following reconstitution: The resultant reconstituted ZINECARD solution prepared with Sterile Water for Injection, USP, MUST be further diluted with Lactated Ringer’s Injection, USP, to a concentration range of 1.3 to 3.0 mg/mL in intravenous infusion bags for rapid intravenous drip infusion. The pH of the resultant solution is 3.5 to 5.5. The resultant solution is stable for one hour at room temperature or if storage is necessary up to 4 hours when stored under refrigeration, 2 to 8°C. DISCARD UNUSED SOLUTIONS. (see STORAGE AND STABILITY).

For management of a suspected drug overdose, contact your regional Poison Control Centre.

There have been no instances of drug overdose in the clinical studies sponsored by either Pharmacia Corporation or the National Cancer Institute, U.S.A. The maximum dose administered during the cardioprotection trials was 1000 mg/m² every three weeks.

Disposition studies with ZINECARD (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.

Unreconstituted Vials: ZINECARD (dexrazoxane) lyophilized powder for injection should be stored at controlled room temperature, 15-30°C.

Reconstituted Solution: The reconstituted solution in Sterile Water for Injection is stable for 30 minutes at room temperature or a maximum of 3 hours under refrigeration, 2°-8°C (see DOSAGE AND ADMINISTRATION, Reconstitution).

Reconstituted and further Diluted Solution: The reconstituted solution when further diluted with Lactated Ringer’s Injection is stable for 1 hour at room temperature or a maximum of 4 hours under refrigeration, 2°-8°C (see DOSAGE AND ADMINISTRATION, Reconstitution).

Special handling instructions

Caution in the handling and preparation of the reconstituted solution must be exercised and the use of gloves is recommended. If ZINECARD (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 ZINECARD. 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 1000°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 decolourize 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 non-disposable equipment: Rinse equipment with an appropriate quantity of sodium hypochlorite solution. Discard the solution and disposable equipment in a safe manner. Thoroughly wash non-disposable 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.