8 USE IN SPECIFIC POPULATIONS
Based on findings from animal studies and its mechanism of action, ELLENCE can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]; avoid the use of ELLENCE during the 1st trimester. Available human data do not establish the presence or absence of major birth defects and miscarriage related to the use of epirubicin during the 2nd and 3rd trimesters. There are reports of fetal and/or neonatal cardiotoxicity following in utero exposure to epirubicin (see Clinical Considerations). In animal reproduction studies in pregnant rats, epirubicin was embryo-fetal lethal and caused structural abnormalities when administered during organogenesis at doses less than the maximum recommended human dose on a body surface area basis (see Data). Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Fetal/Neonatal Adverse Reactions
There have been rare reports of fetal and/or neonatal transient ventricular hypokinesia, transient elevation of cardiac enzymes, and a case of fetal demise from suspected anthracycline-induced cardiotoxicity following in utero exposure to epirubicin in 2nd and/or 3rd trimesters. Cardiotoxicity is a known risk of anthracycline treatment in adults [see Warnings and Precautions (5.1)]. Monitor the fetus and/or neonate for cardiotoxicity and perform testing consistent with community standards of care.
Intravenous administration of 0.8 mg/kg/day epirubicin (about 0.04 times the maximum recommended single human dose on a body surface area basis) to rats during Days 5 to 15 of gestation resulted in embryofetal lethality (increased resorptions and post-implantation loss) and caused fetal growth retardation (decreased body weight). Intravenous administration of 2 mg/kg/day epirubicin (about 0.1 times the maximum recommended single human dose on a body surface area basis) to rats on Days 9 and 10 of gestation resulted in embryo-fetal lethality (increased late resorptions, post-implantation losses, and dead fetuses; and decreased live fetuses), retarded fetal growth (decreased body weight), and caused decreased placental weight and numerous external (anal atresia, misshapen tail, abnormal genital tubercle), visceral (primarily gastrointestinal, urinary, and cardiovascular systems), and skeletal (deformed long bones and girdles, rib abnormalities, irregular spinal ossification) malformations. Administration of intravenous epirubicin to rabbits at doses up to 0.2 mg/kg/day (about 0.02 times the maximum recommended single human dose on a body surface area basis) during Days 6 to 18 of gestation was not teratogenic, but a maternally toxic dose of 0.32 mg/kg/day increased abortions and delayed ossification. Administration of a maternally toxic intravenous dose of 1 mg/kg/day epirubicin to rabbits (about 0.1 times the maximum recommended single human dose on a body surface area basis) on Days 10 to 12 of gestation induced abortion, but no other signs of teratogenicity were observed. When doses up to 0.5 mg/kg/day epirubicin were administered to rat dams from Day 17 of gestation to Day 21 after delivery (about 0.025 times the maximum recommended single human dose on a body surface area basis), no permanent changes were observed in the development, functional activity, behavior, or reproductive performance of the offspring.
There are no data on the presence of epirubicin in human milk, the effects on the breastfed child, or the effects on milk production. Epirubicin is present in rat milk (see Data). When a drug is present in animal milk it is likely the drug will be present in human milk. Because of the potential for serious adverse reactions in the breastfed child, advise lactating women not to breastfeed during treatment with ELLENCE and for at least 7 days after the last dose.
8.3 Females and Males of Reproductive Potential
Verify the pregnancy status in female patients of reproductive potential prior to initiating ELLENCE.
ELLENCE can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise female patients of reproductive potential to use effective contraception during treatment and for 6 months after the last dose of ELLENCE.
Based on clinical findings and animal studies, ELLENCE may cause oligospermia, azoospermia, and permanent loss of fertility. Sperm counts have been reported to return to normal levels in some men. This may occur several years after the end of therapy [see Nonclinical Toxicology (13.1)].
Based on clinical findings and animal studies, ELLENCE may impair female fertility and result in amenorrhea. Premature menopause can occur. Recovery of menses and ovulation is related to age at treatment [see Nonclinical Toxicology (13.1)].
Based on its mechanism of action and genotoxicity studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of ELLENCE. Advise male patients with pregnant partners use condoms during treatment and for at least 7 days after the last dose of ELLENCE [see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1)].
8.4 Pediatric Use
Safety and effectiveness of ELLENCE have not been established in pediatric patients. Pediatric patients may be at greater risk for anthracycline-induced acute manifestations of cardiotoxicity or late cardiovascular dysfunction. The pharmacokinetics of epirubicin in pediatric patients have not been evaluated.
8.5 Geriatric Use
Clinical experience in patients who were 65 years of age and older who received ELLENCE chemotherapy regimens for primary breast cancer showed no overall differences in safety and effectiveness compared with younger patients.
In elderly female patients, closely monitor for increased toxicity due to the risk of decreased clearance of epirubicin [see Clinical Pharmacology (12.3)].
8.6 Hepatic Impairment
Epirubicin is eliminated by both hepatic metabolism and biliary excretion and clearance is reduced in patients with hepatic dysfunction. Do not treat patients with severe hepatic impairment with ELLENCE [see Contraindications (4)]. Reduce the starting dose for patients with less severe hepatic impairment [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
8.7 Renal Impairment
No significant alterations in the pharmacokinetics of epirubicin or its major metabolite, epirubicinol, have been observed in patients with serum creatinine <5 mg/dL. Consider lower doses in patients with severe renal impairment (serum creatinine >5 mg/dL), as a reduction in plasma clearance was reported in these patients [see Dosage and Administration (2.3), and Clinical Pharmacology (12.3)]. Patients on dialysis have not been studied.