Leukoencephalopathy Syndrome (RPLS).
7 DRUG INTERACTIONS
Formal drug interaction studies have not been performed with rituximab products. In patients withanother indication, rituximab did not alter systemic exposure to fludarabine or cyclophosphamide.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Based on human data, rituximab products can cause adverse developmental outcomes includingB-cell lymphocytopenia in infants exposed in-utero (see Clinical Considerations). In animalreproduction studies, intravenous administration of rituximab to pregnant cynomolgus monkeysduring the period of organogenesis caused lymphoid B-cell depletion in the newborn offspringat doses resulting in 80% of the exposure (based on AUC) of those achieved following a doseof 2 grams in humans. Advise pregnant women of the risk to a fetus.
Adverse outcomes in pregnancy occur regardless of the health of the mother or the use ofmedications. The background risk of major birth defects and miscarriage for the indicatedpopulations is unknown. The estimated background risk in the U.S. general population ofmajor birth defects is 2%-4% and of miscarriage is 15%-20% ofclinically recognizedpregnancies.
Clinical Considerations
Fetal/Neonatal Adverse Reactions
Observe newborns and infants for signs of infection and manage accordingly.
Data
Human data
Postmarketing data indicate that B-cell lymphocytopenia generally lasting less than six monthscan occur in infants exposed to rituximab in-utero. Rituximab was detected postnatally in theserum of infants exposed in-utero.
Animal Data
An embryo-fetal developmental toxicity study was performed on pregnant cynomolgusmonkeys. Pregnant animals received rituximab via the intravenous route during early gestation(organogenesis period; post coitum days 20 through 50). Rituximab was administered asloading doses on post coitum (PC) Days 20, 21 and 22, at 15, 37.5 or 75 mg/kg/day, and thenweekly on PC Days 29, 36, 43 and 50, at 20, 50 or 100 mg/kg/week. The 100 mg/kg/week doseresulted in 80% of the exposure (based on AUC) of those achieved following a dose of 2 gramsin humans. Rituximab crosses the monkey placenta. Exposed offspring did not exhibit anyteratogenic effects but did have decreased lymphoid tissue B cells.
A subsequent pre-and postnatal reproductive toxicity study in cynomolgus monkeys wascompleted to assess developmental effects including the recovery of B cells and immunefunction in infants exposed to rituximab in utero. Animals were treated with a loading dose of0, 15, or 75 mg/kg every day for 3 days, followed by weekly dosing with 0, 20, or 100 mg/kgdose. Subsets of pregnant females were treated from PC Day 20 through postpartum Day 78,PC Day 76 through PC Day 134, and from PC Day 132 through delivery and postpartum Day 28. Regardless of the timing of treatment, decreased B cells and immunosuppression werenoted in the offspring of rituximab-treated pregnant animals. The B-cell counts returned tonormal levels, and immunologic function was restored within 6 months postpartum.
8.2 Lactation
There are no data on the presence of rituximab products in human milk, the effect on thebreastfed child, or the effect on milk production. However, rituximab is detected in the milk oflactating cynomolgus monkeys, and IgG is present in human milk. Since many drugs includingantibodies are present in human milk, advise a lactating woman not to breastfeed duringtreatment and for at least |
