Vorapaxar (Monograph)

Brand name: Zontivity
Drug class: Platelet-aggregation Inhibitors
ATC class: B01AC04
Chemical name: [(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(1E)-2-[5-(3-Fluorophenyl)-2-pyridinyl]ethenyl]dodecahydro-1-methyl-3-oxonaphtho[2,3-c]furan-6-yl]-carbamic acid, ethyl ester
Molecular formula: C₂₉H₃₃FN₂O₄
CAS number: 618385-01-6

Warning

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

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 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

Oral

2.08 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

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 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.
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 (QT_c) 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.)

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.