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. |
| Molecular Weight | 591.1 |
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 | ZONTIVITY (vorapaxar) is contraindicated in pregnancy due to increased risk of bleeding, including placental abruption and fetal hemorrhage. Limited human data, but animal studies show adverse effects at high doses. |
| 2nd trimester | Contraindicated in pregnancy due to bleeding risk. Avoid use unless no alternative and potential benefit outweighs risks. |
| 3rd trimester | Contraindicated in pregnancy, especially near term, due to risk of maternal and fetal hemorrhage during delivery. |
Clinical note
Comprehensive clinical and safety monograph for ZONTIVITY (ZONTIVITY).
| Placental transfer | Vorapaxar is a small molecule (MW 591 Da) and is likely to cross the placenta. In animal studies, transfer to fetus was observed. Human data limited, but based on physicochemical properties, placental transfer is expected. |
| Breastfeeding | It is unknown if vorapaxar is excreted in human breast milk. Due to the potential for serious adverse reactions (bleeding) in nursing infants, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. |
■ 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 or transient ischemic attack (TIA)Active pathological bleeding (e.g., peptic ulcer, intracranial hemorrhage)Severe hepatic impairment (Child-Pugh C)
| 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. |
| Food/Dietary | No significant food interactions. Take with or without food. Avoid grapefruit juice? (Grapefruit may inhibit CYP3A4, but interaction is not considered clinically significant; however, caution is advised.) |
Loading safety data…
| Lactation Rating | L5 (Contraindicated) |
| 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. |
| 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. |
| Clinical Pearls | ZONTIVITY (vorapaxar) is a protease-activated receptor-1 antagonist that inhibits thrombin-mediated platelet aggregation. It is indicated for reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction or with peripheral arterial disease. Do not use in patients with a history of stroke, TIA, or intracranial hemorrhage. It is added to aspirin and/or clopidogrel. Monitor for bleeding, especially in patients with low body weight, age >75, or renal impairment. Avoid concomitant use with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin) or inducers (e.g., rifampin). |
| Patient Advice | Take one tablet daily with or without food. · Do not stop taking this medication without consulting your doctor, as it may increase risk of heart attack or stroke. · Avoid taking with other anticoagulants or antiplatelet drugs unless prescribed. · Report any signs of bleeding (unusual bruising, nosebleeds, black/tarry stools, blood in urine, coughing up blood) immediately. · Tell all healthcare providers that you are taking ZONTIVITY, especially before any surgery or dental procedure. · Do not take with strong CYP3A4 inhibitors (certain antifungals, antibiotics) or inducers (rifampin); inform your doctor of all medications. · If you have a history of stroke or TIA, do not take this medication. |