r, excessive levels of vitamin A are associated with adverse developmental effects. The effects on the fetus of areduction in maternal serum TTR caused by ONPATTRO and of vitamin A supplementation are unknown [see ClinicalPharmacology (12.2), Warnings and Precautions (5.2)].
In animal studies, intravenous administration of patisiran lipid complex (patisiran-LC) to pregnant rabbits resulted indevelopmental toxicity (embryofetal mortality and reduced fetal body weight) at doses that were also associated withmaternal toxicity. No adverse developmental effects were observed when patisiran-LC or a rodent-specific(pharmacologically active) surrogate were administered to pregnant rats (see Data).
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. The background risk of major birth defects and
miscarriage for the indicated population is unknown.
Data
Animal Data
Intravenous administration of patisiran-LC (0, 0.15, 0.50, or 1.5 mg/kg) or a rodent-specific (pharmacologically active)
surrogate (1.5 mg/kg) to female rats every week for two weeks prior to mating and continuing throughout organogenesis
resulted in no adverse effects on fertility or embryofetal development.
Intravenous administration of patisiran-LC (0, 0.1, 0.3, or 0.6 mg/kg) to pregnant rabbits every week during the period of
organogenesis produced no adverse effects on embryofetal development. In a separate study, patisiran-LC (0, 0.3, 1, or
2 mg/kg), administered to pregnant rabbits every week during the period of organogenesis, resulted in embryofetal
mortality and reduced fetal body weight at the mid and high doses, which were associated with maternal toxicity.
Intravenous administration of patisiran-LC (0, 0.15, 0.50, or 1.5 mg/kg) or a rodent-specific surrogate (1.5 mg/kg) to
pregnant rats every week throughout pregnancy and lactation resulted in no adverse developmental effects on the
offspring.
8.2 Lactation
Risk Summary
There is no information regarding the presence of ONPATTRO in human milk, the effects on the breastfed infant, or theeffects on milk production. The developmental and health benefits of breastfeeding should be considered along with themother’s clinical need for ONPATTRO and any potential adverse effects on the breastfed infant from ONPATTRO orfrom the underlying maternal condition.
In lactating rats, patisiran was not detected in milk; however, the lipid components (DLin-MC3-DMA and PEG2000-CDMG)were present in milk.
8.4 Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
8.5 Geriatric Use
No dose adjustment is required in patients ≥65 years old [see Clinical Pharmacology (12.3)]. A total of 62 patients≥65 years of age, including 9 patients ≥75 years of age, received ONPATTRO in the placebo-controlled study. No overalldifferences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity ofsome older individuals cannot be ruled out.
8.6 Hepatic Impairment
No dose adjustment is necessary in patients with mild hepatic impairment (bilirubin ≤1 x ULN and AST >1 x ULN, orbilirubin >1.0 to 1.5 x ULN) [seeClinicalPharmacology (12.3)]. ONPATTRO has not been studied in patients withmoderate or severe hepatic impairment.
8.7 Renal Impairm |
