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warnings and cautions
5 WARNINGS AND PRECAUTIONS Myelosuppression: dexrazoxane is associated with leukopenia, neutropenia, and thrombocytopenia. Dexrazoxane may increase the myelosuppressive effects of chemotherapeutic agents. Perform hematological monitoring. ( 5.1 ) Concomitant chemotherapy: Totect may interfere with the antitumor activity of the chemotherapy regimen. Only use Totect in patients who have received a cumulative doxorubicin dose of 300 mg/m 2 and are continuing doxorubicin therapy. ( 5.2 ) Cardiac toxicity: Totect does not completely eliminate the risk of anthracycline-induced cardiac toxicity. For cardiomyopathy, monitor cardiac function before and periodically during therapy to assess left ventricular ejection fraction (LVEF). If deterioration in cardiac function occurs, consider the benefit of continued therapy against the risk of producing irreversible cardiac damage. ( 5.3 ) Secondary malignancies: combination of dexrazoxane with chemotherapy may lead to increased risk of secondary malignancies. ( 5.4 ) Anaphylactic/Hypersensitivity Reactions: monitor for signs and symptoms. Consider permanent discontinuation for severe hypersensitivity reactions. ( 5.5 ) Embryo-Fetal Toxicity: can cause fetal harm. Advise patients of reproductive potential of the risk to a fetus and to use effective contraception. ( 5.6 , 8.1 , 8.3 ) 5.1 Myelosuppression Treatment with Totect is associated with leukopenia, neutropenia, and thrombocytopenia. Totect may add to the myelosuppression caused by chemotherapeutic agents. With extravasation, grade 2-4 decreased white blood cells (73%), decreased neutrophils (61%), and decreased platelets (26%) occurred in patients treated with Totect and cytotoxic chemotherapy in clinical trials. Febrile neutropenia occurred in 2.5% of patients [see Adverse Reactions ( 6.1 )]. When used to reduce the incidence and severity of cardiomyopathy, obtain a complete blood count prior to each course of therapy, and administer Totect and chemotherapy only when adequate hematologic parameters are met. 5.2 Concomitant Chemotherapy Only use Totect 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 Totect 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 dexrazoxane starting with their first cycle of FAC therapy, patients who were randomized to receive dexrazoxane 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 Totect 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). If deterioration in cardiac function occurs, consider the benefit of continued therapy 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 dexrazoxane in combination with chemotherapy. The safety and efficacy of Totect has not been established for use in pediatric patients. Some adult patients who received dexrazoxane 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 AML) 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 Anaphylactic/Hypersensitivity Reactions Hypersensitivity reactions including anaphylactic reaction, angioedema, skin reactions, bronchospasm, respiratory distress, hypotension and loss of consciousness have occurred in patients treated with dexrazoxane products and anthracyclines [see Adverse Reactions ( 6.1 )] . Previous history of allergy to dexrazoxane products should be carefully considered prior to administration. Consider permanent discontinuation in patients with severe hypersensitivity reactions. 5.6 Embryo-Fetal Toxicity Totect can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings from animal studies. In animal reproduction studies, intravenous administration of dexrazoxane to pregnant rats and rabbits during organogenesis resulted in teratogenicity at maternal doses approximately 0.1 and 0.2 times, respectively, the human dose of 1000 mg/m 2 . Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Totect. Advise males with female partners of reproductive potential to use effective contraception during treatment with Totect and for 3 months after the last dose [see Use in Specific Populations ( 8.1 , 8.3 ) and Clinical Pharmacology ( 12.1 )] .
6 ADVERSE REACTIONS Extravasation : The most common adverse reactions (≥15%) are nausea, pyrexia, injection site pain, vomiting, and postoperative infection. ( 6.1 ) Cardiomyopathy : The most common adverse reactions (>10% and increased versus placebo) was injection site pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Clinigen, Inc. at 1-877-776-5385 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. Extravasation In the clinical studies, Totect was administered to patients also receiving chemotherapeutic agents for cancer, and the adverse reaction profile and laboratory abnormalities presented in Tables 1 and 2 reflect the combination of Totect, underlying disease, and already administered chemotherapy. The adverse reaction data reflect exposure to Totect from two clinical studies in 80 patients who received the first dose, 72 patients who received two doses, and 69 patients who received all three doses. Table 1 summarizes adverse reactions occurring with ≥ 5% frequency. Table 1 Adverse Reactions Occurring at ≥ 5% Frequency System Organ Class (SOC) and Adverse Reaction Study 1 and 2 Combined (All causalities) % (N=80) Total number of patients with at least one event 85 General disorders and administration site conditions 58 Pyrexia 21 Injection site pain/injection site discomfort 16 Fatigue 13 Edema peripheral 10 Injection site phlebitis 6 Gastrointestinal disorders 55 Nausea 43 Vomiting 19 Diarrhea 11 Abdominal pain 6 Constipation 6 Infections and infestations 30 Postoperative infection 16 Nervous system disorders 24 Dizziness 11 Headache 6 Skin and subcutaneous disorders 18 Alopecia 14 Respiratory, thoracic and mediastinal disorders 16 Dyspnea 8 Pneumonia Cough 6 5 Vascular disorders 15 Blood and lymphatic system disorders 14 Anemia 6 Psychiatric disorders 14 Depression Insomnia 8 5 Musculoskeletal and connective tissue disorders 13 Metabolism and nutrition disorders Anorexia 10 5 Cardiac disorders 5 Table 2 summarizes laboratory abnormalities from studies 1 and 2. Table 2: Laboratory Abnormalities Laboratory Abnormality Grade 3 Grade 4 Grade 2 to 4 % % % Hematologic Decreased hemoglobin 3 0 43 Decreased WBC 25 20 73 Decreased neutrophils 22 24 61 Decreased platelets 21 0 26 Hepatic Increased bilirubin 2 0 11 Increased AST 1 1 28 Increased ALT 1 5 22 Increased alkaline phosphatase 0 0 4 Increased LDH 0 0 5 Metabolic Increased creatinine 2 2 14 Decreased sodium 5 1 6 Increased calcium total 2 2 7 Cardiomyopathy 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 fluorouracil, doxorubicin, and cyclophosphamide (FAC) chemotherapy regimen with or without dexrazoxane. 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 dexrazoxane experienced more severe leukopenia, granulocytopenia, and thrombocytopenia than patients receiving FAC without dexrazoxane [see Warnings and Precautions ( 5.1 )]. Table 3 below lists the incidence of adverse reactions for patients receiving FAC with either dexrazoxane or placebo in the breast cancer studies. Adverse experiences occurring during courses 1 through 6 are displayed for patients receiving dexrazoxane 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 dexrazoxane or placebo with FAC are also displayed (columns 2 and 4, respectively). The adverse reactions listed below in Table 3 demonstrate that the frequency of adverse reaction "Pain on Injection" has been greater for dexrazoxane arm, as compared to placebo. Table 3: Adverse Reactions for Patients Receiving FAC with either Dexrazoxane or Placebo Adverse Reaction Percentage (%) of Breast Cancer Patients With Adverse Reaction FAC + Dexrazoxane 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