8 USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed. (8.2) Renal impairment: Monitor patient for signs of hematological toxicity. Reduce the Totect dose by 50% in patients with creatinine clearance values < 40 mL/min. (8.6) Hepatic impairment: Use in patients with hepatic impairment is not recommended. (8.7) 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, Totect can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. Limited available data with Totect use in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. In animal reproduction studies, intravenous administration of dexrazoxane to pregnant rats and rabbits during organogenesis resulted in teratogenicity at maternal doses that were approximately 0.1 and 0.2 times, respectively, the human dose of 1000 mg/m² . Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15–20%, respectively. Data Animal Data In an embryo-fetal development study in rats, pregnant females received intravenous doses of up to 8 mg/kg dexrazoxane during the period of organogenesis. A dose of 8 mg/kg (approximately 0.1 times the human dose of 1000 mg/m²) was teratogenic, resulting in imperforate anus, microphthalmia, and anophthalmia. Doses ≥ 2 mg/kg (approximately 0.01 times the human dose of 1000 mg/m²) caused maternal toxicity. In an embryo-fetal development study in rabbits, pregnant females received intravenous doses of up to 20 mg/kg (approximately 0.2 times the human dose of 1000 mg/m²) were teratogenic, resulting in several skeletal malformations such as short tail, rib and thoracic malformations, and soft tissue variations including subcutaneous, eye and cardiac hemorrhagic areas, as well as agenesis of the gallbladder and of the intermediate lobe of the lung. Doses ≥ 5 mg/kg (approximately 0.1 times the human dose of 1000 mg/m²) caused maternal toxicity. In a pre and postnatal development study in rats, intravenous administration of 8 mg/kg dexrazoxane to pregnant rats during organogenesis resulted in impairment of fertility in the male and female offspring. A dose of 8 mg/kg in rats is approximately 0.1 times the human dose of 1000 mg/m². 8.2 Lactation Risk Summary There are no data on the presence of dexrazoxane in human milk, the effects on the breastfed child, or the effect on milk production. Because of the potential for serious adverse reactions, such as myelosuppression, in a breastfed child from Totect, advise women not to breastfeed during treatment and for 2 weeks following the final dose of Totect. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Pregnancy testing should be performed prior to initiation of chemotherapy. Therefore, repeat pregnancy testing prior to administration of Totect is not recommended, because treatment of extravasation of anthracycline chemotherapy should not be delayed. Contraception Females Totect can cause fetal harm when administered to a pregnant woman [see Warnings and Precautions (5.3), Use in Specific Populations (8.1)]. Because of the potential for genotoxicity, advise females of reproductive potential to use effective contraception during treatment and for 6 months following the final dose of Totect. Males Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 months following the final dose of Totect [see Nonclinical Toxicology (13.1)]. Infertility Males Based on findings in animal studies, Totect may impair fertility in males of reproductive potential. It is not known whether these effects on fertility are reversible [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of Totect in pediatric patients have not been established. 8.5 Geriatric Use In total, 21% of the patients treated with Totect were age 65 years or older and 9% were 75 and older. No differences in safety or efficacy were observed between older and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal and hepatic function, care should be taken in dose selection, and it may be useful to monitor renal and hepatic function [see Dosage and Administration (2.2)]. 8.6 Renal Impairment Greater exposure to dexrazoxane may occur in patients with compromised renal function. Monitor patients with impaired renal function for signs of hematological toxicity. The Totect dose should be reduced by 50% in patients with creatinine clearance values < 40 mL/min. [see Dosage and Administration (2.2)] 8.7 Hepatic Impairment Totect has not been studied in patients with hepatic impairment. Since liver dysfunction (increases in transaminases and bilirubin) may occur (especially after doses of above 1000 mg/m² dexrazoxane), it is recommended that routine liver function tests be performed before each administration of dexrazoxane in patients with known liver function disorders. Use in patients with hepatic impairment is not recommended.