ts receiving placebo (6%). The most common cardiac adverse events were tachycardia (reported in 4% of PREVYMIS subjects and in 2% of placebo subjects) and atrial fibrillation (reported in 3% of PREVYMIS subjects and in 1% of placebo subjects). Among those subjects who experienced one or more cardiac adverse events, 85% of PREVYMIS and 92% of placebo subjects had events reported as mild or moderate in severity.
Common Adverse EventsThe rate of adverse events occurring in at least 10% of subjects in the PREVYMIS group and at a frequency at least 2% greater than placebo are outlined in Table 1.Table 1: Trial P001 All Grade Adverse Events Reported in ≥ 10% of PREVYMIS-Treated HSCT Recipients at a Frequency at least 2% Greater than PlaceboAdverse EventsPREVYMIS(N=373)Placebo(N=192)nausea27%23%diarrhea26%24%vomiting19%14%peripheral edema14%9%cough14%10%headache14%9%fatigue13%11%abdominal pain12%9%Overall, similar proportions of subjects in each group discontinued study medication due to an adverse event (13% of PREVYMIS subjects vs. 12% of placebo subjects). The most frequently reported adverse event that led to study drug discontinuation was nausea, occurring in 2% of PREVYMIS subjects and 1% of placebo subjects. Hypersensitivity reaction, with associated moderate dyspnea, occurred in one subject following the first infusion of IV PREVYMIS after switching from oral PREVYMIS, leading to treatment discontinuation.
Laboratory AbnormalitiesSelected laboratory abnormalities reported during treatment or within 2 weeks of stopping treatment are presented in the table below.Table 2: Trial P001 Selected Laboratory AbnormalitiesPREVYMISN=373PlaceboN=192Absolute neutrophil count (cells/μL) < 50019%19% 500 – < 7504%7% 750 – < 10008%9%Hemoglobin (g/dL) < 6.52%1% 6.5 – < 8.014%15% 8.0 – < 9.541%43%Platelets (cells/μL) < 2500027%21% 25000 – < 5000017%18% 50000 – < 10000020%30%Serum creatinine (mg/dL) > 2.52%3% > 1.5 – 2.517%20%The median time to engraftment (defined as absolute neutrophil count ≥ 500/mm3 on 3 consecutive days after transplantation) was 19 days in the PREVYMIS group and 18 days in the placebo group.
Risk SummaryNo adequate human data are available to establish whether PREVYMIS poses a risk to pregnancy outcomes. In animal reproduction studies, embryo-fetal developmental toxicity (including fetal malformations) was observed in rats during the period of organogenesis at letermovir exposures (AUC) 11 times higher than human exposure at the recommended human dose (RHD). In rabbits, no embryo-fetal developmental toxicity was noted at exposures that were not maternally toxic (up to letermovir exposures 2 times higher than human exposure at the RHD). In a rat pre/post-natal development study, total litter loss was observed at maternal letermovir exposures approximately 2 times higher than human exposure at the RHD (see Data).The 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 2-4% and 15-20%, respectively.
Data
Animal DataLetermovir was administered orally to pregnant rats at 0, 10, 50 or 250 mg/kg/day from gestation days 6 to 17. Developmental toxicities, including skeletal |
