erformance, the incidence of antibody development in patients receiving IMFINZI has not been adequately determined. Of 1124 patients who were treated with IMFINZI 10 mg/kg every 2 weeks and eva luable for the presence of anti-drug antibodies (ADAs), 3.3% patients tested positive for treatment-emergent ADAs. The clinical significance of anti-durvalumab antibodies is unknown.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk summary
Based on its mechanism of action and data from animal studies, IMFINZI can cause fetal harm when administered to a pregnant woman [see CLINICAL PHARMACOLOGY (12.1)]. There are no data on the use of IMFINZI in pregnant women.
In animal reproduction studies, administration of durvalumab to pregnant cynomolgus monkeys from the confirmation of pregnancy through delivery resulted in increased in premature delivery, fetal loss and premature neonatal death (see Data). Human immunoglobulin G1 (IgG1) is known to cross the placental barrier; therefore, durvalumab has the potential to be transmitted from the mother to the developing fetus. Apprise pregnant women of the potential risk to a fetus.
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
As reported in the literature, the PD-1/PD-L1 pathway plays a central role in preserving pregnancy by maintaining maternal immune tolerance to the fetus. In mouse allogeneic pregnancy models, disruption of PD-L1 signaling was shown to result in an increase in fetal loss. The effects of durvalumab on prenatal and postnatal development were eva luated in reproduction studies in cynomolgus monkeys. Durvalumab was administered from the confirmation of pregnancy through delivery at exposure levels approximately 6 to 20 times higher than those observed at the clinical dose of 10 mg/kg of durvalumab (based on AUC). Administration of durvalumab resulted in premature delivery, fetal loss (abortion and stillbirth) and increase in neonatal deaths. Durvalumab was detected in infant serum on postpartum Day 1, indicating the presence of placental transfer of durvalumab. Based on its mechanism of action, fetal exposure to durvalumab may increase the risk of developing immune-mediated disorders or altering the normal immune response and immune-mediated disorders have been reported in PD-1 knockout mice.
8.2 Lactation
Risk Summary
There is no information regarding the presence of durvalumab in human milk, the effects on the breastfed infant, or the effects on milk production. Human IgG1 is excreted in human milk. Durvalumab was present in the milk of lactating cynomolgus monkeys and was associated with premature neonatal death (see Data).
Because of the potential for adverse reactions in breastfed infants from durvalumab, advise a lactating woman not to breastfeed during treatment with IMFINZI and for at least 3 months after the last dose.
Data
In lactating cynomolgus monkeys, durvalumab was present in breast milk at about 0.15% of maternal serum concentrations after administration of durvalumab from the confirmation of pregnancy through delivery at exposure levels approximately 6 to 20 times higher than those observed at the clinical dose of 10 mg/kg of durvalumab (based on AUC). Administration of durvalumab resulted in premature neonatal death.
8.3 Females and Males of Reproductive Potential
Contraception
Females
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