ZONTIVITY
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ZONTIVITY (ZONTIVITY).
ZONTIVITY (vorapaxar) is a protease-activated receptor-1 (PAR-1) antagonist that inhibits thrombin-induced and thrombin receptor agonist peptide (TRAP)-induced platelet aggregation. It does not directly inhibit thrombin activity but blocks thrombin-mediated platelet activation.
| Metabolism | Primarily metabolized by CYP3A4 and CYP2J2 to multiple metabolites, with the major metabolite M20 being active. Vorapaxar is a substrate of P-glycoprotein (P-gp). |
| Excretion | Primarily as unchanged drug via renal excretion (approximately 80%) and fecal/biliary elimination (approximately 20%). |
| Half-life | Terminal elimination half-life is approximately 10-12 hours in patients with normal renal function; prolonged in renal impairment. |
| Protein binding | Approximately 95% bound to serum proteins, primarily albumin. |
| Volume of Distribution | Volume of distribution is approximately 10-12 L (0.14 L/kg) indicating minimal distribution into extravascular tissues. |
| Bioavailability | Oral bioavailability is approximately 50-60% after administration. |
| Onset of Action | Oral: Onset within 2-4 hours for inhibition of platelet aggregation; peak effect at 6-12 hours. |
| Duration of Action | Duration of antiplatelet effect persists for the life of the platelet (approximately 7-10 days) due to irreversible inhibition of COX-1. |
1 mg orally once daily, with or without food.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (eGFR ≥30 mL/min). Not recommended for patients with severe renal impairment (eGFR <30 mL/min) or end-stage renal disease. |
| Liver impairment | No dose adjustment required for mild hepatic impairment (Child-Pugh A). Not recommended for patients with moderate or severe hepatic impairment (Child-Pugh B or C). |
| Pediatric use | Safety and efficacy in pediatric patients have not been established; no recommended dose. |
| Geriatric use | No specific dose adjustment recommended for elderly patients based on age alone. Monitor renal function and concomitant medications due to increased risk of bleeding. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for ZONTIVITY (ZONTIVITY).
| Breastfeeding | It is not known whether vorapaxar is excreted in human milk. No studies have assessed its presence in breast milk; M/P ratio is unknown. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from vorapaxar, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. |
| Teratogenic Risk | ZONTIVITY (vorapaxar) is classified as Pregnancy Category B. No adequate and well-controlled studies in pregnant women. In animal reproduction studies, no evidence of fetal harm was observed at exposures up to 4 times the human exposure. However, because animal studies are not always predictive of human response, ZONTIVITY should be used during pregnancy only if clearly needed. Risk cannot be ruled out; first trimester risks unknown, second and third trimester risks uncertain. |
■ FDA Black Box Warning
WARNING: BLEEDING RISK - ZONTIVITY increases the risk of bleeding, including fatal bleeding. Do not use in patients with a history of stroke, TIA, or intracranial hemorrhage. Do not use in patients with active pathological bleeding. Discontinue ZONTIVITY in patients with acute intracranial hemorrhage.
| Serious Effects |
["History of stroke, transient ischemic attack (TIA), or intracranial hemorrhage.","Active pathological bleeding (e.g., peptic ulcer, intracranial hemorrhage).","Concomitant use with strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, St. John's wort)."]
| Precautions | ["Increased risk of bleeding, especially in patients with prior stroke or TIA.","Avoid use in patients with active bleeding or at high risk for bleeding.","Concomitant use with anticoagulants, antiplatelet agents, NSAIDs, or SSRIs may increase bleeding risk.","No specific antidote available; management is supportive.","Renal or hepatic impairment: dosage adjustment not required, but caution advised in severe hepatic impairment."] |
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| Fetal Monitoring | No specific maternal-fetal monitoring requirements beyond standard pregnancy monitoring. In patients with risk factors for bleeding, monitor for signs and symptoms of bleeding. No known fetal monitoring requirements specific to vorapaxar. |
| Fertility Effects | No human studies on fertility effects. In animal studies, vorapaxar had no effect on male or female fertility in rats at exposures up to 4 times the human exposure. Effects on human fertility are unknown. |