Source: FDA, National Drug Code (US) Revision Year: 2021
ZINECARD (dexrazoxane) is a potent drug and should be used only by physicians experienced with cancer chemotherapy drugs.
ZINECARD should only be used in those patients who have received a cumulative doxorubicin dose of 300 mg/m² and are continuing with doxorubicin therapy.
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.
It is important that physicians use the product according to the recommended dosage as indicated in the label (10:1 Ratio) as any other dosages outside label recommendations can potentially compromise the safety of the patient.
Currently, the only clinical experience with late administration is in patients who were crossed-over from placebo and received ZINECARD after 6 courses of chemotherapy. ZINECARD 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 ZINECARD administration. Therefore, the administration of ZINECARD should not be delayed beyond the 7th course of therapy.
Second primary malignancies: Secondary acute myeloid leukaemia (AML) / myelodysplastic syndrome (MDS) have been observed in paediatric patients with Hodgkin’s disease or acute lymphoblastic leukaemia receiving dexrazoxane in combination with chemotherapy. Cases of AML have also been reported in adult breast cancer patients treated with dexrazoxane in combination with chemotherapy. ZINECARD is not indicated for use in patients below the age of 18 years.
Although clinical studies have shown that patients receiving FAC with ZINECARD may receive a higher cumulative dose of doxorubicin before experiencing cardiac toxicity than patients receiving FAC without ZINECARD, the use of ZINECARD in patients who have already received a cumulative dose of doxorubicin of 300 mg/m² without ZINECARD, does not eliminate the potential for anthracycline induced cardiac toxicity. Therefore, cardiac function should be carefully monitored.
ZINECARD may add to the myelosuppression caused by chemotherapeutic agents. ZINECARD may interfere with the antitumour activity of chemotherapeutic agents.
Combination of dexrazoxane with chemotherapy may lead to an increased risk of thromboembolism.
Hepatic insufficiency: The pharmacokinetics of ZINECARD have not been evaluated in patients with hepatic impairment. The ZINECARD dose is dependent upon the dose of doxorubicin. Since a doxorubicin dose reduction is recommended in the presence of hyperbilirubinemia, the ZINECARD dosage is proportionately reduced in patients with hepatic impairment (see DOSAGE AND ADMINISTRATION).
In controlled studies, a slightly higher incidence of infection associated with granulocytopenia occurred in patients receiving ZINECARD. As ZINECARD will always be used with cytotoxic drugs, patients should be monitored closely. While the myelosuppressive effects of ZINECARD at the recommended dose are considered to be mild, additive effects upon the myelosuppressive activity of chemotherapeutic agents may occur.
Patients with moderate or severe renal insufficiency: Greater exposure to dexrazoxane may occur in patients with compromised renal function. The ZINECARD dose should be reduced by 50% in patients with creatinine clearance values <40 mL/min (see DOSAGE AND ADMINISTRATION).
Anaphylactic reaction including angioedema, skin reactions, bronchospasm, respiratory distress, hypotension and loss of consciousness have been observed in patients treated with dexrazoxane and anthracyclines.
There is no conclusive information about dexrazoxane adversely affecting human fertility.
ZINECARD can cause fetal harm when administered to pregnant women. Dexrazoxane administration resulted in maternal toxicity, embryotoxicity and teratogenicity in rats and rabbits at doses significantly lower than the clinically recommended dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus (see PHARMACEUTICAL INFORMATION, Toxicology).
ZINECARD should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Women of child-bearing potential should be advised to practice effective contraception.
Mothers should be advised not to breastfeed while undergoing therapy with ZINECARD.
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.
ZINECARD is not indicated for use in patients below the age of 18 years. Since dexrazoxane is a cytotoxic agent, with topoisomerase II inhibition activity, combination of dexrazoxane with chemotherapy may lead to an increased risk of second primary malignancy. In clinical trials, second primary malignancies, in particular acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS), have been reported in paediatric patients with Hodgkin’s disease and acute lymphoblastic leukaemia receiving chemotherapy regimens including several cytotoxics (e.g. etoposide, doxorubicin, cyclophosphamide).
Clinical studies of ZINECARD did not include sufficient numbers of subjects 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, elderly patients should be treated with caution due to the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy.
Unless specific compatibility data are available, ZINECARD should not be mixed with other drugs.
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
ZINECARD (dexrazoxane) at a dose of 500 mg/m² has 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/m² in each of the trials. Courses were repeated every three weeks provided recovery from toxicity had occurred. Table 1 lists the incidence of clinical adverse experiences for patients receiving either ZINECARD or placebo in the breast cancer studies.
Table 1. Percentage of breast cancer patients with adverse experience:
<_.Adverse experience|<>_.FAC + Zinecard N=244 () |<>_.FAC + PLACEBO N=280 () |
| Alopecia | 94 | 96 |
| Nausea | 82 | 89 |
| Vomiting | 63 | 77 |
| Fatigue/Malaise | 62 | 64 |
| Anorexia | 50 | 52 |
| Stomatitis | 36 | 45 |
| Fever | 35 | 33 |
| Infection and/or Sepsis | 31 | 28 |
| Diarrhea | 22 | 24 |
| Neurotoxicity | 16 | 13 |
| Pain on Injection | 11 | 4 |
| Streaking/Erythema | 7 | 5 |
| Dysphagia | 6 | 10 |
| Phlebitis | 5 | 5 |
| Urticaria | 4 | 2 |
| Esophagitis | 5 | 9 |
| Hemorrhage | 2 | 2 |
| Extravasation | 2 | 1 |
| Recall Skin Reaction | 1 | 2 |
| CHF | 1 | 5 |
The only adverse experience that was observed in 5% more patients on FAC + ZINECARD than on FAC + placebo was pain on injection. However, the early drop-out rate for patients receiving Zinecard was higher than for patients receiving placebo.
Myelosuppression: Eighty-eight percent (88%) of breast cancer patients receiving FAC + 500 mg/m² ZINECARD and 85% of patients receiving FAC + placebo experienced Grade 3 or 4 granulocytopenia. Ten percent (10%) of patients receiving FAC + ZINECARD 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 + ZINECARD or FAC + placebo.
Hepatic and Renal: Very few patients receiving FAC + ZINECARD 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.
Based on a kinetic study, ZINECARD (dexrazoxane) does not appear to influence the pharmacokinetics of doxorubicin.
The use of ZINECARD concurrently with fluorouracil, doxorubicin and cyclophosphamide (FAC) therapy (a chemotherapy regimen) might interfere with the antitumour efficacy of the FAC.
Interactions with other drugs have not been established.
Interactions with food have not been established.
Interactions with herbal product have not been established.
Interactions with laboratory tests have not been established.
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