ld be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
toxicity study, pregnant rats received daily oral doses of vorapaxar at 0, 5, 25, and 75 mg/kg from implantation to closure of the fetal hard palate (6th to 17th day of gestation). Maternal systemic exposures were approximately 0, 7, 56, and 285 times greater than exposures in women treated at the RHD based on AUC. No embryo/fetal toxicities, malformations, or maternal toxicities were observed in rats receiving exposures up to 56 times the human systemic exposure at the RHD.
In the rabbit embryo/fetal developmental toxicity study, pregnant rabbits received daily oral doses of vorapaxar at 0, 2, 10, or 20 mg/kg from implantation to closure of the fetal hard palate (7th to 19th day of gestation). The NOAEL for maternal and fetal toxicity was equal to or above the highest dose tested. However, an overall increase in the number of litters with any malformation was observed at the highest dose, where systemic exposures were 89-fold higher than the human exposure at RHD.
The effects of vorapaxar on prenatal and postnatal development were assessed in pregnant rats dosed at 0, 5, 25, or 50 mg/kg/day from implantation through the end of lactation. Rat pups had decreased survival and body weight gain from birth to postnatal day 4 and decreased body weight gain for the overall pre-weaning period at exposures 67 times the human exposure at the RHD. Both male and female pups displayed effects on sensory function (acoustic startle) and neurobehavioral (locomotor assay) development on post-natal day (PND) 20 and 21, but not later (PND 60, 61) in development, whereas decreased memory was observed in female pups on PND 27 at 31 times the human exposure at the RHD. In utero and lactational exposure did not affect fertility or reproductive behavior of offspring at exposures up to 67 times the RHD.
8.3 Nursing Mothers
It is unknown whether vorapaxar or its metabolites are excreted in human milk, but it is actively secreted in milk of rats. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZONTIVITY, discontinue nursing or discontinue ZONTIVITY.
8.4 Pediatric Use
The safety and effectiveness of ZONTIVITY in pediatric patients have not been established.
8.5 Geriatric Use
In TRA 2°P, in post-MI or PAD patients without a history of stroke or TIA, 33% of patients were ≥65 years of age and 9% were ≥75 years of age. The relative risk of bleeding (ZONTIVITY compared with placebo) was similar across age groups. No overall differences in safety or effectiveness were observed between these patients and younger patients. ZONTIVITY increases the risk of bleeding in proportion to a patient’s underlying risk. Because older patients are generally at a higher risk of bleeding, consider patient age before initiating ZONTIVITY [see Adverse Reactions (6.1)].
8.6 Renal Impairment
No dose adjustment is required in patients with renal impairment [see Clinical Pharmacology (12.3)].
8.7 Hepatic Impairment
No dose adjustment is required in patients with mild and moderate hepatic impairment. Based on the increased inherent risk of bleeding in patients with severe hepatic impairment, ZONTIVITY is not recommended in such patients [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
10 OVERDOSAGE
There is no known treatment to reverse the antiplatelet effect of ZONTIVITY, and neither dialysis n |
