Vorapaxar Sulfate (Monograph)
Brand name: Zontivity
Drug class: Platelet-aggregation Inhibitors
Warning
Vorapaxar is no longer commercially available in the U.S. See the FDA website ([Web]) for information on drugs that have been discontinued.
Because this drug is no longer available in the U.S. market, the material in this monograph is no longer updated by AHFS DI. If this drug is used in countries other than the U.S., it is essential that the manufacturers’ labeling be consulted for more recently available information.
Warning
- Bleeding
-
Risk of bleeding, including intracranial hemorrhage and fatal bleeding. (See Bleeding under Cautions.)
-
Avoid use in patients with active pathological bleeding or history of stroke/TIA or intracranial hemorrhage. (See Contraindications under Cautions.)
Introduction
Platelet-aggregation inhibitor; protease-activated receptor-1 (PAR-1) antagonist.
Uses for Vorapaxar Sulfate
Cardiovascular Risk Reduction in Established Atherosclerotic Disease
Reduction of the risk of thrombotic cardiovascular events (e.g., cardiovascular death, MI, stroke, urgent coronary revascularization) in patients with a history of MI or with peripheral arterial disease (PAD).
Use in conjunction with aspirin and/or clopidogrel; data lacking on use of vorapaxar in combination with other antiplatelet agents (e.g., prasugrel, ticagrelor) or as monotherapy.
Efficacy and safety established in patients with stable atherosclerotic disease; favorable benefit versus risk not established in the setting of acute coronary syndrome (ACS). (See Acute Coronary Syndrome under Uses.)
The American Heart Association (AHA), American College of Cardiology Foundation (ACCF), American College of Chest Physicians (ACCP), and other experts recommend long-term antiplatelet therapy (e.g., aspirin and/or clopidogrel) in patients with established coronary artery disease. Long-term antiplatelet therapy (e.g., clopidogrel, aspirin) also recommended in patients with symptomatic PAD, including those with intermittent claudication, critical limb ischemia, or prior revascularization or amputation of the lower extremity. When added to aspirin and/or clopidogrel therapy, vorapaxar reduces cardiovascular events (e.g., composite outcome of cardiovascular death, MI, stroke, and urgent coronary revascularization) but increases risk of bleeding, including intracranial hemorrhage.
Balance incremental benefits against risk of bleeding; certain patients (e.g., those with a history of MI who are at high risk of recurrence but low risk of bleeding and who have not had a previous stroke or TIA) may have greater potential for net clinical benefits. Overall risk-benefit of vorapaxar in routine clinical practice remains to be fully elucidated.
Acute Coronary Syndrome
Has been used in patients with ACS† [off-label]; however, current evidence suggests that the addition of vorapaxar to standard antiplatelet therapy in such patients does not substantially reduce rate of ischemic events but substantially increases risk of clinically important bleeding.
Many clinicians currently advise against use of vorapaxar in patients with ACS.
Vorapaxar Sulfate Dosage and Administration
Administration
Oral Administration
Administer orally without regard to food.
Dosage
Available as vorapaxar sulfate; dosage expressed in terms of vorapaxar.
Adults
Cardiovascular Risk Reduction in Established Atherosclerotic Disease
Patients with Previous MI or with PAD
Oral2.08 mg once daily in conjunction with aspirin and/or clopidogrel therapy.
Managing Antiplatelet Therapy During Invasive Procedures
Oral
ACCP recommends individualizing decision to interrupt antiplatelet therapy prior to surgery or other invasive procedure based on risks of thromboembolism and perioperative bleeding. In principal efficacy study of vorapaxar, investigators were encouraged not to discontinue study drug prior to surgery (e.g., coronary artery bypass grafting [CABG]).
Manufacturer recommends use of clinical judgment and consideration of patient-specific information such as type of procedure, risk and potential consequences of bleeding, and pharmacologic properties of the drug.
Special Populations
Hepatic Impairment
No dosage adjustment necessary in patients with mild or moderate hepatic impairment; use not recommended in patients with severe hepatic impairment. (See Hepatic Impairment under Cautions.)
Renal Impairment
No dosage adjustment necessary in patients with renal impairment, including those with end-stage renal disease. (See Renal Impairment under Cautions.)
Geriatric Patients
No dosage adjustment necessary.
Other Special Populations
No dosage adjustments necessary based on age, race, gender, or weight.
Cautions for Vorapaxar Sulfate
Contraindications
-
History of stroke, TIA, or intracranial hemorrhage.
-
Active pathological bleeding (e.g., intracranial hemorrhage, peptic ulcer).
Warnings/Precautions
Warnings
Bleeding
Moderate to severe bleeding, including intracranial hemorrhage and fatal bleeding, reported. (See Boxed Warning.)
Prior history of stroke associated with substantially greater risk of intracranial hemorrhage; do not use in patients with previous stroke or TIA. (See Contraindications under Cautions.)
Because bleeding risk with vorapaxar increases in proportion to underlying risk, evaluate baseline bleeding risk prior to initiating therapy. Risk factors for bleeding generally include advanced age, low body weight (e.g., <60 kg), renal or hepatic impairment, history of bleeding disorders, and concomitant use of certain drugs (e.g., anticoagulants, fibrinolytics, NSAIAs, SSRIs, SNRIs). (See Interactions.)
Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, PCI, CABG, or other surgical procedure. If bleeding occurs during therapy, initiate standard treatment measures. Withholding dose for a brief period unlikely to resolve an acute bleeding episode because of the drug’s prolonged half-life and inhibitory effects on platelet function. No known reversal agent for drug's antiplatelet effects; drug not expected to be dialyzable.
Other Warnings and Precautions
Concomitant Use of Potent CYP3A Inhibitors or Inducers
Avoid concomitant use of potent CYP3A inhibitors and inducers. (See Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes under Interactions.)
Specific Populations
Pregnancy
Category B.
Animal studies suggest low risk of adverse fetal effects and maternal toxicity; however, no adequate and well-controlled studies in pregnant women. Use during pregnancy only if potential benefits justify potential risks to fetus.
Lactation
Distributed into milk in rats; not known whether distributed into human milk. Discontinue nursing or the drug.
Pediatric Use
Safety and efficacy not established in pediatric patients.
Geriatric Use
No overall differences in safety and efficacy relative to younger adults. However, consider that older patients generally are at higher risk of bleeding.
Hepatic Impairment
Pharmacokinetics of vorapaxar and its main active metabolite not substantially altered in patients with hepatic impairment (mild, moderate, or severe).
Use not recommended in patients with severe hepatic impairment because of inherent increased bleeding risk in such patients.
Renal Impairment
Pharmacokinetics and inhibition of platelet aggregation not substantially altered in patients with renal impairment, including those with end-stage renal impairment.
Common Adverse Effects
Bleeding.
Drug Interactions
Metabolized by CYP3A4 and 2J2. Does not appear to inhibit or induce major CYP isoenzymes.
Weak inhibitor of P-glycoprotein (P-gp). Does not inhibit organic anion-transporting polypeptides (OATP) 1B1 and 1B3, organic anion transporters (OAT) 1 and 3, organic cation transporter (OCT) 2, and the breast cancer resistance protein (BCRP).
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Potent CYP3A inhibitors or inducers: Possible increased or decreased vorapaxar concentrations, respectively. Avoid concomitant use. (See Specific Drugs under Interactions.)
Weak to moderate CYP3A inhibitors: Clinically important pharmacokinetic interactions unlikely; may be administered concomitantly without the need for dosage adjustment.
CYP2C8/9 substrates: Clinically important pharmacokinetic interactions unlikely.
Drugs Affected by Efflux Transport Systems
P-gp substrates: Possible increased plasma concentrations of the substrate.
Drugs Affecting Hemostasis
Possible increased risk of bleeding. (See Specific Drugs under Interactions.)
Specific Drugs
Drug |
Interaction |
Comments |
---|---|---|
Antacids (aluminum- and magnesium-containing) |
Peak plasma concentrations and systemic exposure of vorapaxar slightly decreased |
Dosage adjustment not necessary |
Anticoagulants (e.g., warfarin) |
Possible increased risk of bleeding Warfarin: Clinically important pharmacokinetic and pharmacodynamic interactions unlikely |
Avoid concomitant use |
Anticonvulsants (carbamazepine, phenytoin) |
Potential for decreased vorapaxar concentrations via CYP3A induction |
Avoid concomitant use |
Antifungals, azole (itraconazole, ketoconazole, posaconazole) |
Potential for increased vorapaxar concentrations via CYP3A inhibition Ketoconazole: Substantially (approximately twofold) increased peak plasma concentrations and systemic exposure of vorapaxar |
Avoid concomitant use |
Antiplatelet agents (e.g., aspirin, clopidogrel, prasugrel) |
Aspirin, clopidogrel: Used concomitantly as part of dual or triple antiplatelet therapy in clinical studies evaluating efficacy and safety of vorapaxar Clopidogrel: Specific pharmacokinetic interaction studies not conducted Prasugrel: Pharmacokinetics of prasugrel or vorapaxar not substantially altered; however, very limited clinical experience with concomitant use |
Consider possibility that risk of bleeding may be increased with concomitant antiplatelet therapy |
Clarithromycin |
Potential for increased vorapaxar concentrations via CYP3A inhibition |
Avoid concomitant use |
Conivaptan |
Potential for increased vorapaxar concentrations via CYP3A inhibition |
Avoid concomitant use |
Digoxin |
Peak plasma concentrations of digoxin (P-gp substrate) increased, but systemic exposure not affected |
Dosage adjustment not necessary |
Fibrinolytics |
Potentially increased risk of hemorrhage |
|
HCV protease inhibitors (boceprevir, telaprevir) |
Potential for increased vorapaxar concentrations via CYP3A inhibition |
Avoid concomitant use |
HIV protease inhibitors (ritonavir, saquinavir, nelfinavir, indinavir) |
Potential for increased vorapaxar concentrations via CYP3A inhibition |
Avoid concomitant use |
Nefazodone |
Potential for increased vorapaxar concentrations via CYP3A inhibition |
Avoid concomitant use |
NSAIAs |
Potentially increased risk of hemorrhage |
|
Proton-pump inhibitors |
Pantoprazole: Peak plasma concentrations and systemic exposure of vorapaxar not substantially affected |
Dosage adjustment not necessary |
Rifampin |
Peak plasma concentrations and systemic exposure of vorapaxar reduced by approximately 50% |
Avoid concomitant use |
Rosiglitazone |
Pharmacokinetics of rosiglitazone not substantially altered |
Dosage adjustment not necessary |
SNRIs |
Potentially increased risk of hemorrhage |
|
SSRIs |
Potentially increased risk of hemorrhage |
|
St. John's wort (Hypericum perforatum) |
Potential for decreased vorapaxar concentrations via CYP3A induction |
Avoid concomitant use |
Telithromycin |
Potential for increased vorapaxar concentrations via CYP3A inhibition |
Avoid concomitant use |
Vorapaxar Sulfate Pharmacokinetics
Absorption
Bioavailability
Rapidly absorbed after oral administration; peak plasma concentrations occur within approximately 60 minutes (range 1–2 hours).
Mean absolute bioavailability approximately 100%.
Onset
Following oral administration of recommended dose, complete inhibition (≥80%) of thrombin receptor agonist peptide (TRAP)-induced platelet aggregation observed within 1 week.
Duration
Dose- and concentration-dependent; following discontinuance of recommended dosage, platelet-inhibitory effects expected to persist at a level of 50% inhibition for about 4 weeks.
Food
Administration with a high-fat meal moderately decreased peak plasma concentrations and delayed time to peak concentrations, but did not substantially alter systemic exposure.
Distribution
Plasma Protein Binding
Both drug and active M20 metabolite extensively (>99%) bound to human plasma proteins.
Extent
Does not preferentially distribute into RBCs.
Not known whether vorapaxar is distributed into human milk.
Elimination
Metabolism
Extensively metabolized by CYP3A4 and CYP2J2. The major circulating metabolite (M20) is pharmacologically active and accounts for approximately 20% of total drug exposure.
Elimination Route
Eliminated principally by hepatobiliary excretion; following administration of radiolabeled drug, approximately 84% of dose was recovered (58% in feces and 25% in urine).
Eliminated principally as metabolites.
Half-life
Effective half-life 3–4 days; apparent terminal half-life of drug and active metabolite approximately 8 days (range 5–13 days).
Stability
Storage
Oral
Tablets
20–25°C (may be exposed to 15–30°C). Store in original package.
Actions
-
Platelet-aggregation inhibitor. Binds selectively and reversibly to PAR-1, the primary thrombin receptor expressed on human platelets, resulting in potent inhibition of thrombin-induced platelet aggregation.
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Produces rapid and prolonged dose-dependent inhibition of thrombin- and TRAP-induced platelet aggregation.
-
Although binding of vorapaxar to PAR-1 is reversible, antiplatelet effects are essentially irreversible because of drug's prolonged half-life.
-
Does not inhibit platelet activation induced by adenosine diphosphate (ADP), collagen, or arachidonic acid; also does not affect standard coagulation tests (PT, aPTT, thrombin time [TT], activated clotting time [ACT], and ecarin clotting time [ECT]).
-
No effect on QT interval corrected for rate (QTc) at usual dosages.
Advice to Patients
-
Importance of advising patients to read the manufacturer's patient information (medication guide).
-
Importance of counseling patients about the potential risks versus benefits of vorapaxar.
-
Importance of taking vorapaxar exactly as prescribed and not discontinuing therapy without first consulting the prescribing clinician.
-
Importance of informing patients that they may bruise and/or bleed more easily when taking vorapaxar; such effects may last for 4 weeks after drug discontinued. Patients should be advised to report to their clinician any unexpected, prolonged, or excessive bleeding.
-
Importance of informing clinicians (e.g., physicians, dentists) about vorapaxar therapy before any invasive procedure or surgery is scheduled. Clinicians performing invasive procedures should consult with prescribing clinician before discontinuing vorapaxar.
-
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription drugs, dietary supplements, and OTC drugs, particularly drugs that affect bleeding risk (e.g., warfarin, NSAIAs).
-
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
-
Importance of informing patients of other important precautionary information. (See Cautions.)
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes |
Dosage Forms |
Strengths |
Brand Names |
Manufacturer |
---|---|---|---|---|
Oral |
Tablets |
2.08 mg (of vorapaxar) |
Zontivity |
Merck |
AHFS DI Essentials™. © Copyright 2024, Selected Revisions October 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.
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