Vorapaxar
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]
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Black Box Warning
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WARNING: BLEEDING RISK
See full prescribing information for complete Boxed Warning.
Bleeding: Do not use vorapaxar in patients with a history of stroke, transient ischemic attack (TIA), or intracranial hemorrhage (ICH); or active pathological bleeding.
Antiplatelet agents, including vorapaxar , increase the risk of bleeding, including ICH and fatal bleeding
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Overview
Vorapaxar is a platelet aggregation inhibitor that is FDA approved for the prophylaxis of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or with peripheral arterial disease (PAD). There is a Black Box Warning for this drug as shown here. Common adverse reactions include bleeding, anemia.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Patients with History of Myocardial Infarction (MI) or with Peripheral Arterial Disease (PAD)
- Dosing Information
- 2.08 mg orally once daily, with or without food.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vorapaxar in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Vorapaxar in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Vorapaxar FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vorapaxar in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Vorapaxar in pediatric patients.
Contraindications
History of Stroke, Transient Ischemic Attack (TIA), or Intracranial Hemorrhage (ICH)
- Vorapaxar is contraindicated in patients with a history of stroke, TIA, or ICH because of an increased risk of ICH in this population.
- Discontinue vorapaxar in patients who experience a stroke, TIA, or ICH.
Active Pathologic Bleeding
- Vorapaxar is contraindicated in patients with active pathological bleeding such as ICH or peptic ulcer
Warnings
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WARNING: BLEEDING RISK
See full prescribing information for complete Boxed Warning.
Bleeding: Do not use vorapaxar in patients with a history of stroke, transient ischemic attack (TIA), or intracranial hemorrhage (ICH); or active pathological bleeding.
Antiplatelet agents, including vorapaxar , increase the risk of bleeding, including ICH and fatal bleeding
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General Risk of Bleeding
- Antiplatelet agents, including vorapaxar, increase the risk of bleeding, including ICH and fatal bleeding.
- vorapaxar increases the risk of bleeding in proportion to the patient's underlying bleeding risk.
- Consider the underlying risk of bleeding before initiating vorapaxar. General risk factors for bleeding include older age, low body weight, reduced renal or hepatic function, history of bleeding disorders, and use of certain concomitant medications (e.g., anticoagulants, fibrinolytic therapy, chronic nonsteroidal anti-inflammatory drugs [NSAIDS], selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors) increases the risk of bleeding
- Avoid concomitant use of warfarin or other anticoagulants.
- Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (PCI), coronary artery bypass graft surgery (CABG), or other surgical procedures.
- Withholding vorapaxar for a brief period will not be useful in managing an acute bleeding event because of its long half-life.
- There is no known treatment to reverse the antiplatelet effect of vorapaxar.
- Significant inhibition of platelet aggregation remains 4 weeks after discontinuation.
Strong CYP3A Inhibitors or Inducers
- Strong CYP3A inhibitors increase and inducers decrease vorapaxar exposure.
- Avoid concomitant use of vorapaxar with strong CYP3A inhibitors or inducers
Adverse Reactions
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
vorapaxar was evaluated for safety in 13,186 patients, including 2,187 patients treated for more than 3 years, in the Phase 3 study TRA 2°P TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events). The overall study population, patients who had evidence or a history of atherosclerosis involving the coronary (post-MI), cerebral (ischemic stroke), or peripheral vascular (documented history of PAD) systems, was treated once a day with vorapaxar (n=13,186) or placebo (n=13,166). Patients randomized to vorapaxar received treatment for a median of 2.3 years.
The adverse events in the vorapaxar-treated (n=10,059) and placebo-treated (n=10,049) post-MI or PAD patients with no history of stroke or TIA are shown below.
Bleeding
GUSTO severe bleeding was defined as fatal, intracranial, or bleeding with hemodynamic compromise requiring intervention; GUSTO moderate bleeding was defined as bleeding requiring transfusion of whole blood or packed red blood cells without hemodynamic compromise. (GUSTO: Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries.)
The results for the bleeding endpoints in the post-MI or PAD patients without a history of stroke or TIA are shown in Table 1. vorapaxar increased GUSTO moderate or severe bleeding by 55%.
† Hazard ratio is vorapaxar group vs. placebo group.
‡K-M estimate at 1,080 days.
The effects of vorapaxar on bleeding were examined in a number of subsets based on demographic and other baseline characteristics. Many of these are shown in Figure 1. Such analyses must be interpreted cautiously, as differences can reflect the play of chance among a large number of analyses.
In TRA 2°P, 367 post-MI or PAD patients without a history of stroke or TIA underwent CABG surgery. Study investigators were encouraged not to discontinue treatment with study drug (i.e., vorapaxar or placebo) prior to surgery. Approximately 12.3% of patients discontinued vorapaxar more than 30 days prior to CABG. The relative risk for GUSTO moderate or severe bleeding was approximately 1.2 on vorapaxar vs. placebo.
Bleeding events that occurred on vorapaxar were treated in the same manner as for other antiplatelet agents.
Use in Patients with History of Stroke, TIA, or ICH
In the TRA 2°P study, patients with a history of ischemic stroke had a higher rate for ICH on vorapaxar than on placebo. vorapaxar is contraindicated in patients with a history of stroke, TIA, or ICH.
Other Adverse Reactions
Adverse reactions other than bleeding were evaluated in 19,632 patients treated with vorapaxar [13,186 patients in the TRA 2°P study and 6,446 patients in the TRA•CER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) study]. Adverse events other than bleeding that occurred at a rate that was at least 2% in the vorapaxar group and also 10% greater than the rate in the placebo group are shown in Table 2.
The following adverse reactions occurred at a rate less than 2% in the vorapaxar group but at least 40% greater than placebo. In descending order of rate in the vorapaxar group: iron deficiency, retinopathy or retinal disorder, and diplopia/oculomotor disturbances.
An increased rate of diplopia and related oculomotor disturbances was observed with vorapaxar treatment (30 subjects, 0.2%) vs. placebo (10 subjects, 0.06%). While some cases resolved during continued treatment, information on resolution of symptoms was not available for some cases.
Postmarketing Experience
There is limited information regarding Vorapaxar Postmarketing Experience in the drug label.
Drug Interactions
Vorapaxar is eliminated primarily by metabolism, with contributions from CYP3A4 and CYP2J2.
Strong CYP3A Inhibitors
Avoid concomitant use of vorapaxar with strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, posaconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, boceprevir, telaprevir, telithromycin and conivaptan).
Strong CYP3A Inducers
Avoid concomitant use of vorapaxar with strong inducers of CYP3A (e.g., rifampin, carbamazepine, St. John's Wort and phenytoin).
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA): B There are no adequate and well-controlled studies of ZONTIVITY use in pregnant women.
Risk Summary
Based on data in rats and rabbits, ZONTIVITY is predicted to have a low probability of increasing the risk of adverse developmental outcomes above background. No embryo/fetal toxicities, malformations or maternal toxicities were observed in rats exposed during gestation to 56 times the human systemic exposure at the recommended human dose (RHD). No embryo/fetal toxicities, malformations or maternal toxicities were observed in rabbits exposed during gestation to 26 times the human systemic exposure at the RHD. The No Adverse Effect Level (NOAEL) for decreased perinatal survival and body weight in off-spring exposed in utero and during lactation was 31 times the human systemic exposure at the RHD. Both male and female pups displayed transient effects on sensory function and neurobehavioral development at weaning at 67 times the human exposure at the RHD, whereas female pups displayed decreased memory at 31 times the human exposure at the RHD. However, animal studies are not always predictive of a human response. ZONTIVITY should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
Animal Data
In the rat embryo/fetal developmental toxicity study, pregnant rats received daily oral doses of vorapaxar at 0, 5, 25, and 75 mg/kg from implantation to closure of the fetal hard palate (6th to 17th day of gestation). Maternal systemic exposures were approximately 0, 7, 56, and 285 times greater than exposures in women treated at the RHD based on AUC. No embryo/fetal toxicities, malformations, or maternal toxicities were observed in rats receiving exposures up to 56 times the human systemic exposure at the RHD.
In the rabbit embryo/fetal developmental toxicity study, pregnant rabbits received daily oral doses of vorapaxar at 0, 2, 10, or 20 mg/kg from implantation to closure of the fetal hard palate (7th to 19th day of gestation). The NOAEL for maternal and fetal toxicity was equal to or above the highest dose tested. However, an overall increase in the number of litters with any malformation was observed at the highest dose, where systemic exposures were 89-fold higher than the human exposure at RHD.
The effects of vorapaxar on prenatal and postnatal development were assessed in pregnant rats dosed at 0, 5, 25, or 50 mg/kg/day from implantation through the end of lactation. Rat pups had decreased survival and body weight gain from birth to postnatal day 4 and decreased body weight gain for the overall pre-weaning period at exposures 67 times the human exposure at the RHD. Both male and female pups displayed effects on sensory function (acoustic startle) and neurobehavioral (locomotor assay) development on post-natal day (PND) 20 and 21, but not later (PND 60, 61) in development, whereas decreased memory was observed in female pups on PND 27 at 31 times the human exposure at the RHD. In utero and lactational exposure did not affect fertility or reproductive behavior of offspring at exposures up to 67 times the RHD.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Vorapaxar in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Vorapaxar during labor and delivery.
Nursing Mothers
It is unknown whether vorapaxar or its metabolites are excreted in human milk, but it is actively secreted in milk of rats. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZONTIVITY, discontinue nursing or discontinue ZONTIVITY.
Pediatric Use
The safety and effectiveness of ZONTIVITY in pediatric patients have not been established.
Geriatic Use
In TRA 2°P, in post-MI or PAD patients without a history of stroke or TIA, 33% of patients were ≥65 years of age and 9% were ≥75 years of age. The relative risk of bleeding (ZONTIVITY compared with placebo) was similar across age groups. No overall differences in safety or effectiveness were observed between these patients and younger patients. ZONTIVITY increases the risk of bleeding in proportion to a patient's underlying risk. Because older patients are generally at a higher risk of bleeding, consider patient age before initiating ZONTIVITY
Gender
There is no FDA guidance on the use of Vorapaxar with respect to specific gender populations.
Race
There is no FDA guidance on the use of Vorapaxar with respect to specific racial populations.
Renal Impairment
No dose adjustment is required in patients with renal impairment
Hepatic Impairment
No dose adjustment is required in patients with mild and moderate hepatic impairment. Based on the increased inherent risk of bleeding in patients with severe hepatic impairment, ZONTIVITY is not recommended in such patients.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Vorapaxar in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Vorapaxar in patients who are immunocompromised.
Administration and Monitoring
Administration
Oral
Monitoring
There is limited information regarding Vorapaxar Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Vorapaxar and IV administrations.
Overdosage
There is no known treatment to reverse the antiplatelet effect of ZONTIVITY, and neither dialysis nor platelet transfusion can be expected to be beneficial if bleeding occurs after overdose. Inhibition of platelet aggregation can be expected for weeks after discontinuation of normal dosing. There is no standard test available to assess the risk of bleeding in an overdose situation.
Pharmacology
Vorapaxar
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Mechanism of Action
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Structure
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Pharmacodynamics
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Nonclinical Toxicology
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Clinical Studies
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How Supplied
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Storage
There is limited information regarding Vorapaxar Storage in the drug label.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
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Precautions with Alcohol
Alcohol-Vorapaxar interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
There is limited information regarding Vorapaxar Brand Names in the drug label.
Look-Alike Drug Names
- (Paired Confused Name 1a) — (Paired Confused Name 1b)
- (Paired Confused Name 2a) — (Paired Confused Name 2b)
- (Paired Confused Name 3a) — (Paired Confused Name 3b)
Drug Shortage Status
Drug Shortage
Price
References
The contents of this FDA label are provided by the National Library of Medicine.