Zontivity Prescribing Information
- Do not use ZONTIVITY in patients with a history of stroke, transient ischemic attack (TIA), or intracranial hemorrhage (ICH); or active pathological bleeding [see CONTRAINDICATIONS (4.1, 4.2)] .
- Antiplatelet agents, including ZONTIVITY, increase the risk of bleeding, including ICH and fatal bleeding [see Warnings and Precautions (5.1)].
Patients with History of Myocardial Infarction (MI) or with Peripheral Arterial Disease (PAD)
ZONTIVITY ® is indicated for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or with peripheral arterial disease (PAD). ZONTIVITY has been shown to reduce the rate of a combined endpoint of cardiovascular death, MI, stroke, and urgent coronary revascularization (UCR).
General Dosing Information
Take one tablet of ZONTIVITY 2.08 mg orally once daily, with or without food.
Coadministration with Other Antiplatelet Drugs
There is no experience with use of ZONTIVITY alone as the only administered antiplatelet agent. ZONTIVITY has been studied only as an addition to aspirin and/or clopidogrel. Use ZONTIVITY with aspirin and/or clopidogrel according to their indications or standard of care [see Clinical Studies (14)] . There is limited clinical experience with other antiplatelet drugs.
ZONTIVITY tablets, 2.08 mg vorapaxar, are yellow, oval-shaped, film-coated tablets with "351" on one side.
Pregnancy
Risk Summary
Based on the potential for serious adverse reactions (such as maternal bleeding/hemorrhage) and the long half-life which makes it effectively irreversible, discontinue vorapaxar when pregnancy is detected and initiate alternative therapy with a shorter duration of action [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.1, 12.2)] . Available data from postmarketing experience with ZONTIVITY use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, no embryo/fetal toxicities, malformations or maternal toxicities were observed in rats and rabbits exposed during the period of organogenesis at exposures 56 times and 26 times, respectively, the human systemic exposure at the recommended human dose (RHD) (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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.
Data
Animal Data
In the rat embryo/fetal developmental 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.
Lactation
Risk Summary
There are no data on the presence of vorapaxar or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. When vorapaxar was administered to lactating rats, vorapaxar was actively secreted in the milk of rats. When a drug is present in animal milk, it is likely the drug will be present in human milk. Because of the potential for serious adverse reactions in the breastfed infant, such as bleeding, advise patients that breastfeeding is not recommended during treatment with ZONTIVITY.
Pediatric Use
The safety and effectiveness of ZONTIVITY in pediatric patients have not been established.
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)].
Renal Impairment
No dose adjustment is required in patients with renal impairment [see Clinical Pharmacology (12.3)].
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)].
History of Stroke, Transient Ischemic Attack (TIA), or Intracranial Hemorrhage (ICH)
ZONTIVITY is contraindicated in patients with a history of stroke, TIA, or ICH because of an increased risk of ICH in this population [see Adverse Reactions (6)] .
Discontinue ZONTIVITY in patients who experience a stroke, TIA, or ICH [see Adverse Reactions (6.1) and Clinical Studies (14)] .
Active Pathologic Bleeding
ZONTIVITY is contraindicated in patients with active pathological bleeding such as ICH or peptic ulcer [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)] .