Version May 2024
Do not use vorapaxar in patients with a history of stroke, transient ischemic attack, or intracranial hemorrhage; or active pathological bleeding. Antiplatelet agents, including vorapaxar, increase the risk of bleeding, including intracranial hemorrhage and fatal bleeding.
Note: Vorapaxar 2.08 mg is equivalent to vorapaxar sulfate 2.5 mg.
History of MI or established peripheral arterial disease (PAD): Note: Role in therapy not well established. The overall clinical benefit of adding vorapaxar to other antiplatelet therapy is uncertain; must consider the risk-benefit of bleeding versus reduction in cardiovascular events (Ref).
Oral: 2.08 mg once daily in combination with aspirin and/or clopidogrel; there is no experience with use of vorapaxar as monotherapy or with antiplatelet agents other than aspirin and/or clopidogrel.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
No dosage adjustment necessary.
Hemodialysis: Unknown if dialyzable, but unlikely (Ref).
Mild to moderate impairment: No dosage adjustment necessary.
Severe impairment: Use is not recommended.
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Hematologic and oncologic: Hemorrhage (any GUSTO [Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries] bleeding [severe, moderate, mild]): 25%), major hemorrhage, life-threatening (13%; clinically significant bleeding, including any bleeding requiring medical attention such as intracranial hemorrhage, or clinically significant overt signs of hemorrhage associated with a drop in hemoglobin of ≥3 g/dL [or when hemoglobin is unavailable, an absolute drop in hematocrit of ≥15% or a fall in hematocrit of 9% to <15%])
1% to 10%:
Central nervous system: Depression (2%)
Dermatologic: Skin rash (2%, includes cutaneous eruptions and exanthemas)
Endocrine & metabolic: Iron deficiency (<2%)
Gastrointestinal: Gastrointestinal hemorrhage (4%)
Hematologic and oncologic: Anemia (5%), major hemorrhage (GUSTO bleeding category “moderate or severe”: 3%; GUSTO bleeding category “severe”: 1%)
Ophthalmic: Retinopathy (<2%)
<1%, postmarketing, and/or case reports: Diplopia (or oculomotor disturbance), hemorrhagic death, intracranial hemorrhage
History of stroke, transient ischemic attack (TIA), or intracranial hemorrhage (ICH); active pathological bleeding (eg, ICH, peptic ulcer bleeding)
Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to vorapaxar or any ingredient in the formulation; severe hepatic impairment
Concerns related to adverse effects:
• Bleeding: [US Boxed Warning]: Use is contraindicated in patients with history of stroke, TIA, or ICH; or active pathological bleeding. Discontinue use in patients who experience a stroke, TIA, or ICH during therapy. Vorapaxar increases the risk of bleeding, including ICH and fatal bleeding. The risk of bleeding is proportional to the patient's underlying bleeding risk. General risk factors for bleeding include older age, low body weight, reduced renal or hepatic function, history of bleeding disorders, and concomitant use of medications known to increase the risk of bleeding (eg, anticoagulants, NSAIDS, SSRIs, SNRI); avoid use with anticoagulants. Note: No specific antidote exists for vorapaxar reversal. Significant inhibition of platelet aggregation remains 4 weeks after discontinuation.
Disease-related concerns:
• Hepatic impairment: Due to increased risk of bleeding, use is not recommended in patients with severe hepatic impairment; use with caution in patients with mild or moderate hepatic impairment.
• Renal impairment: Due to increased risk of bleeding, use with caution in patients with renal impairment.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral, as sulfate:
Zontivity: 2.08 mg
No
Tablets (Zontivity Oral)
2.08 mg (per each): $18.43
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Administer with or without food.
An FDA-approved patient medication guide, which is available with the product information and at https://www.fda.gov/media/92207/download, must be dispensed with this medication.
History of MI or established peripheral arterial disease: To reduce thrombotic cardiovascular events (cardiovascular death, MI, stroke, urgent coronary revascularization) in patients with a history of MI or with peripheral arterial disease (PAD)
Substrate of CYP2J2 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Abrocitinib: Agents with Antiplatelet Properties may enhance the antiplatelet effect of Abrocitinib. Management: Do not use antiplatelet drugs with abrocitinib during the first 3 months of abrocitinib therapy. The abrocitinib prescribing information lists this combination as contraindicated. This does not apply to low dose aspirin (81 mg/day or less). Risk X: Avoid combination
Acalabrutinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the antiplatelet effect of other Agents with Antiplatelet Properties. Risk C: Monitor therapy
Anagrelide: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Anticoagulants: Vorapaxar may enhance the adverse/toxic effect of Anticoagulants. More specifically, this combination is expected to increase the risk of bleeding. Risk X: Avoid combination
Caplacizumab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Caplacizumab. Specifically, the risk of bleeding may be increased. Management: Avoid coadministration of caplacizumab with antiplatelets if possible. If coadministration is required, monitor closely for signs and symptoms of bleeding. Interrupt use of caplacizumab if clinically significant bleeding occurs. Risk D: Consider therapy modification
Cephalothin: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Cephalothin. Specifically, the risk for bleeding may be increased. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Collagenase (Systemic): Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and or bleeding may be increased. Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Vorapaxar. Risk X: Avoid combination
CYP3A4 Inducers (Strong): May decrease the serum concentration of Vorapaxar. Risk X: Avoid combination
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Vorapaxar. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Vorapaxar. Risk X: Avoid combination
Dasatinib: May enhance the anticoagulant effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Deoxycholic Acid: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Risk C: Monitor therapy
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Herbal Products with Anticoagulant/Antiplatelet Effects (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. Risk C: Monitor therapy
Ibritumomab Tiuxetan: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Ibritumomab Tiuxetan. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Risk C: Monitor therapy
Ibrutinib: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Icosapent Ethyl: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Inotersen: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Lecanemab: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Specifically, the risk of hemorrhage may be increased. Risk C: Monitor therapy
Limaprost: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Lipid Emulsion (Fish Oil Based): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Multivitamins/Fluoride (with ADE): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Multivitamins/Minerals (with AE, No Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Obinutuzumab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Risk C: Monitor therapy
Omega-3 Fatty Acids: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Pentosan Polysulfate Sodium: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Specifically, the risk of bleeding may be increased by concurrent use of these agents. Risk C: Monitor therapy
Pentoxifylline: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Pirtobrutinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Selumetinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
St John's Wort: May decrease the serum concentration of Vorapaxar. Risk X: Avoid combination
Thrombolytic Agents: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents. Risk C: Monitor therapy
Tipranavir: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Urokinase: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Urokinase. Risk X: Avoid combination
Vitamin E (Systemic): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Zanubrutinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Due to the potential for serious adverse events (eg, maternal bleeding, hemorrhage) and the long half-life of vorapaxar, alternate agents may be preferred in pregnant women. Discontinue use if pregnancy is detected.
It is not known if vorapaxar is present in breast milk.
Due to the potential for adverse events in a breastfed infant (eg, bleeding), breastfeeding is not recommended by the manufacturer.
Signs of bleeding; hemoglobin and hematocrit periodically
Vorapaxar, an antagonist of the protease-activated receptor-1 (PAR-1) expressed on platelets, inhibits thrombin-induced and thrombin receptor agonist peptide (TRAP)-induced platelet aggregation. Due to the very long half-life, vorapaxar is effectively irreversible. Vorapaxar reversibly binds to the PAR-1 receptor with a long receptor dissociation half-life of approximately 20 hours; additionally, vorapaxar displays significant inhibition of platelet aggregation that remains for up to 4 weeks after discontinuation due to the very long elimination half-life (Ueno 2010).
Onset of action: ≥80% inhibition of TRAP-induced platelet aggregation within 1 week
Duration: Dose and concentration dependent; with the recommended dosing, inhibition of TRAP-induced platelet aggregation at a level of 50% can be expected 4 weeks after discontinuation
Absorption: Rapidly absorbed (Kosoglou 2012)
Distribution: ~424 L
Protein binding: ≥99% to albumin
Metabolism: Hepatic via CYP3A4 and CYP2J2. Major active metabolite: M20 (accounts for ~20% of exposure to vorapaxar)
Bioavailability: ~100%
Half-life elimination: Effective half-life: 3 to 4 days; Terminal elimination half-life (vorapaxar and active metabolite): ~8 days (range: 5 to 13 days)
Time to peak: 1 to 2 hours
Excretion: Primarily in the form of metabolites through feces (58%); urine (25%)
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