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Prasugrel

Pronunciation

Pronunciation

(PRA soo grel)

Index Terms

  • CS-747
  • LY-640315
  • Prasugrel Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Effient: 5 mg, 10 mg

Brand Names: U.S.

  • Effient

Pharmacologic Category

  • Antiplatelet Agent
  • Antiplatelet Agent, Thienopyridine

Pharmacology

Prasugrel, an inhibitor of platelet activation and aggregation, is a prodrug that is metabolized to both active (R-138727) and inactive metabolites. The active metabolite irreversibly blocks the P2Y12 component of ADP receptors on the platelet, which prevents activation of the GPIIb/IIIa receptor complex, thereby reducing platelet activation and aggregation

Absorption

Rapid; ≥79%

Distribution

Active metabolite: Vd: 44-68 L

Metabolism

Rapid intestinal and serum metabolism via esterase-mediated hydrolysis to a thiolactone intermediate (inactive), which is then converted, via CYP450-mediated (primarily CYP3A4 and CYP2B6) oxidation, to an active metabolite (R-138727) (Farid, 2007; Riley, 2008)

Excretion

Urine (~68% inactive metabolites); feces (27% inactive metabolites)

Onset of Action

Inhibition of platelet aggregation (IPA): Dose dependent: 60 mg loading dose: <30 minutes; median time to reach ≥20% IPA: 30 minutes (Brandt, 2007)

Peak effect: Time to maximal IPA: Dose-dependent: Note: Degree of IPA based on adenosine diphosphate (ADP) concentration used during light aggregometry: 60 mg loading dose: Occurs ~4 hours post administration; Mean IPA (ADP 5 micromol/L): ~84.1%; Mean IPA (ADP 20 micromole/L): ~78.8% (Brandt, 2007)

Time to Peak

Active metabolite: ~30 minutes; With high-fat/high-calorie meal: 1.5 hours

Duration of Action

Duration of effect: Platelet aggregation gradually returns to baseline values over 5-9 days after discontinuation; reflective of new platelet production

Half-Life Elimination

Half-life elimination: Active metabolite: ~7 hours (range: 2-15 hours)

Protein Binding

Active metabolite: ~98%

Special Populations: Renal Function Impairment

In patients with ESRD, both Cmax and AUC0-t last of the active metabolite were approximately half that in healthy patients and in patients with moderate renal impairment.

Special Populations: Elderly

The AUC of active metabolite was 19% higher in patients 75 years and older than in patients younger than 75 years.

Special Populations: Race

The AUC of active metabolite was approximately 19% higher in Chinese, Japanese, and Korean subjects than in white subjects.

Special Populations Note

Body weight: The AUC of the active metabolite is approximately 30% to 40% higher in subjects with a body weight of less than 60 kg compared to those weighing 60 kg or more.

Use: Labeled Indications

Acute coronary syndrome to be managed with percutaneous coronary intervention (PCI): To reduce the rate of thrombotic cardiovascular events (including stent thrombosis) in patients who are to be managed with PCI for unstable angina (UA), non-ST-segment elevation MI (NSTEMI), or ST-elevation MI (STEMI).

Use: Unlabeled

Initial treatment of UA/NSTEMI in patients undergoing PCI with allergy or major gastrointestinal intolerance to aspirin; Note: Dual antiplatelet therapy with another P2Y12 receptor inhibitor is not recommended in this situation (ACCF/AHA [Anderson, 2013]).

Contraindications

Active pathological bleeding such as peptic ulcer or intracranial hemorrhage; prior TIA or stroke; hypersensitivity (eg, anaphylaxis) to prasugrel or any component of the formulation.

Dosing: Adult

Acute coronary syndrome (ACS): Oral:

Percutaneous coronary intervention (PCI) for ACS: Loading dose: 60 mg administered promptly (as soon as coronary anatomy is known) and no later than 1 hour after PCI; Maintenance dose: 10 mg once daily (in combination with aspirin 75 to 325 mg/day; 81 mg/day recommended [Levine, 2011]). For patients with STEMI, a loading dose may also be administered if PCI is performed >24 hours after treatment with a fibrin-specific thrombolytic (ie, alteplase, reteplase, tenecteplase) (ACCF/AHA [O’Gara, 2013]).

Duration of prasugrel (in combination with aspirin) after stent placement: Premature interruption of therapy may result in stent thrombosis, MI, and death. According to the ACCF/AHA/SCAI PCI guidelines, those with ACS receiving either stent type (bare metal [BMS] or drug-eluting stent [DES]) or those receiving a DES for a non-ACS indication, prasugrel for at least 12 months is recommended (ACCF/AHA/SCAI [Levine, 2011]). The ACCF/AHA guidelines for the management of UA/NSTEMI recommend up to 12 months of prasugrel in patients with ACS who receive a BMS (ACCF/AHA [Anderson, 2013]). A duration >12 months may be considered in patients with DES placement. Recent data has demonstrated that continued dual antiplatelet therapy for a total of 30 months (compared to 12 months) significantly reduced the risk of stent thrombosis and major adverse cardiovascular/cerebrovascular events but was associated with a higher risk of bleeding (Mauri, 2014). Those receiving a BMS for a non-ACS indication should be given at least 1 month and ideally up to 12 months; if patient is at increased risk of bleeding, give for a minimum of 2 weeks (ACCF/AHA/SCAI [Levine, 2011]).

Maintenance dosing in low body weight (ie, <60 kg) individuals: Due to a higher incidence of bleeding in patients weighing <60 kg, a maintenance dose of 5 mg once daily may be considered. In aspirin-treated patients weighing <60 kg (mean: 56.4 ± 3.7 kg) with stable coronary artery disease, the use of prasugrel 5 mg once daily was shown to reduce platelet reactivity to a similar extent as prasugrel 10 mg administered once daily to patients >60 kg (mean: 84.7 ± 14.9 kg); clinical events were not evaluated (Erlinge, 2012). In patients with ACS (medically managed) treated with aspirin, a 5 mg daily maintenance dose (after a 30 mg loading dose) in patients <60 kg did not demonstrate a significant difference in the composite primary end point of death from cardiovascular causes, MI, or stroke compared to patients >60 kg treated with a 10 mg maintenance dose; bleeding risk was not increased (Roe, 2012).

Conversion from clopidogrel to prasugrel: Beginning 24 hours after the last clopidogrel dose (loading or maintenance), may initiate prasugrel 10 mg once daily or a 60 mg loading dose followed in 24 hours with 10 mg once daily (Angiolillo, 2010; Payne, 2008; Wiviott, 2007).

Dosing: Geriatric

Refer to adult dosing. Patients ≥75 years: Use not recommended; may be considered in high-risk situations (eg, patients with diabetes or history of MI).

Dosing: Renal Impairment

No dosage adjustment necessary.

Dosing: Hepatic Impairment

Mild to moderate hepatic impairment (Child-Pugh class A and B): No dosage adjustment necessary for mild-to-moderate hepatic impairment.

Severe hepatic impairment (Child-Pugh class C): No dosage adjustment provided in manufacturer's labeling (has not been studied).

Administration

Administer without regard to meals. Per the prescribing information, do not break the tablet. According to the manufacturer, however, chewing, breaking, or crushing the tablet is not expected to alter the stability or potency of prasugrel if administered immediately (not evaluated). Therefore, if it becomes necessary, tablets may be chewed and swallowed (bitter to taste) or crushed and mixed in food or liquid (eg, applesauce, juice, water) and immediately administered by mouth or gastric tube. Note: Administration via an enteral tube that bypasses the acidic environment of the stomach may result in reduced bioavailability of prasugrel (data on file, Daiichi Sankyo-Lilly, 2012).

Storage

Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Drug Interactions

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the antiplatelet effect of other Agents with Antiplatelet Properties. Monitor therapy

Anticoagulants: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Apixaban: Antiplatelet Agents (P2Y12 Inhibitors) may enhance the adverse/toxic effect of Apixaban. Specifically, the risk for bleeding may be increased. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Consider therapy modification

Cangrelor: May diminish the antiplatelet effect of Prasugrel. More specifically, while the use of Cangrelor is expected to increase total platelet inhibition in patients who have previously received Prasugrel, Cangrelor is expected to decrease binding of Prasugrel metabolites to P2Y12 receptors and thus reduce the extent of irreversible platelet inhibition. Management: Avoid administration of prasugrel until cangrelor is discontinued. Consider therapy modification

Cephalothin: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Cephalothin. Specifically, the risk for bleeding may be increased. 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. Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease serum concentrations of the active metabolite(s) of Prasugrel. Monitor therapy

Dabigatran Etexilate: Antiplatelet Agents (P2Y12 Inhibitors) may enhance the adverse/toxic effect of Dabigatran Etexilate. Specifically, the risk of bleeding may be increased. Antiplatelet Agents (P2Y12 Inhibitors) may increase the serum concentration of Dabigatran Etexilate. Specifically, clopidogrel may increase dabigatran serum concentrations. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Consider therapy modification

Dasatinib: May enhance the anticoagulant effect of Agents with Antiplatelet Properties. 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. Monitor therapy

Edoxaban: Antiplatelet Agents (P2Y12 Inhibitors) may enhance the adverse/toxic effect of Edoxaban. Specifically, the risk of bleeding may be increased. Management: Carefully consider the anticipated risks and benefits of this combination. If combined, increased monitoring for bleeding is recommended. Consider therapy modification

Glucosamine: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. Consider therapy modification

Ibritumomab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Monitor therapy

Ibrutinib: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Monitor therapy

Limaprost: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Morphine (Liposomal): May diminish the antiplatelet effect of Antiplatelet Agents (P2Y12 Inhibitors). Morphine (Liposomal) may decrease the serum concentration of Antiplatelet Agents (P2Y12 Inhibitors). Management: Consider alternative anti-ischemic/analgesic therapies (eg, beta-blockers, nitroglycerin) in patients with acute coronary syndromes treated with a P2Y12 inhibitor when possible. The risks associated with other opioids are unknown. Consider therapy modification

Morphine (Systemic): May diminish the antiplatelet effect of Antiplatelet Agents (P2Y12 Inhibitors). Morphine (Systemic) may decrease the serum concentration of Antiplatelet Agents (P2Y12 Inhibitors). Management: Consider alternative anti-ischemic/analgesic therapies (eg, beta-blockers, nitroglycerin) in patients with acute coronary syndromes treated with a P2Y12 inhibitor when possible. The risks associated with other opioids are unknown. Consider therapy modification

Multivitamins/Fluoride (with ADE): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Multivitamins/Minerals (with AE, No Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. 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. Monitor therapy

Omega-3 Fatty Acids: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. 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. Monitor therapy

Pentoxifylline: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Prostacyclin Analogues: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

RaNITIdine: May decrease serum concentrations of the active metabolite(s) of Prasugrel. Monitor therapy

RifAMPin: May diminish the antiplatelet effect of Prasugrel. Monitor therapy

Rivaroxaban: Antiplatelet Agents (P2Y12 Inhibitors) may enhance the adverse/toxic effect of Rivaroxaban. Specifically, the risk of bleeding may be increased. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Consider therapy modification

Salicylates: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result. Monitor therapy

Thrombolytic Agents: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents. Monitor therapy

Tipranavir: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Tositumomab and Iodine I 131 Tositumomab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse events may be increased. Monitor therapy

Urokinase: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Urokinase. Avoid combination

Vitamin E (Systemic): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Adverse Reactions

As with all drugs which may affect hemostasis, bleeding is associated with prasugrel. Hemorrhage may occur at virtually any site. Risk is dependent on multiple variables, including patient susceptibility and concurrent use of multiple agents which alter hemostasis.

2% to 10%:

Cardiovascular: Hypertension (8%), hypotension (4%), atrial fibrillation (3%), bradycardia (3%), noncardiac chest pain (3%), peripheral edema (3%)

Central nervous system: Headache (6%), dizziness (4%), fatigue (4%), fever (3%), extremity pain (3%)

Dermatologic: Rash (3%)

Endocrine & metabolic: Hypercholesterolemia/hyperlipidemia (7%)

Gastrointestinal: Nausea (5%), diarrhea (2%), gastrointestinal hemorrhage (2%)

Hematologic: Leukopenia (3%), anemia (2%)

Neuromuscular & skeletal: Back pain (5%)

Respiratory: Epistaxis (6%), dyspnea (5%), cough (4%)

<2% (Limited to important or life-threatening): Allergic reaction, anaphylaxis, angioedema, hematoma, hemoptysis, hemorrhage (postprocedural, retinal, retroperitoneal), liver function (abnormal), thrombocytopenia, thrombotic thrombocytopenic purpura

ALERT: U.S. Boxed Warning

Bleeding risk:

Prasugrel can cause significant, sometimes fatal, bleeding. Do not use prasugrel in patients with active pathological bleeding or a history of transient ischemic attack (TIA) or stroke.

In patients ≥75, prasugrel is generally not recommended because of the increased risk of fatal and intracranial bleeding and uncertain benefit, except in high-risk situations (patients with diabetes or a history of myocardial infarction [MI]) in which its effect appears to be greater and its use may be considered.

Do not start prasugrel in patients likely to undergo urgent coronary artery bypass graft (CABG) surgery. When possible, discontinue prasugrel at least 7 days prior to any surgery.

Additional risk factors for bleeding include body weight <60 kg, propensity to bleed, and concomitant use of medications that increase the risk of bleeding (eg, warfarin, heparin, fibrinolytic therapy, long-term use of nonsteroidal anti-inflammatory drugs [NSAIDs]).

Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (PCI), CABG, or other surgical procedures in the setting of prasugrel.

If possible, manage bleeding without discontinuing prasugrel. Discontinuing prasugrel, particularly in the first few weeks after acute coronary syndrome (ACS), increases the risk of subsequent cardiovascular events.

Warnings/Precautions

Concerns related to adverse effects:

• Bleeding: [US Boxed Warning]: May cause significant or fatal bleeding. Use is contraindicated in patients with active pathological bleeding or history of TIA or stroke. Additional risk factors for bleeding include age ≥75 years, propensity to bleed (eg, recent trauma or surgery, recent or recurrent GI bleeding, active PUD, severe hepatic impairment, moderate-to-severe renal impairment), body weight <60 kg, CABG or other surgical procedure, concomitant use of medications that increase risk of bleeding (eg, warfarin, heparin, fibrinolytic therapy, long term use of NSAIDs). Bleeding should be suspected if patient becomes hypotensive after undergoing recent coronary angiography, PCI, CABG, or other surgical procedure even if overt signs of bleeding do not exist; if possible, do not discontinue prasugrel. Management of bleeding episodes includes the use of PRBCs and platelet transfusion.

• Hypersensitivity: Hypersensitivity, including angioedema, has been reported, including in patients with a previous history of thienopyridine hypersensitivity. Because of structural similarities, cross-reactivity is possible among the thienopyridines (clopidogrel, prasugrel, and ticlopidine); use with caution or avoid in patients with previous history of thienopyridine hypersensitivity. Use of prasugrel is contraindicated in patients with hypersensitivity (eg, anaphylaxis) to prasugrel.

• Thrombotic thrombocytopenic purpura (TTP): Cases of TTP (usually occurring within the first 2 weeks of therapy), resulting in some fatalities, have been reported with prasugrel; urgent plasmapheresis is required.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with severe hepatic impairment (patients are generally at higher risk of bleeding).

• Renal impairment: Use with caution in patients with end-stage renal disease (patients are generally at higher risk of bleeding).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Medications that increase the risk of bleeding (eg, oral anticoagulants, fibrinolytics, NSAIDs): Use with caution ; bleeding risk is increased.

Special populations:

• Elderly: [US Boxed Warning]: In patients ≥75 years, use is generally not recommended due to increased risk of fatal and intracranial bleeding and uncertain benefit; use may be considered in high-risk situations (eg, patients with diabetes or history of MI).

• Low-weight patients: In patients weighing <60 kg, risk of bleeding increased; consider lower maintenance dose.

Other warnings/precautions:

• Appropriate use: Surgical patients: [US Boxed Warning]: Do not initiate therapy in patients likely to undergo urgent CABG surgery; when possible, discontinue ≥7 days prior to any surgery; increased risk of bleeding. The American College of Chest Physicians (ACCP) recommends discontinuing prasugrel 5 days before surgery (Guyatt, 2012). When urgent CABG is necessary, the ACCF/AHA suggests that it may be reasonable to perform surgery within 7 days of discontinuing prasugrel especially if the benefits of prompt revascularization outweigh the risks of bleeding (ACCF/AHA [Hillis, 2011]; ACCF/AHA [O’Gara, 2013]).

• Drug discontinuation: Discontinue therapy for active bleeding, elective surgery, stroke, or TIA; reinitiate therapy as soon as possible unless patient suffers stroke or TIA where subsequent use is contraindicated; if possible, manage bleeding without discontinuing therapy since premature discontinuation of treatment may cause increased risk for cardiac adverse events; lapses in treatment should be avoided.

Monitoring Parameters

Hemoglobin and hematocrit periodically; may consider platelet function testing to determine platelet inhibitory response if results of testing may alter management (ACCF/AHA [Anderson, 2013]).

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events have not been observed in animal reproduction studies. Information related to use during pregnancy is limited (Tello-Montoliu, 2012).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Have patient report immediately to prescriber signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that will not stop), angina, passing out, severe headache, purple patches on skin or mouth, or signs of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (bruising or bleeding; feeling very tired or weak; dark urine or yellow skin or eyes; pale skin; change in the amount of urine passed; vision changes; change in strength on one side is greater than the other, trouble speaking or thinking, or change in balance; or fever) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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