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warnings and cautions
5 WARNINGS AND PRECAUTIONS • Myelosuppression: ZINECARD may increase the myelosuppresive effects of chemotherapeutic agents. Perform hematological monitoring. ( 5.1 ) • Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.5 , 8.1 , 8.3 ) 5.1 Myelosuppression ZINECARD may add to the myelosuppression caused by chemotherapeutic agents. Obtain a complete blood count prior to and during each course of therapy, and administer ZINECARD and chemotherapy only when adequate hematologic parameters are met. 5.2 Concomitant Chemotherapy Only use ZINECARD in those patients who have received a cumulative doxorubicin dose of 300 mg/m 2 and are continuing with doxorubicin therapy. Do not use with chemotherapy initiation as ZINECARD may interfere with the antitumor activity of the chemotherapy regimen. In a trial conducted in patients with metastatic breast cancer who were treated with fluorouracil, doxorubicin, and cyclophosphamide (FAC) with or without ZINECARD starting with their first cycle of FAC therapy, patients who were randomized to receive ZINECARD had a lower response rate (48% vs. 63%) and shorter time to progression than patients who were randomized to receive placebo. 5.3 Cardiac Toxicity Treatment with ZINECARD does not completely eliminate the risk of anthracycline-induced cardiac toxicity. Monitor cardiac function before and periodically during therapy to assess left ventricular ejection fraction (LVEF). In general, if test results indicate deterioration in cardiac function associated with doxorubicin, the benefit of continued therapy should be carefully evaluated against the risk of producing irreversible cardiac damage. 5.4 Secondary Malignancies Secondary malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) have been reported in studies of pediatric patients who have received ZINECARD in combination with chemotherapy. ZINECARD is not indicated for use in pediatric patients. Some adult patients who received ZINECARD in combination with anti-cancer agents known to be carcinogenic have also developed secondary malignancies, including AML and MDS. Razoxane is the racemic mixture, of which dexrazoxane is the S(+)-enantiomer. Secondary malignancies (primarily acute myeloid leukemia) have been reported in patients treated chronically with oral razoxane. In these patients, the total cumulative dose of razoxane ranged from 26 to 480 grams and the duration of treatment was from 42 to 319 weeks. One case of T-cell lymphoma, one case of B-cell lymphoma, and six to eight cases of cutaneous basal cell or squamous cell carcinoma have also been reported in patients treated with razoxane. Long-term administration of razoxane to rodents was associated with the development of malignancies [see Nonclinical Toxicology (13.1) ] . 5.5 Embryo-Fetal Toxicity Based on finding from animal studies and its mechanism of action, ZINECARD can cause fetal harm when administered to pregnant women [see Clinical Pharmacology (12.1) ] . In animal reproduction studies, dexrazoxane administration during the period of organogenesis resulted in maternal toxicity and teratogenicity in rats and rabbits at doses significantly lower than the clinically recommended dose. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ZINECARD and for 6 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ZINECARD and for 3 months after the last dose [see Use in Specific Populations (8.1 , 8.3 )] .
6 ADVERSE REACTIONS In clinical studies, ZINECARD was administered to patients also receiving chemotherapeutic agents for cancer. Pain on injection was observed more frequently in patients receiving ZINECARD versus placebo. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. The adverse reaction profile described in this section was identified from randomized, placebo-controlled, double-blind studies in patients with metastatic breast cancer who received the combination of the FAC chemotherapy regimen with or without ZINECARD. The dose of doxorubicin was 50 mg/m 2 in each of these trials. Treatment was administered every three weeks until disease progression or cardiac toxicity. Patients in clinical trials who received FAC with ZINECARD experienced more severe leukopenia, granulocytopenia, and thrombocytopenia than patients receiving FAC without ZINECARD [see Warnings and Precautions (5.1) ] . Table 1 below lists the incidence of adverse reactions for patients receiving FAC with either ZINECARD or placebo in the breast cancer studies. Adverse experiences occurring during courses 1 through 6 are displayed for patients receiving ZINECARD or placebo with FAC beginning with their first course of therapy (columns 1 and 3, respectively). Adverse experiences occurring at course 7 and beyond for patients who received placebo with FAC during the first six courses and who then received either ZINECARD or placebo with FAC are also displayed (columns 2 and 4, respectively). The adverse reactions listed below in Table 1 demonstrate that the frequency of adverse reaction "Pain on Injection" has been greater for ZINECARD arm, as compared to placebo. Table 1 Adverse Reaction Percentage (%) of Breast Cancer Patients With Adverse Reaction FAC + ZINECARD FAC + Placebo Courses 1–6 N = 413 Courses ≥ 7 N = 102 Courses 1–6 N = 458 Courses ≥ 7 N = 99 Alopecia 94 100 97 98 Nausea 77 51 84 60 Vomiting 59 42 72 49 Fatigue/Malaise 61 48 58 55 Anorexia 42 27 47 38 Stomatitis 34 26 41 28 Fever 34 22 29 18 Infection 23 19 18 21 Diarrhea 21 14 24 7 Pain on Injection 12 13 3 0 Sepsis 17 12 14 9 Neurotoxicity 17 10 13 5 Streaking/Erythema 5 4 4 2 Phlebitis 6 3 3 5 Esophagitis 6 3 7 4 Dysphagia 8 0 10 5 Hemorrhage 2 3 2 1 Extravasation 1 3 1 2 Urticaria 2 2 2 0 Recall Skin Reaction 1 1 2 0