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Prasugrel (Monograph)

Brand name: Effient
Drug class: Platelet-aggregation Inhibitors
Chemical name: 5-[2-Cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate hydrochloride
Molecular formula: C20H20FNO3S • HCl
CAS number: 389574-19-0

Medically reviewed by Drugs.com on Sep 25, 2023. Written by ASHP.

Warning

    Bleeding

  • Potential risk of serious (including fatal) bleeding.1 2 6 10 (See Bleeding under Cautions.)

  • Avoid use in patients with active pathological bleeding, history of stroke/ TIA, or in those likely to undergo CABG.1

  • Generally not recommended in patients ≥75 years of age because of increased risk of fatal and intracranial bleeding, except in certain high-risk patients (e.g., those with diabetes, history of MI) who may experience a greater net clinical benefit.1 5 18 994 (See Geriatric Use under Cautions.)

  • Consider additional risk factors for bleeding such as body weight <60 kg, concomitant use of drugs that increase risk of bleeding, or other underlying conditions that may increase risk of bleeding.1

  • Discontinue prasugrel at least 7 days prior to any surgery when possible.1

  • Suspect bleeding in any patient receiving prasugrel who is hypotensive and has recently undergone an invasive (e.g., PCI, coronary angiography) or surgical (e.g., CABG) procedure.1

  • If bleeding occurs, attempt to manage without discontinuing therapy; increased risk of subsequent cardiovascular events possible with premature discontinuance, particularly in first few weeks following an acute coronary event or in patients with intracoronary stents.1 43 44 45 46 47 48 49 54 (See Discontinuance of Therapy under Cautions.)

Introduction

Platelet-activation and aggregation inhibitor; thienopyridine P2Y12 platelet adenosine diphosphate (ADP)-receptor antagonist.1 2 3 4 5 6 8 13 14 15 28 30

Uses for Prasugrel

Acute Coronary Syndrome Managed with PCI

Used in conjunction with aspirin to reduce the risk of thrombotic cardiovascular events (e.g., stent thrombosis, MI) in patients with acute coronary syndrome (ACS) undergoing PCI.1 2 991 992 994 1005

May be used in patients with unstable angina or non-ST-segment-elevation MI (NSTEMI) undergoing PCI and in patients with ST-segment-elevation MI (STEMI) managed with primary or delayed (after medical treatment) PCI.1 2 991 992 994 1005

Dual antiplatelet therapy (DAPT) with a P2Y12 inhibitor (e.g., clopidogrel, prasugrel, ticagrelor) and aspirin is considered the current standard of care in patients with ACS.33 991 992 994 1005

The American College of Cardiology (ACC)/American Heart Association (AHA) has issued guidelines for treatment options and duration of DAPT.991 992 994 1005 Aspirin should almost always be continued indefinitely; decisions about specific P2Y12 inhibitor and duration of therapy should be based on risks of bleeding versus benefits of ischemic reduction, clinical judgment, and patient preference.1005

ACC/AHA generally recommends a shorter duration of DAPT for patients at reduced ischemic, but high bleeding, risk and a longer duration for patients at high ischemic, but reduced bleeding, risk.1005

In ACS patients managed with PCI and stent implantation (bare-metal or drug-eluting), P2Y12 inhibitor therapy should be given for at least 12 months; in patients who have tolerated DAPT without bleeding complications and do not have a high risk of bleeding, continuation of such therapy for longer than 12 months may be reasonable.1005

With regard to the specific P2Y12 inhibitor, evidence supports use of clopidogrel, prasugrel, or ticagrelor in ACS patients treated with PCI.991 992 994 1005

Prasugrel should not be administered to patients with a history of stroke or transient ischemic attack (TIA).991 1005

In patients treated with DAPT after coronary stent implantation who subsequently undergo CABG, P2Y12 inhibitor therapy should be resumed after surgery to complete 12 months of therapy.1005

Unlike clopidogrel, genetic polymorphism of the CYP2C19 isoenzyme does not appear to affect pharmacodynamic or clinical response to prasugrel.140 142 143 144 145 The Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines recommend prasugrel as an alternative antiplatelet agent to clopidogrel when not contraindicated in patients who are poor or intermediate metabolizers of CYP2C19.1000

Prasugrel produces more rapid and potent inhibition of platelet aggregation than standard dosages of clopidogrel and also greater reductions in ischemic outcomes (e.g., stent thrombosis, MI); however, such benefits have been accompanied by an increased risk of bleeding.1 3 5 6 7 8 9 11 13 14 15 17 18

Some evidence suggests that certain patient populations (e.g., those with diabetes, previous MI) may be more likely to benefit from prasugrel’s greater inhibition of platelet aggregation, while others (e.g., patients ≥75 years, those weighing <60 kg, or with previous TIA/stroke) may experience harm;2 5 14 16 17 19 additional studies needed to confirm these findings.2 5 13 19

When selecting an appropriate antiplatelet regimen, consider individual patient (e.g., ischemic and bleeding risk) and drug-related (e.g., adverse effects, drug interaction potential) factors.140 141 When considering use of prasugrel over other P2Y12-receptor antagonists, balance anticipated greater benefits against increased risk of bleeding.1 2 8 9 13 14 17

Acute Coronary Syndrome Managed Medically Without Revascularization† [off-label]

Has been evaluated, but not currently indicated for use in ACS patients undergoing conservative noninvasive (medical) management without revascularization.1 34

In the TRILOGY-ACS study that evaluated prasugrel in this setting, the drug was not superior to clopidogrel in reducing major ischemic events despite signs of intensified platelet inhibition.34 Although treatment effect diverged after 12 months showing benefits of prasugrel and no increased bleeding compared with clopidogrel, additional study is needed.34

Prasugrel Dosage and Administration

Administration

Oral Administration

Administer orally without regard to meals.1

Dosage

Available as prasugrel hydrochloride; dosage expressed in terms of prasugrel.1

Adults

ACS
Patients Managed with PCI
Oral

60-mg initial loading dose followed by maintenance dosage of 10 mg daily; give in conjunction with aspirin (75–325 mg daily).1

Majority of patients in pivotal efficacy study (TRITON-TIMI 38) received loading dose after first coronary guidewire was placed or within 1 hour of PCI.1 2 3

In a trial of patients with NSTEMI, administration of the loading dose prior to coronary angiography did not offer clear benefit compared with administration at the time of PCI.1 35 Risk of bleeding was increased with early administration in patients undergoing PCI or early CABG.1 35

Consider reduced maintenance dosage in patients weighing <60 kg.1 6 18 (See Low Body Weight under Dosage and Administration.)

Optimum duration of maintenance therapy not known; premature discontinuance of antiplatelet therapy in patients managed with PCI and coronary stents can result in stent thrombosis, MI, and/or death.1 45 (See Discontinuance of Therapy under Cautions.) Recommendations for duration of dual antiplatelet therapy can be found in ACC/AHA guidelines.1005 (See Acute Coronary Syndrome Managed with PCI under Uses.)

Special Populations

Hepatic Impairment

No dosage adjustments required in patients with mild to moderate hepatic impairment (Child-Pugh class A or B).1 Not studied in patients with severe hepatic disease.1

Renal Impairment

No dosage adjustments required.1

Low Body Weight

May reduce maintenance dosage to 5 mg daily in patients who weigh <60 kg, although safety and efficacy of such lower dosages not established.1 6 18 (See Bleeding under Cautions.)

Detailed Prasugrel dosage information

Cautions for Prasugrel

Contraindications

Warnings/Precautions

Warnings

Bleeding

Risk of serious, sometimes fatal bleeding.1 2 6 10 (See Boxed Warning.) Major and minor bleeding events, including life-threatening and fatal bleeding, reported more frequently in patients receiving prasugrel than those who received clopidogrel in pivotal clinical study.1 2 6 10

Greater risk of bleeding observed in patients ≥75 years of age, those weighing <60 kg, and those with prior stroke or TIA.1 2 Additional risk factors include recent trauma, recent surgery (e.g., CABG), recent or recurrent GI bleeding, active peptic ulcer disease, severe hepatic impairment, and concurrent use of drugs that increase risk of bleeding (e.g., oral anticoagulants, NSAIAs, thrombolytic agents).1

Do not use in patients who are actively bleeding and/or who have a history of stroke or TIA.1 17 18 Not recommended in patients likely to undergo emergent CABG.1 (See Coronary Artery Bypass Grafting Surgery under Cautions.)

Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, PCI, CABG, or any other surgical procedure, even if there are no overt manifestations of bleeding.1

If possible, manage bleeding without discontinuing prasugrel; premature discontinuance is associated with an increased risk of subsequent cardiovascular events.1 (See Discontinuance of Therapy under Cautions.) May treat bleeding with platelet transfusions; however, transfusions within 6 hours of a loading dose or 4 hours of a maintenance dose may be less effective.1 Withholding a dose not likely to resolve or prevent bleeding.1

Cerebrovascular Events

Higher incidence of stroke (thrombotic and hemorrhagic) and no evidence of clinical benefit reported among patients with a history of stroke or TIA receiving prasugrel compared with clopidogrel in TRITON-TIMI 38 study.1 2 Use not recommended in patients with a history of stroke or TIA; in general, discontinue prasugrel in those who experience such cerebrovascular events during therapy.1 18

Coronary Artery Bypass Grafting Surgery

Increased risk of bleeding in patients who undergo CABG surgery.1 2 (See Bleeding under Cautions.) CABG-related major and minor bleeding events occurred substantially more frequently in patients who received prasugrel versus clopidogrel in pivotal clinical study.1 2

Discontinue prasugrel at least 7 days prior to CABG.1 Do not initiate in patients who are likely to undergo urgent CABG.1 May treat CABG-related bleeding with blood product transfusions (e.g., packed RBCs, platelets).1

Discontinuance of Therapy

Discontinue prasugrel in patients who develop active bleeding, stroke, or TIA during therapy.1 Temporarily discontinue drug at least 7 days prior to elective surgery.1

In general, avoid premature discontinuance of thienopyridine treatment because of the subsequent increased risk of ischemic complications.1 6 45

Premature discontinuance of antiplatelet therapy in patients with intracoronary stents, particularly drug-eluting stents, associated with increased risk of stent thrombosis, MI, and/or death.43 44 45 46 47 48 49 54 At least 12 months of dual-drug antiplatelet therapy is recommended following placement of coronary artery stent (bare-metal or drug-eluting).994

Advise patients to never discontinue such therapy without first consulting their prescribing clinician, even if instructed to do so by another health-care professional.1 45 (See Advice to Patients.) If prasugrel must be temporarily discontinued because of an adverse event, reinstitute therapy as soon as possible.1

Thrombotic Thrombocytopenic Purpura (TTP)

Reported rarely with use of other thienopyridine derivatives, sometimes after brief exposure (<2 weeks); potentially fatal.1 31 Characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes on peripheral blood smear), neurologic findings, renal dysfunction, and fever.1 31 Requires urgent treatment (e.g., plasmapheresis).1

Specific Populations

Pregnancy

No adequate and controlled studies in pregnant women.1 In animal studies, no malformations were observed when prasugrel was administered during organogenesis.1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Use during nursing only if potential benefits outweigh risks.1

Pediatric Use

Safety and efficacy not established in pediatric patients.1

Geriatric Use

Geriatric patients, particularly those ≥75 years of age, appear to be at greater risk of bleeding (including fatal bleeding) with prasugrel therapy compared with younger patients.1 Fatal bleeding and symptomatic intracranial hemorrhage occurred more often in patients ≥75 years of age receiving prasugrel compared with that in clopidogrel-treated patients in a large clinical study.1

In general, avoid use in patients ≥75 years of age, but may consider use in certain geriatric patients with high-risk conditions (e.g., diabetes, previous MI) in whom a greater net clinical benefit has been demonstrated.1 5 18 994

Hepatic Impairment

In patients with mild to moderate hepatic impairment (Child-Pugh class A or B), inhibition of platelet aggregation was similar to that of healthy individuals.1 Not specifically studied in patients with severe hepatic impairment; such patients generally are at higher risk of bleeding.1

Renal Impairment

Inhibition of platelet aggregation similar in patients with moderate renal impairment (Clcr of 30–50 mL/minute) and healthy individuals.1

Low Body Weight

Patients with low body weight (<60 kg) have increased exposure to the active metabolite of prasugrel and appear to be at increased risk of bleeding.1 (See Bleeding under Cautions.)

Common Adverse Effects

Bleeding, including life-threatening and fatal bleeding events.1 2

Drug Interactions

Metabolized principally by CYP3A4 and CYP2B6; to a lesser extent by CYP2C9 and CYP2C19.1 13 14 22 23 30 Not likely to inhibit CYP isoenzymes 1A2, 2C9, 2C19, 2D6, or 3A4 nor induce isoenzymes 1A2 or 3A4.1 13 Weak inhibitor of CYP2B6.1 25

Does not inhibit P-glycoprotein (Pgp) transport system.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Clinically important interactions mediated by CYP enzymes unlikely.1 13 25

CYP3A4 inhibitors: No substantial effect on systemic exposure or antiplatelet activity of prasugrel’s active metabolite.1 22

CYP3A4 inducers: Not expected to substantially alter pharmacokinetic or pharmacodynamic response to prasugrel.1 25

Drugs metabolized by CYP2B6: Potential for increased plasma concentrations and exposure to concomitantly administered drug; however, clinically important interactions not expected because of weak inhibition of CYP2B6.1 25

Other Antiplatelet or Antithrombotic Agents

Manufacturer states that prasugrel may be administered concomitantly with aspirin, heparin, and GP IIb/IIIa-receptor inhibitors.1 While evidence from drug interaction studies with other antiplatelet or antithrombotic agents generally is lacking, increased risk of bleeding likely with concomitant use of such agents.13 14

Specific Drugs or Foods

Drug

Interaction

Comments

Aspirin

Possible increased bleeding time and greater levels of platelet inhibition1 26

May be administered concomitantly1

Carbamazepine

Pharmacokinetic/pharmacodynamic response to prasugrel not expected to be substantially altered1 25

Ciprofloxacin

Systemic exposure and antiplatelet activity of prasugrel active metabolite not affected1 22

Clarithromycin

Systemic exposure and antiplatelet activity of prasugrel active metabolite not affected1 22

Cyclophosphamide

Possible increased plasma concentrations and exposure to concomitant drug; clinically important interaction not expected1 25

Digoxin

Concurrent administration not expected to affect digoxin clearance1

May be administered concomitantly1

Diltiazem

Systemic exposure and antiplatelet activity of prasugrel active metabolite not affected1 22

Grapefruit juice

Systemic exposure and antiplatelet activity of prasugrel active metabolite not affected1 22

Heparin

Possible increased bleeding time, but no associated changes in coagulation or platelet inhibition1

May be administered concomitantly1

Histamine H2-receptor antagonists (e.g., ranitidine)

Decreased plasma concentrations of active prasugrel metabolite by approximately 14%, but systemic exposure unaffected

May be administered concomitantly1

HMG-CoA reductase inhibitors (e.g., atorvastatin)

Minor effect on exposure to active prasugrel metabolite, but no effect on inhibition of platelet aggregation1 17 23

May be used concomitantly; no dosage adjustments necessary1 23

Ketoconazole

Decreased plasma concentrations of prasugrel’s active metabolite by 34–46%; no change in systemic exposure or platelet inhibition1 14 17 22

Nevirapine

Possible increased plasma concentrations and exposure to concomitant drug; clinically important interaction not expected1 25

NSAIAs

Increased risk of bleeding with concomitant long-term use of NSAIAs1

Opiate agonists

Possible delayed or reduced absorption of prasugrel’s active metabolite because of slowed gastric emptying1

Consider use of parenteral antiplatelet agent1

Propofol

Possible increased plasma concentrations and exposure to concomitant drug; clinically important interaction not expected1 25

Proton-pump inhibitors (e.g., lansoprazole)

Possible decreased systemic exposure and peak plasma concentrations of prasugrel’s active metabolite, but no effect on platelet inhibition1 13 17 24

May be administered concomitantly1

Rifampin

Pharmacokinetic/pharmacodynamic response to prasugrel not expected to be substantially altered1 25

Thrombolytic agents

Increased risk of bleeding1

Warfarin

Increased risk of bleeding; prolonged bleeding time observed with concomitant use1
Prasugrel drug interactions (more detail)

Prasugrel Pharmacokinetics

Absorption

Bioavailability

Rapidly and completely absorbed following oral administration.1 13 27 28

Onset

Peak plasma concentrations of active metabolite attained approximately 30 minutes following oral administration; no evidence of accumulation with repeated administration.1 13 25 28

Following a 60-mg loading dose, approximately 90% of patients achieve at least 50% inhibition of platelet aggregation by 1 hour; maximum platelet inhibition was approximately 80%.1 Steady-state platelet inhibition (70%) occurs within 3–5 days following maintenance therapy with repeated dosages of 10 mg daily.1

Duration

Following discontinuance, platelet aggregation gradually returns to baseline values in about 5–9 days.1

Food

In healthy individuals, food (high-fat or high-caloric meal) decreased peak plasma concentrations by 49% but did not alter exposure to active metabolite.1

Special Populations

In patients with end-stage renal impairment, exposure to active metabolite was decreased to approximately half that in healthy individuals and those with moderate renal impairment.1

In low-weight individuals (weight <60 kg), increased exposure to active metabolite observed.1 Clearance of active metabolite appears to increase exponentially with increasing body weight.30

In patients ≥75 years of age, mean exposure to active metabolite increased by 19% compared with younger patients.1 In patients ≥75 years of age receiving a prasugrel maintenance dosage of 5 mg daily, mean exposure was approximately half of that in younger patients receiving a dosage of 10 mg daily.1

Distribution

Plasma Protein Binding

Approximately 98% for active metabolite.1

Elimination

Metabolism

Rapidly hydrolyzed by esterases to an inactive thiolactone; subsequently metabolized to active metabolite by CYP isoenzymes (primarily by 3A4 and 2B6, and to a lesser extent by 2C9 and 2C19).1 13 14 22 23 28 30 Requires a single step for metabolic activation compared with clopidogrel, which undergoes a 2-step oxidative process.13 14 22 29 30 31

Elimination Route

Excreted in urine (68%) and feces (27%) as inactive metabolites.1 14 28 Active metabolite not expected to be removed by dialysis.1

Half-life

Manufacturer reports half-life of active metabolite about 7 hours (range 2–15 hours);1 half-life of about 3.7 hours also reported.13 14

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1 Dispense and store in original container; keep container closed and do not remove desiccant from bottle.1

Actions

Advice to Patients

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.

Prasugrel Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

5 mg (of prasugrel)

Effient

Eli Lilly and Company (also promoted by Daiichi Sankyo Inc.)

10 mg (of prasugrel)

Effient

Eli Lilly and Company (also promoted by Daiichi Sankyo Inc.)

AHFS DI Essentials™. © Copyright 2024, Selected Revisions October 4, 2021. 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.

References

1. Eli Lilly/Daiichi Sankyo. Effient (prasugrel) tablets prescribing information. Indianapolis, IN; 2010 Apr.

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3. Wiviott SD, Antman EM, Gibson CM et al. Evaluation of prasugrel compared with clopidogrel in patients with acute coronary syndromes: design and rationale for the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet InhibitioN with prasugrel Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38). Am Heart J. 2006; 152:627-35. http://www.ncbi.nlm.nih.gov/pubmed/16996826?dopt=AbstractPlus

4. Montalescot G, Wiviott SD, Braunwald E et al. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet. 2009; 373:723-31. http://www.ncbi.nlm.nih.gov/pubmed/19249633?dopt=AbstractPlus

5. Wiviott SD, Braunwald E, Angiolillo DJ et al. Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-Thrombolysis in Myocardial Infarction 38. Circulation. 2008; 118:1626-36. http://www.ncbi.nlm.nih.gov/pubmed/18757948?dopt=AbstractPlus

6. Antman EM, Wiviott SD, Murphy SA et al. Early and late benefits of prasugrel in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel-Thrombolysis In Myocardial Infarction) analysis. J Am Coll Cardiol. 2008; 51:2028-33. http://www.ncbi.nlm.nih.gov/pubmed/18498956?dopt=AbstractPlus

7. Wiviott SD, Braunwald E, Murphy SA et al. A perspective on the efficacy and safety of intensive antiplatelet therapy in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-thrombolysis in myocardial infarction 38. Am J Cardiol. 2008; 101:1367-70. http://www.ncbi.nlm.nih.gov/pubmed/18435974?dopt=AbstractPlus

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18. Bhatt DL. Prasugrel in clinical practice. N Engl J Med. 2009; 361:940-2. http://www.ncbi.nlm.nih.gov/pubmed/19605807?dopt=AbstractPlus

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20. Graber MA, Dachs R, Darby-Stewart A. Is prasugrel more effective than clopidogrel in patients with acute coronary syndrome scheduled for PCI?. Am Fam Physician. 2008; 78:1252-3. http://www.ncbi.nlm.nih.gov/pubmed/19069017?dopt=AbstractPlus

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25. Farid NA, Payne CD, Ernest CS et al. Prasugrel, a new thienopyridine antiplatelet drug, weakly inhibits cytochrome P450 2B6 in humans. J Clin Pharmacol. 2008; 48:53-9. http://www.ncbi.nlm.nih.gov/pubmed/18094219?dopt=AbstractPlus

26. Jakubowski JA, Payne CD, Weerakkody GJ et al. Dose-dependent inhibition of human platelet aggregation by prasugrel and its interaction with aspirin in healthy subjects. J Cardiovasc Pharmacol. 2007; 49:167-73. http://www.ncbi.nlm.nih.gov/pubmed/17414229?dopt=AbstractPlus

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28. Farid NA, Smith RL, Gillespie TA et al. The disposition of prasugrel, a novel thienopyridine, in humans. Drug Metab Dispos. 2007; 35:1096-104. http://www.ncbi.nlm.nih.gov/pubmed/17403916?dopt=AbstractPlus

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30. Ernest CS, Small DS, Rohatagi S et al. Population pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel in aspirin-treated patients with stable coronary artery disease. J Pharmacokinet Pharmacodyn. 2008; 35:593-618. http://www.ncbi.nlm.nih.gov/pubmed/19023649?dopt=AbstractPlus

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35. Montalescot G, Bolognese L, Dudek D et al. Pretreatment with prasugrel in non-ST-segment elevation acute coronary syndromes. N Engl J Med. 2013; 369:999-1010. http://www.ncbi.nlm.nih.gov/pubmed/23991622?dopt=AbstractPlus

43. Pfisterer M, Brunner-La Rocca HP, Buser PT et al. Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents. JACC. 2006; 48:2584-91. http://www.ncbi.nlm.nih.gov/pubmed/17174201?dopt=AbstractPlus

44. Eisenstein EL, Anstrom KJ, Kong DF et al. Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation. JAMA. 2007;297:159-168.

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