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    Protease-Activated Receptor-1 (PAR-1) Antagonist

    BOXED WARNING

    Bleeding, hepatic disease, intracranial bleeding, renal impairment, stroke

    Vorapaxar is contraindicated in patients with active pathological bleeding including intracranial bleeding or GI bleeding (e.g., peptic ulcer). Vorapaxar is also contraindicated in patients with a history of stroke, transient ischemic attack, or intracranial bleeding due to an increased risk of intracranial hemorrhage in such patients. Vorapaxar increases the risk of bleeding in proportion to the patient’s underlying bleeding risk. Clinicians should consider the underlying bleeding risk prior to initiation of vorapaxar. General risk factors for bleeding include older age (i.e., elderly patients), low body weight, renal impairment, history of bleeding disorders, use of certain concomitant medications (e.g., anticoagulants, fibrinolytic therapy, chronic nonsteroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors), and hepatic disease. Use of vorapaxar is not recommended in patients with severe hepatic impairment. Significant inhibition of platelet aggregation remains for 4 weeks after discontinuation of vorapaxar; therefore, withholding a dose of vorapaxar will not be useful in managing a bleeding event or reducing the risk of bleeding in preparation for an invasive procedure. There is no known treatment to reverse the antiplatelet effect of vorapaxar.

    DEA CLASS

    Rx

    DESCRIPTION

    Protease-activated receptor-1 (PAR-1) antagonist which inhibits thrombin-related platelet aggregation
    Used for reduction in risk of myocardial infarction, stroke, cardiovascular death, and need for coronary revascularization in patients with a previous myocardial infarction or peripheral arterial disease
    Increased risk of bleeding, including life-threatening or fatal bleeding

    COMMON BRAND NAMES

    Zontivity

    HOW SUPPLIED

    Vorapaxar/Zontivity Oral Tab: 2.08mg

    DOSAGE & INDICATIONS

    For secondary myocardial infarction prophylaxis or stroke prophylaxis or thrombosis prophylaxis for reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction or with peripheral arterial disease.
    NOTE: Vorapaxar has been shown to reduce the rate of a combined endpoint of cardiovascular death, myocardial infarction, stroke, and urgent coronary revascularization.
    Oral dosage
    Adults

    2.08 mg PO once daily with aspirin and/or clopidogrel according to their indications or standard of care.

    MAXIMUM DOSAGE

    Adults

    2.08 mg/day PO.

    Geriatric

    2.08 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Due to an increased risk of bleeding, vorapaxar is not recommended for use in patients with severe hepatic impairment. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment.

    Renal Impairment

    No dosage adjustment is necessary.

    ADMINISTRATION

    Oral Administration

    May be administered with or without food.

    STORAGE

    Zontivity:
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in original package until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    Bleeding, hepatic disease, intracranial bleeding, renal impairment, stroke

    Vorapaxar is contraindicated in patients with active pathological bleeding including intracranial bleeding or GI bleeding (e.g., peptic ulcer). Vorapaxar is also contraindicated in patients with a history of stroke, transient ischemic attack, or intracranial bleeding due to an increased risk of intracranial hemorrhage in such patients. Vorapaxar increases the risk of bleeding in proportion to the patient’s underlying bleeding risk. Clinicians should consider the underlying bleeding risk prior to initiation of vorapaxar. General risk factors for bleeding include older age (i.e., elderly patients), low body weight, renal impairment, history of bleeding disorders, use of certain concomitant medications (e.g., anticoagulants, fibrinolytic therapy, chronic nonsteroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors), and hepatic disease. Use of vorapaxar is not recommended in patients with severe hepatic impairment. Significant inhibition of platelet aggregation remains for 4 weeks after discontinuation of vorapaxar; therefore, withholding a dose of vorapaxar will not be useful in managing a bleeding event or reducing the risk of bleeding in preparation for an invasive procedure. There is no known treatment to reverse the antiplatelet effect of vorapaxar.

    Coronary artery bypass graft surgery (CABG), surgery

    Bleeding should be suspected in any patient presenting with hypotension who has recently undergone surgery, coronary angiography, percutaneous coronary intervention (PCI), or coronary artery bypass graft surgery (CABG).

    Geriatric

    Because geriatric patients are generally at a higher risk of bleeding, consider patient age before starting vorapaxar. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities. According to the OBRA guidelines, platelet inhibitors may cause thrombocytopenia and increase the risk of bleeding. Common side effects of platelet inhibitors include headache, dizziness, and vomiting. Concurrent use with warfarin or NSAIDs may increase the risk of bleeding.

    Pregnancy

    Due to the potential for serious adverse reactions, such as maternal bleeding or hemorrhage, and long half-life, which makes vorapaxar effectively irreversible, discontinue vorapaxar when pregnancy is detected and initiate alternate therapy with a shorter duration of action. Data form postmarketing experience with vorapaxar use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. No adverse embryo or fetal toxicities, malformations, or maternal toxicities were observed in rats and rabbits exposed to vorapaxar during organogenesis at exposures 56 times and 26 times, respectively, the human systemic exposure at the recommended human dose (RHD).[57151]

    Breast-feeding

    Because of the potential for serious adverse reactions in the breast-fed infant, such as bleeding, breast-feeding is not recommended during treatment with vorapaxar. There are no data on the presence of vorapaxar or its metabolites in human milk, the effects on the breast-fed 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.

    ADVERSE REACTIONS

    Severe

    GI bleeding / Delayed / 4.0-4.0
    retinopathy / Delayed / 0-2.0
    intracranial bleeding / Delayed / 0.4-0.4

    Moderate

    bleeding / Early / 25.0-25.0
    anemia / Delayed / 5.0-5.0
    depression / Delayed / 2.4-2.4

    Mild

    rash / Early / 2.2-2.2
    diplopia / Early / 0.2-0.2

    DRUG INTERACTIONS

    Abciximab: (Moderate) Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as platelet glycoprotein IIb/IIIa inhibitors including abciximab, eptifibatide, and tirofiban.
    Abrocitinib: (Contraindicated) Concurrent use with vorapaxar is contraindicated during the first 3 months of abrocitinib therapy due to an increased risk of bleeding with thrombocytopenia.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Although indicated for concomitant use, both vorapaxar and aspirin are associated with bleeding. Monitor for bleeding during concomitant therapy.
    Ado-Trastuzumab emtansine: (Moderate) Use caution if coadministration of platelet inhibitors with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
    ADP receptor antagonists: (Moderate) Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as ADP receptor antagonists including clopidogrel, prasugrel, ticagrelor, or ticlopidine.
    Altretamine: (Moderate) An additive risk of bleeding may occur when platelet inhibitors is used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as altretamine.
    Aminolevulinic Acid: (Minor) Agents, such as platelet inhibitors, that decrease clotting could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    Amiodarone: (Moderate) Use caution during concurrent use of vorapaxar and amiodarone. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with amiodarone, a CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Amobarbital: (Moderate) Use caution during concurrent use of vorapaxar and other barbiturates. Vorapaxar is a CYP3A4 substrate. Barbiturates induce CYP3A. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible during concurrent use.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of vorapaxar and clarithromycin. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with clarithromycin, a strong CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Anagrelide: (Moderate) Because vorapaxar and anagrelide inhibit platelet aggregation, a potential additive risk for bleeding exists if they are coadminsitered.
    Antithrombin III: (Major) Avoid concomitant use of vorapaxar and anticoagulants. Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as anticoagulants.
    Antithymocyte Globulin: (Moderate) An increased risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia, such as antithymocyte globulin. Platelet inhibitors should be used cautiously in patients with thrombocytopenia following the administration of antithymocyte globulin or other drugs that cause significant thrombocytopenia due to the increased risk of bleeding.
    Apalutamide: (Major) Avoid coadministration of vorapaxar and apalutamide due to decreased serum concentrations of vorapaxar. Vorapaxar is a CYP3A4 substrate and apalutamide is a strong CYP3A inducer. Coadministration with another strong CYP3A4 inducer decreased vorapaxar exposure by 55%; the impact on efficacy for a change in exposure of this magnitude is not known.
    Apixaban: (Major) The concomitant use of apixaban and platelet inhibitors (e.g, aspirin) may increase the risk of bleeding. In the ARISTOTLE trial (comparative trial of apixaban and warfarin in patients with nonvalvular atrial fibrillation), concomitant use of aspirin increased the bleeding risk of apixaban from 1.8%/year to 3.4%/year. If given concomitantly, patients should be educated about the signs and symptoms of bleeding and be instructed to report them immediately or go to an emergency room.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if vorapaxar and aprepitant, fosaprepitant are used concurrently and monitor for an increase in vorapaxar-related adverse effects for several days after administration of a multi-day aprepitant regimen. Vorapaxar is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of vorapaxar. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Ardeparin: (Major) Avoid concomitant use of vorapaxar and warfarin or other anticoagulants. Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as anticoagulants.
    Argatroban: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., clopidogrel, platelet glycoprotein IIb/IIIa inhibitors, ticlopidine, etc.) in combination with argatroban.
    Armodafinil: (Minor) Use caution during concurrent use of vorapaxar and armodafinil. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with armodafinil, a mild inducer of CYP3A4 in vitro.
    Aspirin, ASA: (Moderate) Although indicated for concomitant use, both vorapaxar and aspirin are associated with bleeding. Monitor for bleeding during concomitant therapy.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Although indicated for concomitant use, both vorapaxar and aspirin are associated with bleeding. Monitor for bleeding during concomitant therapy. (Moderate) Use caution during concurrent use of vorapaxar and other barbiturates. Vorapaxar is a CYP3A4 substrate. Barbiturates induce CYP3A. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible during concurrent use.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Although indicated for concomitant use, both vorapaxar and aspirin are associated with bleeding. Monitor for bleeding during concomitant therapy. (Moderate) Use caution during concurrent use of vorapaxar and other barbiturates. Vorapaxar is a CYP3A4 substrate. Barbiturates induce CYP3A. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible during concurrent use.
    Aspirin, ASA; Caffeine: (Moderate) Although indicated for concomitant use, both vorapaxar and aspirin are associated with bleeding. Monitor for bleeding during concomitant therapy.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Although indicated for concomitant use, both vorapaxar and aspirin are associated with bleeding. Monitor for bleeding during concomitant therapy.
    Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Although indicated for concomitant use, both vorapaxar and aspirin are associated with bleeding. Monitor for bleeding during concomitant therapy.
    Aspirin, ASA; Carisoprodol: (Moderate) Although indicated for concomitant use, both vorapaxar and aspirin are associated with bleeding. Monitor for bleeding during concomitant therapy.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Although indicated for concomitant use, both vorapaxar and aspirin are associated with bleeding. Monitor for bleeding during concomitant therapy.
    Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Although indicated for concomitant use, both vorapaxar and aspirin are associated with bleeding. Monitor for bleeding during concomitant therapy.
    Aspirin, ASA; Dipyridamole: (Moderate) Although indicated for concomitant use, both vorapaxar and aspirin are associated with bleeding. Monitor for bleeding during concomitant therapy. (Moderate) Because vorapaxar and dipyridamole inhibit platelet aggregation, a potential additive risk for bleeding exists if they are coadminsitered.
    Aspirin, ASA; Omeprazole: (Moderate) Although indicated for concomitant use, both vorapaxar and aspirin are associated with bleeding. Monitor for bleeding during concomitant therapy.
    Aspirin, ASA; Oxycodone: (Moderate) Although indicated for concomitant use, both vorapaxar and aspirin are associated with bleeding. Monitor for bleeding during concomitant therapy.
    Aspirin, ASA; Pravastatin: (Moderate) Although indicated for concomitant use, both vorapaxar and aspirin are associated with bleeding. Monitor for bleeding during concomitant therapy.
    Atazanavir: (Moderate) Use caution during concurrent use of vorapaxar and atazanavir. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with atazanavir, a CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Atazanavir; Cobicistat: (Major) Avoid coadministration of vorapaxar with cobicistat due to increased plasma concentrations of vorapaxar and the risk of treatment-related adverse reactions. Vorapaxar is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased vorapaxar exposure by 2-fold; the bleeding risk for a change in exposure of this magnitude is not known. (Moderate) Use caution during concurrent use of vorapaxar and atazanavir. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with atazanavir, a CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid coadministration of vorapaxar and phenobarbital or primidone. Use caution during concurrent use of vorapaxar and other barbiturates. Vorapaxar is a CYP3A4 substrate. Phenobarbital and primidone are strong CYP3A inducers. Other barbiturates also induce CYP3A. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible during concurrent use.
    Betrixaban: (Major) Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if betrixaban and platelet inhibitors are used concomitantly. Coadministration of betrixaban and platelet inhibitors may increase the risk of bleeding.
    Bexarotene: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including bexarotene.
    Bivalirudin: (Moderate) When used as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI), bivalirudin is intended for use with aspirin (300 to 325 mg/day PO) and has been studied only in patients receiving concomitant aspirin. Generally, an additive risk of bleeding may be seen in patients receiving other platelet inhibitors (other than aspirin). In clinical trials in patients undergoing PTCA, patients receiving bivalirudin with heparin, warfarin, or thrombolytics had increased risks of major bleeding events compared to those receiving bivalirudin alone. According to the manufacturer, the safety and effectiveness of bivalirudin have not been established when used in conjunction with platelet inhibitors other than aspirin. However, bivalirudin has been safely used as an alternative to heparin in combination with provisional use of platelet glycoprotein IIb/IIIa inhibitors during angioplasty (REPLACE-2). In addition, two major clinical trials have evaluated the use of bivalirudin in patients receiving streptokinase following acute myocardial infarction (HERO-1, HERO-2). Based on the these trials, bivalirudin may be considered an alternative to heparin therapy for use in combination with streptokinase for ST-elevation MI. Bivalirudin has not been sufficiently studied in combination with other more specific thrombolytics.
    Boceprevir: (Major) Avoid coadministration of vorapaxar and boceprevir. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with boceprevir, a strong CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Bosentan: (Moderate) Use caution during concurrent use of vorapaxar and bosentan. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with bosentan, a CYP3A inducer.
    Butabarbital: (Moderate) Use caution during concurrent use of vorapaxar and other barbiturates. Vorapaxar is a CYP3A4 substrate. Barbiturates induce CYP3A. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible during concurrent use.
    Butalbital; Acetaminophen: (Moderate) Use caution during concurrent use of vorapaxar and other barbiturates. Vorapaxar is a CYP3A4 substrate. Barbiturates induce CYP3A. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible during concurrent use.
    Butalbital; Acetaminophen; Caffeine: (Moderate) Use caution during concurrent use of vorapaxar and other barbiturates. Vorapaxar is a CYP3A4 substrate. Barbiturates induce CYP3A. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible during concurrent use.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Use caution during concurrent use of vorapaxar and other barbiturates. Vorapaxar is a CYP3A4 substrate. Barbiturates induce CYP3A. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible during concurrent use.
    Caplacizumab: (Major) Avoid concomitant use of caplacizumab and platelet inhibitors when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
    Carbamazepine: (Major) Avoid coadministration of vorapaxar and carbamazepine. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with carbamazepine, a strong CYP3A inducer.
    Ceritinib: (Major) Avoid coadministration of vorapaxar with ceritinib due to increased plasma concentrations of vorapaxar and the risk of treatment-related adverse reactions. Vorapaxar is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased vorapaxar exposure by 2-fold; the bleeding risk for a change in exposure of this magnitude is not known.
    Chlorambucil: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as chlorambucil.
    Chloramphenicol: (Moderate) Use caution during concurrent use of vorapaxar and chloramphenicol. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with chloramphenicol, a CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Cilostazol: (Moderate) Because vorapaxar and cilostazol inhibit platelet aggregation, a potential additive risk for bleeding exists if they are coadminsitered.
    Cimetidine: (Moderate) Use caution during concurrent use of vorapaxar and cimetidine. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with cimetidine, a mild CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Citalopram: (Moderate) Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as selective serotonin reuptake inhibitors (SSRIs). Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion. In addition, fluoxetine and fluvoxamine are CYP3A4 inhibitors and coadministration with vorapaxar, a CYP3A4 substrate, may result in increased serum concentrations of vorapaxar. Increased exposure to vorapaxar may increase the risk of bleeding complications. Patients should be instructed to monitor for signs and symptoms of bleeding while taking a SSRI with vorapaxar and to promptly report any bleeding events.
    Cladribine: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Clarithromycin: (Major) Avoid coadministration of vorapaxar and clarithromycin. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with clarithromycin, a strong CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Clofarabine: (Moderate) Due to the thrombocytopenic effects of antineoplastics an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Clopidogrel: (Moderate) Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as ADP receptor antagonists including clopidogrel, prasugrel, ticagrelor, or ticlopidine.
    Cobicistat: (Major) Avoid coadministration of vorapaxar with cobicistat due to increased plasma concentrations of vorapaxar and the risk of treatment-related adverse reactions. Vorapaxar is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased vorapaxar exposure by 2-fold; the bleeding risk for a change in exposure of this magnitude is not known.
    Cocaine: (Moderate) Use caution during concurrent use of vorapaxar and cocaine. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with cocaine, a mild CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Collagenase: (Moderate) Cautious use of injectable collagenase by patients taking platelet inhibitors is advised. The efficacy and safety of administering injectable collagenase to a patient taking a platelet inhibitor within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Cyclosporine: (Moderate) Use caution during concurrent use of vorapaxar and cyclosporine. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with cyclosporine, a mild CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Dabigatran: (Major) Avoid concomitant use of vorapaxar and warfarin or other anticoagulants. Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as anticoagulants. In a phase II trial, aspirin (81 mg or 325 mg) was randomly assigned to patients with atrial fibrillation receiving dabigatran (150 mg twice daily). Data obtained from logistic regression analysis suggest that the concomitant administration of aspirin and dabigatran may increase the risk of bleeding from 12% to 18% (81 mg aspirin) or 24% (325 mg aspirin). Monitor patients closely for signs of bleeding if dabigatran is given concomitantly with other platelet inhibitors.
    Dabrafenib: (Moderate) Use caution during concurrent use of vorapaxar and dabrafenib. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with dabrafenib, a CYP3A inducer.
    Dalteparin: (Major) Avoid concomitant use of vorapaxar and warfarin or other anticoagulants. Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as anticoagulants.
    Danaparoid: (Major) Avoid concomitant use of vorapaxar and warfarin or other anticoagulants. Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as anticoagulants.
    Danazol: (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with platelet inhibitors.
    Darunavir: (Moderate) Use caution during concurrent use of vorapaxar and darunavir. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with darunavir, a CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Darunavir; Cobicistat: (Major) Avoid coadministration of vorapaxar with cobicistat due to increased plasma concentrations of vorapaxar and the risk of treatment-related adverse reactions. Vorapaxar is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased vorapaxar exposure by 2-fold; the bleeding risk for a change in exposure of this magnitude is not known. (Moderate) Use caution during concurrent use of vorapaxar and darunavir. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with darunavir, a CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of vorapaxar with cobicistat due to increased plasma concentrations of vorapaxar and the risk of treatment-related adverse reactions. Vorapaxar is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased vorapaxar exposure by 2-fold; the bleeding risk for a change in exposure of this magnitude is not known. (Moderate) Use caution during concurrent use of vorapaxar and darunavir. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with darunavir, a CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of vorapaxar and ritonavir. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with ritonavir, a strong CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Dasatinib: (Moderate) Use caution during concurrent use of vorapaxar and dasatinib. Due to the thrombocytopenic and possible platelet inhibiting effects of dasatinib, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with dasatinib, a CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Defibrotide: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like platelet inhibitors is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue antithrombotic agents prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
    Delavirdine: (Major) Avoid coadministration of vorapaxar and delavirdine. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with delavirdine, a strong CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Desirudin: (Major) Avoid concomitant use of vorapaxar and warfarin or other anticoagulants. Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as anticoagulants.
    Desogestrel; Ethinyl Estradiol: (Moderate) Use caution during concurrent use of vorapaxar and ethinyl estradiol. Vorapaxar is a CYP3A4 substrate. Ethinyl estradiol inhibits CYP3A4 in vitro. Increased serum concentrations of vorapaxar are possible when vorapaxar is coadministered with ethinyl estradiol. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Desvenlafaxine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with a platelet inhibitor and to promptly report any bleeding events to the practitioner.
    Dexamethasone: (Moderate) Use caution during concurrent use of vorapaxar and dexamethasone. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with dexamethasone, a CYP3A inducer.
    Diltiazem: (Moderate) Use caution during concurrent use of vorapaxar and diltiazem. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with diltiazem, a CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Dipyridamole: (Moderate) Because vorapaxar and dipyridamole inhibit platelet aggregation, a potential additive risk for bleeding exists if they are coadminsitered.
    Dronedarone: (Moderate) Use caution during concurrent use of vorapaxar and dronedarone. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with dronedarone, a CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Drospirenone; Ethinyl Estradiol: (Moderate) Use caution during concurrent use of vorapaxar and ethinyl estradiol. Vorapaxar is a CYP3A4 substrate. Ethinyl estradiol inhibits CYP3A4 in vitro. Increased serum concentrations of vorapaxar are possible when vorapaxar is coadministered with ethinyl estradiol. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Use caution during concurrent use of vorapaxar and ethinyl estradiol. Vorapaxar is a CYP3A4 substrate. Ethinyl estradiol inhibits CYP3A4 in vitro. Increased serum concentrations of vorapaxar are possible when vorapaxar is coadministered with ethinyl estradiol. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Drotrecogin Alfa: (Major) Treatment with drotrecogin alfa should be carefully considered in patients who are receiving or have received any platelet inhibitors within 7 days. These patients are at increased risk of bleeding during drotrecogin alfa therapy.
    Duloxetine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with a platelet inhibitor and to promptly report any bleeding events to the practitioner.
    Edoxaban: (Major) Coadministration of edoxaban and platelet inhibitors should be avoided due to an increased risk of bleeding during concurrent use. Occasionally, short-term coadministration may be necessary in patients transitioning to and from edoxaban. Long-term coadminstration is not recommended. Promptly evaluate any signs or symptoms of blood loss in patients on concomitant therapy.
    Efavirenz: (Moderate) Use caution during concurrent use of vorapaxar and efavirenz. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with efavirenz, a CYP3A inducer.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Use caution during concurrent use of vorapaxar and efavirenz. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with efavirenz, a CYP3A inducer.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Use caution during concurrent use of vorapaxar and efavirenz. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with efavirenz, a CYP3A inducer.
    Elbasvir; Grazoprevir: (Moderate) Administering vorapaxar with elbasvir; grazoprevir may result in elevated vorapaxar plasma concentrations. Vorapaxar is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of vorapaxar with cobicistat due to increased plasma concentrations of vorapaxar and the risk of treatment-related adverse reactions. Vorapaxar is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased vorapaxar exposure by 2-fold; the bleeding risk for a change in exposure of this magnitude is not known.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of vorapaxar with cobicistat due to increased plasma concentrations of vorapaxar and the risk of treatment-related adverse reactions. Vorapaxar is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased vorapaxar exposure by 2-fold; the bleeding risk for a change in exposure of this magnitude is not known.
    Enoxaparin: (Major) Avoid concomitant use of vorapaxar and warfarin or other anticoagulants. Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as anticoagulants.
    Enzalutamide: (Major) Avoid coadministration of vorapaxar and enzalutamide due to decreased serum concentrations of vorapaxar. Vorapaxar is a CYP3A4 substrate and enzalutamide is a strong CYP3A inducer. Coadministration with another strong CYP3A4 inducer decreased vorapaxar exposure by 55%; the impact on efficacy for a change in exposure of this magnitude is not known.
    Eptifibatide: (Moderate) Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as platelet glycoprotein IIb/IIIa inhibitors including abciximab, eptifibatide, and tirofiban.
    Erythromycin: (Moderate) Use caution during concurrent use of vorapaxar and erythromycin. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with erythromycin, a CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Erythromycin; Sulfisoxazole: (Moderate) Use caution during concurrent use of vorapaxar and erythromycin. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with erythromycin, a CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Escitalopram: (Moderate) Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as selective serotonin reuptake inhibitors (SSRIs). Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion. In addition, fluoxetine and fluvoxamine are CYP3A4 inhibitors and coadministration with vorapaxar, a CYP3A4 substrate, may result in increased serum concentrations of vorapaxar. Increased exposure to vorapaxar may increase the risk of bleeding complications. Patients should be instructed to monitor for signs and symptoms of bleeding while taking a SSRI with vorapaxar and to promptly report any bleeding events.
    Eslicarbazepine: (Moderate) Use caution during concurrent use of vorapaxar and eslicarbazepine. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with eslicarbazepine, a CYP3A inducer.
    Ethinyl Estradiol: (Moderate) Use caution during concurrent use of vorapaxar and ethinyl estradiol. Vorapaxar is a CYP3A4 substrate. Ethinyl estradiol inhibits CYP3A4 in vitro. Increased serum concentrations of vorapaxar are possible when vorapaxar is coadministered with ethinyl estradiol. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) Use caution during concurrent use of vorapaxar and ethinyl estradiol. Vorapaxar is a CYP3A4 substrate. Ethinyl estradiol inhibits CYP3A4 in vitro. Increased serum concentrations of vorapaxar are possible when vorapaxar is coadministered with ethinyl estradiol. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Ethinyl Estradiol; Norelgestromin: (Moderate) Use caution during concurrent use of vorapaxar and ethinyl estradiol. Vorapaxar is a CYP3A4 substrate. Ethinyl estradiol inhibits CYP3A4 in vitro. Increased serum concentrations of vorapaxar are possible when vorapaxar is coadministered with ethinyl estradiol. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Use caution during concurrent use of vorapaxar and ethinyl estradiol. Vorapaxar is a CYP3A4 substrate. Ethinyl estradiol inhibits CYP3A4 in vitro. Increased serum concentrations of vorapaxar are possible when vorapaxar is coadministered with ethinyl estradiol. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Ethinyl Estradiol; Norgestrel: (Moderate) Use caution during concurrent use of vorapaxar and ethinyl estradiol. Vorapaxar is a CYP3A4 substrate. Ethinyl estradiol inhibits CYP3A4 in vitro. Increased serum concentrations of vorapaxar are possible when vorapaxar is coadministered with ethinyl estradiol. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Ethynodiol Diacetate; Ethinyl Estradiol: (Moderate) Use caution during concurrent use of vorapaxar and ethinyl estradiol. Vorapaxar is a CYP3A4 substrate. Ethinyl estradiol inhibits CYP3A4 in vitro. Increased serum concentrations of vorapaxar are possible when vorapaxar is coadministered with ethinyl estradiol. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Etonogestrel; Ethinyl Estradiol: (Moderate) Use caution during concurrent use of vorapaxar and ethinyl estradiol. Vorapaxar is a CYP3A4 substrate. Ethinyl estradiol inhibits CYP3A4 in vitro. Increased serum concentrations of vorapaxar are possible when vorapaxar is coadministered with ethinyl estradiol. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Etravirine: (Moderate) Use caution during concurrent use of vorapaxar and etravirine. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with etravirine, a CYP3A inducer.
    Felbamate: (Moderate) Use caution during concurrent use of vorapaxar and felbamate. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with felbamate, a mild CYP3A inducer.
    Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Moderate) Because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with other platelet inhibitors. Theoretically, the risk of bleeding may be increased.
    Fluconazole: (Moderate) Use caution during concurrent use of vorapaxar and fluconazole. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with fluconazole, a mild CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Fludarabine: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Fluoxetine: (Moderate) Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as selective serotonin reuptake inhibitors (SSRIs). Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion. In addition, fluoxetine and fluvoxamine are CYP3A4 inhibitors and coadministration with vorapaxar, a CYP3A4 substrate, may result in increased serum concentrations of vorapaxar. Increased exposure to vorapaxar may increase the risk of bleeding complications. Patients should be instructed to monitor for signs and symptoms of bleeding while taking a SSRI with vorapaxar and to promptly report any bleeding events.
    Flutamide: (Moderate) Use caution during concurrent use of vorapaxar and flutamide. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with flutamide, an inducer of CYP3A4 in vitro.
    Fluvoxamine: (Moderate) Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as selective serotonin reuptake inhibitors (SSRIs). Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion. In addition, fluoxetine and fluvoxamine are CYP3A4 inhibitors and coadministration with vorapaxar, a CYP3A4 substrate, may result in increased serum concentrations of vorapaxar. Increased exposure to vorapaxar may increase the risk of bleeding complications. Patients should be instructed to monitor for signs and symptoms of bleeding while taking a SSRI with vorapaxar and to promptly report any bleeding events.
    Fondaparinux: (Major) Avoid concomitant use of vorapaxar and other anticoagulants. Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as anticoagulants.
    Fosamprenavir: (Moderate) Use caution during concurrent use of vorapaxar and fosamprenavir. Fosamprenavir may inhibit or induce CYP3A4 and may alter serum concentrations of other drugs metabolized by this enzyme. Increased or decreased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with fosamprenavir. Increased exposure to vorapaxar may increase the risk of bleeding complications while decreased exposure to vorapaxar may reduce efficacy.
    Fosphenytoin: (Major) Avoid coadministration of vorapaxar and phenytoin or fosphenytoin. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with phenytoin, a strong CYP3A inducer.
    Garlic, Allium sativum: (Moderate) Use together with caution. Garlic produces clinically significant antiplatelet effects, and a risk for bleeding may occur if platelet inhibitors are given in combination with garlic.
    Ginger, Zingiber officinale: (Moderate) Ginger inhibits thromboxane synthetase, a platelet aggregation inducer, and is a prostacyclin agonist so additive bleeding may occur if platelet inhibitors are given in combination with ginger, zingiber officinale.
    Ginkgo, Ginkgo biloba: (Moderate) Monitor for signs or symptoms of bleeding with coadministration of ginkgo biloba and platelet inhibitors as an increased bleeding risk may occur. Although data are mixed, ginkgo biloba is reported to inhibit platelet aggregation and several case reports describe bleeding complications with ginkgo biloba, with or without concomitant drug therapy.
    Grapefruit juice: (Moderate) Use caution during concurrent use of vorapaxar and grapefruit juice. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with grapefruit juice, a CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Heparin: (Major) Avoid concomitant use of vorapaxar and warfarin or other anticoagulants. Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as anticoagulants.
    Ibritumomab Tiuxetan: (Major) During and after therapy, avoid the concomitant use of Yttrium (Y)-90 ibrutumomab tiuxetan with drugs that interfere with platelet function such as platelet inhibitors; the risk of bleeding may be increased. If coadministration with platelet inhibitors is necessary, monitor platelet counts more frequently for evidence of thrombocytopenia.
    Icosapent ethyl: (Moderate) Icosapent ethyl is an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA). Because omega-3 fatty acids inhibit platelet aggregation, caution is advised when icosapent ethyl is used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 36 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant icosapent ethyl therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Iloprost: (Moderate) When used concurrently with platelet inhibitors, inhaled iloprost may increase the risk of bleeding.
    Imatinib: (Moderate) Use caution during concurrent use of vorapaxar and imatinib. Due to the thrombocytopenic effects of imatinib an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with imatinib, STI-571, a CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Indinavir: (Major) Avoid coadministration of vorapaxar and indinavir. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with indinavir, a strong CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Inotersen: (Moderate) Use caution with concomitant use of inotersen and vorapaxar due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of vorapaxar in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
    Intravenous Lipid Emulsions: (Moderate) Because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with other platelet inhibitors. Theoretically, the risk of bleeding may be increased.
    Isavuconazonium: (Major) Concomitant use of isavuconazonium with vorapaxar may result in increased serum concentrations of vorapaxar which may increase the risk of bleeding complications. Vorapaxar is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of vorapaxar and rifampin. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with rifampin, a strong CYP3A inducer.
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of vorapaxar and rifampin. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with rifampin, a strong CYP3A inducer.
    Itraconazole: (Major) Avoid vorapaxar during and for 2 weeks after discontinuation of itraconazole treatment due to increase vorapaxar exposure and bleeding risk. Vorapaxar is a CYP3A4 substrate; itraconazole is a strong CYP3A inhibitor.
    Ketoconazole: (Major) Avoid coadministration of vorapaxar and ketoconazole. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with ketoconazole, a strong CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of vorapaxar and clarithromycin. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with clarithromycin, a strong CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Lepirudin: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., clopidogrel, platelet glycoprotein IIb/IIIa inhibitors, ticlopidine, etc.) in combination with lepirudin.
    Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of vorapaxar; monitor for potential reduction in efficacy. Vorapaxar is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of vorapaxar; monitor for potential reduction in efficacy. Vorapaxar is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Letermovir: (Moderate) Administering letermovir with vorapaxar may increase vorapaxar concentration. Avoid coadministration in patients who are also receiving treatment with cyclosporine, because the magnitude of this interaction may be amplified. Vorapaxar is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
    Levoketoconazole: (Major) Avoid coadministration of vorapaxar and ketoconazole. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with ketoconazole, a strong CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Levomilnacipran: (Moderate) Carefully monitor patients for signs and symptoms of bleeding during coadministration of levomilnacipran and platelet inhibitors. Serotonin-norepinephrine reuptake inhibitors (SNRIs) affect platelet activation; therefore, concomitant use may increase the risk of bleeding.
    Levonorgestrel; Ethinyl Estradiol: (Moderate) Use caution during concurrent use of vorapaxar and ethinyl estradiol. Vorapaxar is a CYP3A4 substrate. Ethinyl estradiol inhibits CYP3A4 in vitro. Increased serum concentrations of vorapaxar are possible when vorapaxar is coadministered with ethinyl estradiol. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) Use caution during concurrent use of vorapaxar and ethinyl estradiol. Vorapaxar is a CYP3A4 substrate. Ethinyl estradiol inhibits CYP3A4 in vitro. Increased serum concentrations of vorapaxar are possible when vorapaxar is coadministered with ethinyl estradiol. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Lomustine, CCNU: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as lomustine.
    Lonafarnib: (Major) Avoid coadministration of vorapaxar with lonafarnib due to increased plasma concentrations of vorapaxar and the risk of treatment-related adverse reactions. Vorapaxar is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased vorapaxar exposure by 2-fold; the bleeding risk for a change in exposure of this magnitude is not known.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of vorapaxar and ritonavir. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with ritonavir, a strong CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Low Molecular Weight Heparins: (Major) Avoid concomitant use of vorapaxar and warfarin or other anticoagulants. Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as anticoagulants.
    Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor is expected to reduce the efficacy of vorapaxar by significantly decreasing its systemic exposure; avoid concomitant use. Vorapaxar is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer.
    Mephobarbital: (Moderate) Use caution during concurrent use of vorapaxar and other barbiturates. Vorapaxar is a CYP3A4 substrate. Barbiturates induce CYP3A. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible during concurrent use.
    Mercaptopurine, 6-MP: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Methohexital: (Moderate) Use caution during concurrent use of vorapaxar and other barbiturates. Vorapaxar is a CYP3A4 substrate. Barbiturates induce CYP3A. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible during concurrent use.
    Methoxsalen: (Minor) Agents that affect platelet function, such as platelet inhibitors, could decrease the efficacy of methoxsalen when used during photodynamic therapy.
    Methylsulfonylmethane, MSM: (Moderate) Increased effects from concomitant anticoagulant drugs including increased bruising or blood in the stool have been reported in patients taking methylsulfonylmethane, MSM. Although these effects have not been confirmed in published medical literature or during clinical studies, clinicians should consider using methylsulfonylmethane, MSM with caution in patients who are taking anticoagulants or antiplatelets including clopidogrel until data confirming the safety of these drug combinations are available. During one of the available, published clinical trials in patients with osteoarthritis, those patients with bleeding disorders or using anticoagulants or antiplatelets were excluded from enrollment. Patients who choose to consume methylsulfonylmethane, MSM while receiving clopidogrel should be observed for increased bleeding.
    Mifepristone: (Moderate) Use caution during concurrent use of vorapaxar and mifepristone. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 and CYP2J2 substrate, is coadministered with mifepristone, a CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Milnacipran: (Moderate) Carefully monitor patients for signs and symptoms of bleeding during coadministration of milnacipran and platelet inhibitors. Serotonin-norepinephrine reuptake inhibitors (SNRIs) affect platelet activation; therefore, concomitant use may increase the risk of bleeding.
    Mitotane: (Major) Avoid the concomitant use of mitotane with vorapaxar; if coadministration cannot be avoided, monitor for decreased efficacy of vorapaxar. Mitotane is a strong CYP3A4 inducer and vorapaxar is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of vorapaxar.
    Modafinil: (Moderate) Use caution during concurrent use of vorapaxar and modafinil. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with modafinil, a CYP3A inducer.
    Mycophenolate: (Moderate) Platelet Inhibitors inhibit platelet aggregation and should be used cautiously in patients with thrombocytopenia, as mycophenolate can also cause thrombocytopenia.
    Nafcillin: (Moderate) Use caution during concurrent use of vorapaxar and nafcillin. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with nafcillin, an inducer of CYP3A4 in vitro.
    Nefazodone: (Major) Avoid coadministration of vorapaxar and nefazodone. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with nefazodone, a strong CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Nelarabine: (Moderate) Due to the thrombocytopenic effects of nelarabine, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Nelfinavir: (Major) Avoid coadministration of vorapaxar and nelfinavir. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with nelfinavir, a strong CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Nevirapine: (Moderate) Use caution during concurrent use of vorapaxar and nevirapine. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with nevirapine, a CYP3A inducer.
    Nicardipine: (Moderate) Use caution during concurrent use of vorapaxar and nicardipine. Vorapaxar is a CYP3A4 substrate. Nicardipine inhibits CYP3A4 in vitro. Increased serum concentrations of vorapaxar are possible when vorapaxar is coadministered with nicardipine. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Nirmatrelvir; Ritonavir: (Major) Avoid coadministration of vorapaxar and ritonavir. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with ritonavir, a strong CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications. (Major) Avoid concomitant use of ritonavir-boosted nirmatrelvir and vorapaxar and consider an alternative COVID-19 therapy. Coadministration may increase vorapaxar exposure resulting in increased toxicity. Vorapaxar is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor.
    Nonsteroidal antiinflammatory drugs: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, and prolong bleeding time. If NSAIDs are administered with platelet inhibitors, these pharmacodynamic effects may be increased. The manufacturer of clopidogrel advises that caution be used when used in combination with NSAIDs as an increase in occult GI blood loss occurred when clopidogrel was used concomitantly with naproxen
    Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Use caution during concurrent use of vorapaxar and ethinyl estradiol. Vorapaxar is a CYP3A4 substrate. Ethinyl estradiol inhibits CYP3A4 in vitro. Increased serum concentrations of vorapaxar are possible when vorapaxar is coadministered with ethinyl estradiol. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Norethindrone; Ethinyl Estradiol: (Moderate) Use caution during concurrent use of vorapaxar and ethinyl estradiol. Vorapaxar is a CYP3A4 substrate. Ethinyl estradiol inhibits CYP3A4 in vitro. Increased serum concentrations of vorapaxar are possible when vorapaxar is coadministered with ethinyl estradiol. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Use caution during concurrent use of vorapaxar and ethinyl estradiol. Vorapaxar is a CYP3A4 substrate. Ethinyl estradiol inhibits CYP3A4 in vitro. Increased serum concentrations of vorapaxar are possible when vorapaxar is coadministered with ethinyl estradiol. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Norgestimate; Ethinyl Estradiol: (Moderate) Use caution during concurrent use of vorapaxar and ethinyl estradiol. Vorapaxar is a CYP3A4 substrate. Ethinyl estradiol inhibits CYP3A4 in vitro. Increased serum concentrations of vorapaxar are possible when vorapaxar is coadministered with ethinyl estradiol. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Obinutuzumab: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Octreotide: (Moderate) Use caution during concurrent use of vorapaxar and octreotide. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with octreotide, a CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Olanzapine; Fluoxetine: (Moderate) Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as selective serotonin reuptake inhibitors (SSRIs). Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion. In addition, fluoxetine and fluvoxamine are CYP3A4 inhibitors and coadministration with vorapaxar, a CYP3A4 substrate, may result in increased serum concentrations of vorapaxar. Increased exposure to vorapaxar may increase the risk of bleeding complications. Patients should be instructed to monitor for signs and symptoms of bleeding while taking a SSRI with vorapaxar and to promptly report any bleeding events.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of vorapaxar and ritonavir. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with ritonavir, a strong CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Omeprazole; Amoxicillin; Rifabutin: (Moderate) Use caution during concurrent use of vorapaxar and rifabutin. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with rifabutin, a CYP3A inducer.
    Paroxetine: (Moderate) Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as selective serotonin reuptake inhibitors (SSRIs). Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion. In addition, fluoxetine and fluvoxamine are CYP3A4 inhibitors and coadministration with vorapaxar, a CYP3A4 substrate, may result in increased serum concentrations of vorapaxar. Increased exposure to vorapaxar may increase the risk of bleeding complications. Patients should be instructed to monitor for signs and symptoms of bleeding while taking a SSRI with vorapaxar and to promptly report any bleeding events.
    Pentobarbital: (Moderate) Use caution during concurrent use of vorapaxar and other barbiturates. Vorapaxar is a CYP3A4 substrate. Barbiturates induce CYP3A. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible during concurrent use.
    Pentosan: (Major) Pentosan is a weak anticoagulant with 1/15 the anticoagulant activity of heparin. An additive risk of bleeding may be seen in patients receiving other platelet inhibitors (e.g. aspirin, ASA) in combination with pentosan. Avoid concomitant use of vorapaxar and warfarin or other anticoagulants. Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as anticoagulants.
    Pentostatin: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Pentoxifylline: (Moderate) A potential additive risk for bleeding exists if platelet inhibitors are given in combination with other agents that affect hemostasis such as pentoxifylline.
    Perampanel: (Moderate) Use caution during concurrent use of vorapaxar and perampanel. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with perampanel, an inducer of CYP3A4 in vitro.
    Phenobarbital: (Major) Avoid coadministration of vorapaxar and phenobarbital or primidone. Use caution during concurrent use of vorapaxar and other barbiturates. Vorapaxar is a CYP3A4 substrate. Phenobarbital and primidone are strong CYP3A inducers. Other barbiturates also induce CYP3A. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible during concurrent use.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid coadministration of vorapaxar and phenobarbital or primidone. Use caution during concurrent use of vorapaxar and other barbiturates. Vorapaxar is a CYP3A4 substrate. Phenobarbital and primidone are strong CYP3A inducers. Other barbiturates also induce CYP3A. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible during concurrent use.
    Phentermine; Topiramate: (Moderate) Use caution during concurrent use of vorapaxar and topiramate. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with topiramate, a mild inducer of CYP3A4 in vitro. In addition, concurrent use of topiramate and drugs that affect platelet function such as platelet inhibitors may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (23%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Phenytoin: (Major) Avoid coadministration of vorapaxar and phenytoin. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with phenytoin, a strong CYP3A inducer.
    Photosensitizing agents (topical): (Minor) Agents, such as platelet inhibitors, that decrease clotting could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    Platelet Glycoprotein IIb/IIIa Inhibitors: (Moderate) Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as platelet glycoprotein IIb/IIIa inhibitors including abciximab, eptifibatide, and tirofiban.
    Posaconazole: (Major) Avoid coadministration of vorapaxar and posaconazole. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with posaconazole, a strong CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Moderate) Prasterone is contraindicated for use in patients with active deep vein thrombosis, pulmonary embolism or history of these conditions. Prasterone is also contraindicated in patients with active arterial thromboembolic disease (for example, stroke and myocardial infarction), or a history of these conditions. Thus, patients receiving anticoagulation due to a history of these conditions are not candidates for prasterone treatment. DHEA is converted to androgens and estrogens within the human body and thus may affect hemostasis via androgenic or estrogenic effects. Estrogens increase the production of clotting factors VII, VIII, IX, and X. Androgens, such as testosterone, increase the synthesis of several anticoagulant and fibrinolytic proteins. Because of the potential effects on coagulation, patients receiving prasterone or DHEA concurrently with preventative anticoagulants (e.g., warfarin or heparin) or other platelet inhibitors, including aspirin, ASA should be monitored for side effects or the need for dosage adjustments.
    Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Moderate) Prasterone is contraindicated for use in patients with active deep vein thrombosis, pulmonary embolism or history of these conditions. Prasterone is also contraindicated in patients with active arterial thromboembolic disease (for example, stroke and myocardial infarction), or a history of these conditions. Thus, patients receiving anticoagulation due to a history of these conditions are not candidates for prasterone treatment. DHEA is converted to androgens and estrogens within the human body and thus may affect hemostasis via androgenic or estrogenic effects. Estrogens increase the production of clotting factors VII, VIII, IX, and X. Androgens, such as testosterone, increase the synthesis of several anticoagulant and fibrinolytic proteins. Because of the potential effects on coagulation, patients receiving prasterone or DHEA concurrently with preventative anticoagulants (e.g., warfarin or heparin) or other platelet inhibitors, including aspirin, ASA should be monitored for side effects or the need for dosage adjustments.
    Prasugrel: (Moderate) Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as ADP receptor antagonists including clopidogrel, prasugrel, ticagrelor, or ticlopidine.
    Primidone: (Major) Avoid coadministration of vorapaxar and phenobarbital or primidone. Use caution during concurrent use of vorapaxar and other barbiturates. Vorapaxar is a CYP3A4 substrate. Phenobarbital and primidone are strong CYP3A inducers. Other barbiturates also induce CYP3A. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible during concurrent use.
    Purine analogs: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Quinine: (Moderate) Use caution during concurrent use of vorapaxar and quinine. Quinine inhibits CYP3A and induced CYP3A4 in an in vitro study. Increased or decreased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with quinine. Increased exposure to vorapaxar may increase the risk of bleeding complications while decreased exposure to vorapaxar may reduce efficacy.
    Ranolazine: (Moderate) Use caution during concurrent use of vorapaxar and ranolazine. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with ranolazine, a mild CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Ribociclib: (Major) Avoid coadministration of vorapaxar with ribociclib due to increased plasma concentrations of vorapaxar and the risk of treatment-related adverse reactions. Vorapaxar is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased vorapaxar exposure by 2-fold; the bleeding risk for a change in exposure of this magnitude is not known.
    Ribociclib; Letrozole: (Major) Avoid coadministration of vorapaxar with ribociclib due to increased plasma concentrations of vorapaxar and the risk of treatment-related adverse reactions. Vorapaxar is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased vorapaxar exposure by 2-fold; the bleeding risk for a change in exposure of this magnitude is not known.
    Rifabutin: (Moderate) Use caution during concurrent use of vorapaxar and rifabutin. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with rifabutin, a CYP3A inducer.
    Rifampin: (Major) Avoid coadministration of vorapaxar and rifampin. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with rifampin, a strong CYP3A inducer.
    Rifapentine: (Major) Avoid coadministration of vorapaxar and rifapentine due to decreased serum concentrations of vorapaxar. Vorapaxar is a CYP3A4 substrate and rifapentine is a strong CYP3A inducer. Coadministration with another strong CYP3A4 inducer decreased vorapaxar exposure by 55%; the impact on efficacy for a change in exposure of this magnitude is not known.
    Ritonavir: (Major) Avoid coadministration of vorapaxar and ritonavir. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with ritonavir, a strong CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Rivaroxaban: (Major) Avoid concomitant use of vorapaxar and warfarin or other anticoagulants. Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as anticoagulants.
    Saquinavir: (Major) Avoid coadministration of vorapaxar and saquinavir. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with saquinavir, a strong CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Secobarbital: (Moderate) Use caution during concurrent use of vorapaxar and other barbiturates. Vorapaxar is a CYP3A4 substrate. Barbiturates induce CYP3A. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible during concurrent use.
    Segesterone Acetate; Ethinyl Estradiol: (Moderate) Use caution during concurrent use of vorapaxar and ethinyl estradiol. Vorapaxar is a CYP3A4 substrate. Ethinyl estradiol inhibits CYP3A4 in vitro. Increased serum concentrations of vorapaxar are possible when vorapaxar is coadministered with ethinyl estradiol. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Selective serotonin reuptake inhibitors: (Moderate) Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as selective serotonin reuptake inhibitors (SSRIs). Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion. In addition, fluoxetine and fluvoxamine are CYP3A4 inhibitors and coadministration with vorapaxar, a CYP3A4 substrate, may result in increased serum concentrations of vorapaxar. Increased exposure to vorapaxar may increase the risk of bleeding complications. Patients should be instructed to monitor for signs and symptoms of bleeding while taking a SSRI with vorapaxar and to promptly report any bleeding events.
    Selumetinib: (Moderate) Closely monitor for bleeding if coadministration of selumetinib and platelet inhibitors is necessary as concurrent use may increase the bleeding risk; adjust the platelet inhibitor dose as appropriate. Selumetinib contains vitamin E which can inhibit platelet aggregation.
    Sertraline: (Moderate) Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as selective serotonin reuptake inhibitors (SSRIs). Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion. In addition, fluoxetine and fluvoxamine are CYP3A4 inhibitors and coadministration with vorapaxar, a CYP3A4 substrate, may result in increased serum concentrations of vorapaxar. Increased exposure to vorapaxar may increase the risk of bleeding complications. Patients should be instructed to monitor for signs and symptoms of bleeding while taking a SSRI with vorapaxar and to promptly report any bleeding events.
    Simeprevir: (Moderate) Use caution during concurrent use of vorapaxar and simeprevir. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with simeprevir, a mild CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of vorapaxar and St. John's Wort. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with St. John's Wort, a strong CYP3A inducer.
    Sulfinpyrazone: (Major) Sulfinpyrazone, when used as a uricosuric agent should be avoided when possible with concurrent platelet inhibitors due to potential for additive antiplatelet effects and increased bleeding risk.
    Telaprevir: (Major) Avoid coadministration of vorapaxar and telaprevir. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with telaprevir, a strong CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Telithromycin: (Major) Avoid coadministration of vorapaxar and telithromycin. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with telithromycin, a strong CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Thioguanine, 6-TG: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Thiopental: (Moderate) Use caution during concurrent use of vorapaxar and other barbiturates. Vorapaxar is a CYP3A4 substrate. Barbiturates induce CYP3A. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible during concurrent use.
    Thrombolytic Agents: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution.
    Ticagrelor: (Moderate) Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as ADP receptor antagonists including clopidogrel, prasugrel, ticagrelor, or ticlopidine.
    Ticlopidine: (Moderate) Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as ADP receptor antagonists including clopidogrel, prasugrel, ticagrelor, or ticlopidine.
    Tinzaparin: (Major) Avoid concomitant use of vorapaxar and warfarin or other anticoagulants. Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as anticoagulants.
    Tipranavir: (Major) Avoid coadministration of vorapaxar and tipranavir. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with tipranavir, a strong CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Tirofiban: (Moderate) Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as platelet glycoprotein IIb/IIIa inhibitors including abciximab, eptifibatide, and tirofiban.
    Topiramate: (Moderate) Use caution during concurrent use of vorapaxar and topiramate. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with topiramate, a mild inducer of CYP3A4 in vitro. In addition, concurrent use of topiramate and drugs that affect platelet function such as platelet inhibitors may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (23%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Trandolapril; Verapamil: (Moderate) Use caution during concurrent use of vorapaxar and verapamil. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with verapamil, a CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Treprostinil: (Moderate) Monitor patients for signs and symptoms of bleeding if treprostinil is administered with vorapaxar. Treprostinil inhibits platelet aggregation; vorapaxar is a platelet inhibitor. Coadministration increases the risk of bleeding.
    Tretinoin, ATRA: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as tretinoin.
    Tucatinib: (Major) Avoid coadministration of vorapaxar with tucatinib due to increased plasma concentrations of vorapaxar and the risk of treatment-related adverse reactions. Vorapaxar is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased vorapaxar exposure by 2-fold; the bleeding risk for a change in exposure of this magnitude is not known.
    Vemurafenib: (Moderate) Use caution during concurrent use of vorapaxar and vemurafenib. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with vemurafenib, a CYP3A inducer.
    Venlafaxine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with a platelet inhibitor and to promptly report any bleeding events to the practitioner.
    Verapamil: (Moderate) Use caution during concurrent use of vorapaxar and verapamil. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with verapamil, a CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Verteporfin: (Moderate) Use caution if coadministration of verteporfin with platelet inhibitors is necessary due to the risk of decreased verteporfin efficacy. Verteporfin is a light-activated drug. Once activated, local damage to neovascular endothelium results in a release of procoagulant and vasoactive factors resulting in platelet aggregation, fibrin clot formation, and vasoconstriction. Concomitant use of drugs that decrease platelet aggregation could decrease the efficacy of verteporfin therapy.
    Vilazodone: (Moderate) Patients should be instructed to monitor for signs and symptoms of bleeding while taking vilazodone concurrently with salicylates or other platelet inhibitors and to promptly report any bleeding events to the practitioner. Platelet aggregation may be impaired by vilazodone due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., aspirin, cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors).
    Voriconazole: (Major) Avoid coadministration of vorapaxar with voriconazole due to increased plasma concentrations of vorapaxar and the risk of treatment-related adverse reactions. Vorapaxar is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased vorapaxar exposure by 2-fold; the bleeding risk for a change in exposure of this magnitude is not known.
    Vorinostat: (Moderate) Carefully monitor patients for signs and symptoms of bleeding during coadministration of vorapaxar and vorinostat. Due to the thrombocytopenic effects of vorinostat, an additive risk of bleeding may occur in patients taking platelet inhibitors.
    Vortioxetine: (Moderate) Platelet aggregation may be impaired by vortioxetine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Bleeding events related to drugs that inhibit serotonin reuptake have ranged from ecchymosis to life-threatening hemorrhages. Patients should be instructed to monitor for signs and symptoms of bleeding while taking vortioxetine concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Warfarin: (Major) Avoid concomitant use of vorapaxar and warfarin or other anticoagulants. Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as anticoagulants.
    Zafirlukast: (Moderate) Use caution during concurrent use of vorapaxar and zafirlukast. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with zafirlukast, a CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.

    PREGNANCY AND LACTATION

    Pregnancy

    Due to the potential for serious adverse reactions, such as maternal bleeding or hemorrhage, and long half-life, which makes vorapaxar effectively irreversible, discontinue vorapaxar when pregnancy is detected and initiate alternate therapy with a shorter duration of action. Data form postmarketing experience with vorapaxar use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. No adverse embryo or fetal toxicities, malformations, or maternal toxicities were observed in rats and rabbits exposed to vorapaxar during organogenesis at exposures 56 times and 26 times, respectively, the human systemic exposure at the recommended human dose (RHD).[57151]

    Because of the potential for serious adverse reactions in the breast-fed infant, such as bleeding, breast-feeding is not recommended during treatment with vorapaxar. There are no data on the presence of vorapaxar or its metabolites in human milk, the effects on the breast-fed 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.

    MECHANISM OF ACTION

    Vorapaxar antagonizes the protease-activated receptor-1 (PAR-1) expressed on platelets. Although vorapaxar is a reversible PAR-1 antagonist, its long half-life makes it effectively irreversible. In vitro, vorapaxar inhibits platelet aggregation induced by thrombin and thrombin receptor agonist peptide (TRAP). Vorapaxar does not inhibit platelet aggregation induced by adenosine diphosphate (ADP), collagen, or a thromboxane mimetic and does not affect coagulation parameters ex vivo. PAR-1 receptors are also expressed in a wide variety of cell types, including endothelial cells, neurons, and smooth muscle cells; however, the pharmacodynamic effects of vorapaxar in these cell types have not been assessed.

    PHARMACOKINETICS

    Vorapaxar is administered orally. Within 1 week of treatment initiation, vorapaxar reaches >= 80% inhibition of thrombin receptor agonist peptide (TRAP)-induced platelet aggregation. The effective half-life of vorapaxar is 3—4 days, and the apparent terminal elimination half-life is approximately 8 days (range 5—13 days). Due to the long half-life of vorapaxar, 50% inhibition of TRAP-induced platelet aggregation can be expected at 4 weeks after discontinuation of daily therapy. Vorapaxar and its active metabolite, M20, are both highly bound to plasma proteins (>= 99%). Vorapaxar is highly bound to human serum albumin and does not preferentially distribute into red blood cells. The systemic exposure of M20 is approximately 20% of the exposure to vorapaxar. Vorapaxar is primarily eliminated in the feces. In a 6-week study, 84% of the administered radiolabeled dose was recovered as total radioactivity with 58% collected in feces and 25% in urine. Vorapaxar is eliminated primarily in the form of metabolites, with no unchanged vorapaxar detected in urine.
     
    Affected cytochrome P450 isoenzymes: CYP3A4 and CYP2J2
    Vorapaxar is eliminated by metabolism via CYP3A4 and CYP2J2. Vorapaxar is a weak P-glycoprotein (P-gp) inhibitor; however, based on in vivo test results with digoxin, a P-gp substrate, clinically significant interactions with P-gp substrates are not expected.

    Oral Route

    Following oral administration, the bioavailability of vorapaxar is approximately 100%. Peak serum concentrations are reached approximately 1 hour post-dose (range 1—2 hours) under fasted conditions. Ingestion of a high-fat meal results in a small decrease in Cmax (21%) and delayed time to peak concentration (45 minutes) but does not decrease overall exposure. Therefore, vorapaxar may be administered without regard to meals.