chieved withthe recommended clinical dose of AEMCOLO. Treatment of pregnant rats with AEMCOLO at morethan 1,000 times the maximum plasma concentration (Cmax) and 25,000 times the systemic exposure(based on AUC) during the period of organogenesis resulted in maternal toxicity, decreased fetalweight, and variations in diaphragm formation. Similarly, treatment of pregnant rabbits withAEMCOLO at more than 10 times the maximum human plasma concentration (Cmax), resulted in
maternal toxicity, decreased fetal weight, and slightly delayed fetal ossifications [See Data].
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S.general population, the estimated risk of major birth defects and miscarriage in clinically recognizedpregnancies is 2 to 4% and 15 to 20%, respectively. Advise pregnant women of the potential risk to afetus.
Animal Data
Embryofetal toxicity studies in rats and rabbits did not show malformations up to the maximum testeddoses of 855 and 85.5 mg/kg, (25,000 and 500 times greater plasma exposure based on AUC),respectively, of rifamycin given orally during the period of organogenesis (gestational days 6-17/18).
In rats, the high dose of 855 mg/kg/day caused reduction in maternal food consumption, reduced fetalweight and a higher number of fetuses with thin tendinousdiaphragm. In rabbits, the high dose of85.5 mg/kg/day caused a reduction in food consumption and bodyweight gain in pregnant dams, aswell as reduced fetal weights and slight delay in ossification, including slightly higher incidences offetuses with skull suture bone variations, enlarged skull fontanelle and incompletely ossified digit 5
medial phalanx of both forelimbs. No adverse fetal effects were observed in rats and rabbitsadministered lower doses of oral rifamycin.
8.2 Lactation
Risk Summary
There is no information regarding the presence of AEMCOLO in human milk, the effects on thebreastfed infant, or the effects on milk production. Systemic absorption of AEMCOLO in humans isnegligible following oral administration of the recommended dose of AEMCOLO; therefore, exposureto a breastfed infant through breastmilk is expected to be negligible [see Clinical Pharmacology(12.3)]. There are no animal lactation data following oral rifamycin administration. Following singleintravenous injection of rifamycin to lactating ewes, rifamycin has been shown to pass into milk.
The developmental and health benefits of breastfeeding should be considered along with themother’s clinical need for AEMCOLO and any potential adverse effects on the breast-fed infant fromAEMCOLO or from the underlying maternal condition.
8.4 Pediatric Use
The safety and effectiveness of AEMCOLO has not been established in pediatric patients less than18 years of age with travelers’ diarrhea.
8.5 Geriatric Use
Clinical studies with AEMCOLO for travelers’ diarrhea did not include sufficient numbers of patientsaged 65 and older to determine whether they respond differently than younger subjects. Otherreported clinical experience has not identified differences in responses between the elderly andyounger patients.
8.6 Renal Impairment
The pharmacokinetics of AEMCOLO in patients with impaired renal function has not been studied.
Given the minimal systemic exposure of rifamycin (taken as AEMCOLO) and minor role of renalexcretion in elimination of rifamycin, renal impairment is not expected to have a clinically m |
