Prasugrel is a thienopyridine platelet aggregation inhibitor similar to ticlopidine and clopidogrel. Prasugrel is indicated for the reduction of thrombotic cardiovascular events (including stent thrombosis) in patients with acute coronary syndrome (unstable angina, non-ST-elevation myocardial infarction [NSTEMI], ST-elevation myocardial infarction [STEMI]) being managed with percutaneous coronary intervention (PCI). The approval of prasugrel was based on results from the TRITON-TIMI 38 clinical trial, which compared prasugrel with clopidogrel in reducing cardiovascular events in 13,608 patients with acute coronary syndrome (ACS) managed with PCI. Results from the study showed that patients receiving prasugrel had a greater reduction in the combined endpoint of cardiovascular death, non-fatal heart attack or non-fatal stroke compared to clopidogrel, with the difference being predominantly due to a reduction in myocardial infarction, with no difference in stroke and little difference on cardiovascular death. The benefit of prasugrel compared to clopidogrel was seen as early as 3 days and continued throughout the follow-up period (up to 15 months, average duration of therapy 14.5 months). In addition, there were fewer cases of stent thrombosis in patients treated with prasugrel compared with clopidogrel. Although the benefit of reduction in thrombotic events was greater with prasugrel compared to clopidogrel, bleeding was seen more frequently in patients receiving prasugrel. Prasugrel (Effient) was approved by the FDA in July 2009.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-May be administered with or without food.
-Do not prematurely discontinue therapy.
Oral Solid Formulations
-Tablets are not scored. Patients should be advised to avoid breaking tablets, as dosing accuracy cannot be assured if tablets are split or divided in an attempt to administer a smaller dose.
-Tablets may be broken or crushed and delivered in food or liquid, such as applesauce, juice, or water, or administered via a gastric tube, provided the crushed tablet is administered immediately and completely.
-Although intended to be swallowed, tablets may be chewed. Of note, prasugrel hydrochloride has a characteristic bitter taste and odor that may be apparent if the tablet is chewed or crushed before ingesting orally.
The active metabolite of prasugrel irreversibly inhibits platelet aggregation; thus, patients treated with prasugrel have an increased risk of bleeding from any site. Patient on prasugrel therapy in the TRITON-TIMI 38 trial had a higher incidence of major bleeding not related to surgery when compared with patients treated with clopidogrel (2.4% for prasugrel vs. 1.8% for clopidogrel; hazard ratio, 1.32; 95% CI, 1.03 to 1.68; p = 0.03). In addition, life-threatening bleeds (intracranial bleeding, bleeding requiring inotropes, surgical intervention, or 4 transfusions or more, and fatal bleeds) also occurred more frequently in the prasugrel group (1.4% for prasugrel vs. 0.8% for clopidogrel; hazard ratio, 1.52; 95% CI, 1.08 to 2.13, p = 0.01). During this trial, 437 of the 13,608 patients underwent a coronary-artery bypass graft (CABG). Among those 437 patients, the rate of CABG-related major bleeding was statistically higher in those patients receiving prasugrel (13.4% for prasugrel vs. 3.2% for clopidogrel; hazard ratio, 4.73; 95% CI, 1.90 to 11.82; p less than 0.001). Due to the increased risk of bleeding in patients who undergo CABG, the manufacturer recommends discontinuing prasugrel at least 7 days prior to the procedure. Other bleeding events reported in patients receiving prasugrel during the TRITON-TIMI 38 trial included epistaxis (6.2%), GI bleeding (1.5%), hemoptysis (0.6%), subcutaneous hematoma (0.5%), post-procedural bleeding (0.5%), and retroperitoneal bleeding (0.3%). Risk factors for prasugrel induced bleeding include, concurrent use of medications that increase bleeding risk, propensity to bleed, weight less than 60 kg, and age 75 years or older. Do not initiate prasugrel therapy in any patient with active bleeding. Bleeding should be suspected if a patient becomes hypotensive or has recently undergone a surgical intervention, even if there are not overt signs of bleeding. If bleeding occurs during treatment, manage bleeding without discontinuing prasugrel if possible. Because prasugrel inhibits platelet aggregation for the lifetime of the platelet (7 to 10 days), withholding a single dose will not be useful in managing a bleeding event; instead, consider administering exogenous platelets to restore hemostasis. Platelet transfusions may be less effective within 6 hours of the loading dose or 4 hours of a maintenance dose.
Cardiovascular adverse reactions that have been reported with prasugrel therapy during the TRITON-TIMI 38 trial include atrial fibrillation (2.9%), bradycardia (2.9%), hypertension (7.5%), hypotension (3.9%), and peripheral edema (2.7%).
Hypersensitivity or anaphylactoid reactions may occur with the use of prasugrel. Allergic reactions were reported in 0.36% of the 6,813 patients to receive prasugrel in the TRITON-TIMI 38 trial. Further, angioedema was reported in 0.06% of the prasugrel treated patients. The incidence of allergic reactions and angioedema was similar to the rate experience in patients treated with clopidogrel in this trial (0.36% and 0.04% respectively). Also reported were rash (unspecified) (2.8%), chest pain (unspecified) (3.1%), and dyspnea (4.9%). Monitor patients closely for symptoms of allergic reactions or early signs of hypersensitivity reactions.
Hematologic adverse reactions were reported in patients receiving prasugrel during the TRITON-TIMI 38 trial. These adverse reactions occurred at rates comparable with clopidogrel and included anemia (2.2% vs. 2% for clopidogrel), leukopenia (2.8% vs. 3.5%), neutropenia (less than 0.1% vs. 0.2%), and severe thrombocytopenia (0.3% vs. 0.3%). Thrombotic thrombocytopenic purpura (TTP) has been reported in patients receiving other thienopyridines, sometimes after short exposure (less than 2 weeks). TTP is a serious condition that can be fatal and requires urgent treatment including plasmapheresis. Thrombocytopenia, microangiopathic hemolytic anemia (schistocytes [fragment red blood cells] seen on peripheral blood smear), neurological findings, renal dysfunction, and pyrexia characterize TTP. Although use of prasugrel does not require routine hematologic monitoring, consider the possibility of myelotoxicity in patients receiving the medication.
Adverse reactions that occurred following treatment with prasugrel in the TRITION-TIMI 38 trial include abnormal hepatic function (0.22%), back pain (5%), cough (3.9%), diarrhea (2.3%), dizziness (4.1%), fatigue (3.7%), fever (2.7%), headache (5.5%), hypercholesterolemia and hyperlipidemia (7%), nausea (4.6%), pain in extremity (2.6%), and new primary malignancy (1.6%, primarily colon and lung).
Prasugrel can cause significant, sometimes fatal bleeding. Prasugrel is contraindicated in any patient with active pathological bleeding including GI bleeding and intracranial bleeding. As with other antiplatelet agents, administer prasugrel with caution in patients who may be at risk of increased bleeding from recent trauma or surgery. In the TRITON-TIMI 38 trial, patients who underwent coronary artery bypass graft surgery (CABG) (n = 437) had a significantly higher rate of major and minor bleeding when treated with prasugrel (14%) compared with clopidogrel (4%). If a patient is to undergo elective surgery and an antiplatelet effect is not desired, discontinue prasugrel 7 days prior to the surgery. In addition, patients with a body weight less than 60 kg have an increased exposure to the active metabolite of prasugrel (30% to 40% higher than those weighing 60 kg or more) and are thus at an increased risk of bleeding. In the TRITON-TIMI 38 trial, 4.6% of patients in the prasugrel group weighed less than 60 kg and had a higher rate of major and minor bleeds (10%) when compared with patients in the clopidogrel group weighing less than 60 kg (6%). As a result of the increased bleeding incidence, the net clinical benefit from prasugrel was diminished in this patient population (hazard ratio, 1.03; 95% CI, 0.69 to 1.53; p = 0.89). A lower maintenance dose should be considered for patients weighing less than 60 kg. Patients with diabetes or a past history of myocardial infarction received a greater benefit from prasugrel in the TRITON-TIMI 38 trial compared with patients without such a history; considerations can be made for administering prasugrel to elderly patients 75 years of age and older who have a history of myocardial infarction or diabetes. Also, administer prasugrel cautiously in individuals who have lesions with a propensity to bleed, such as patients with active peptic ulcer disease. In addition, caution is advised when administering prasugrel concurrently with medications that might induce such lesions (such as aspirin or NSAIDs). Further, patients receiving anticoagulant therapy are at increased risk of bleeding when co-administered prasugrel. If possible, manage bleeding without discontinuing prasugrel; consider monitoring blood cell counts and/or other appropriate tests if symptoms of bleeding occur during prasugrel therapy.
Prasugrel is contraindicated in individuals with a history of stroke or transient ischemic attack (TIA). Patients enrolled in the TRITON-TIMI 38 trial with a history of stroke or TIA (> 3 months prior to enrollment), experienced a non-statistical increase in the primary outcome (death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke) while on prasugrel (19%) when compared with clopidogrel (14%). More specifically, the incidence of stroke in the prasugrel group (6.5%; 4.2% thrombotic stroke, 2.3% intracranial hemorrhage [ICH]) was higher than for the clopidogrel group (1.2% all thrombotic stokes) or for patients receiving prasugrel without a previous history of stroke or TIA (0.9%; 0.7% thrombotic stroke, 0.2% ICH). The manufacturer recommends discontinuing therapy for those patients who experience a stroke or TIA while receiving prasugrel.
Administer prasugrel with caution in patients with hepatic disease. Patients with hepatic disease may have a propensity to bleed, especially in those with severe liver disease, which may increase the risk of bleeding associated with prasugrel. In addition, severe hepatic disease may impair the conversion of prasugrel, the prodrug, to its active metabolite.
Thrombotic thrombocytopenic purpura (TTP) has been reported with the use of prasugrel and can occur even after brief exposure (less than 2 weeks). TTP is a serious, sometimes fatal, condition that requires urgent treatment (i.e., plasmapheresis). TTP is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes [fragment red blood cells] seen on peripheral smear), neurological findings, renal dysfunction, and fever.
When possible, avoid premature abrupt discontinuation of prasugrel in patients undergoing percutaneous coronary intervention (PCI) with stent placement. Patients who discontinue prasugrel prematurely may be at increased risk of developing stent thrombosis, myocardial infarction, and death. Avoid lapses in therapy; if treatment is temporarily discontinued, restart prasugrel as soon as possible.
In clinical trials, exposure (AUC) to the active metabolite of prasugrel is 19% higher in Asian patients (Chinese, Japanese, and Korean patients were specifically tested) than in White, African, or Hispanic patients. The manufacturer has not recommended dose adjustments based on ethnicity. Carefully monitor for signs of bleeding when administering prasugrel in the Asian population.
Safe and effective use of prasugrel have not been established in children.
There are no data with the use of prasugrel in pregnant women to inform a drug-associated risk. Reproduction and toxicology studies performed in rats and rabbits at doses up to 30 to 150 times the recommended daily human dose demonstrated no evidence of impaired fertility or fetotoxicity due to prasugrel. Carefully weigh the benefits and risks of prasugrel and possible risks to the fetus when using prasugrel during pregnancy.
There is no information about the presence of prasugrel in human milk, the effects on the breastfed infant, or the effects on milk production; however, prasugrel metabolites were found in rat milk. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for prasugrel and any potential adverse effects on the breast-fed infant from prasugrel or the mother's underlying condition.
Administer prasugrel with caution in patients with moderate to severe renal impairment. These patients may have a propensity to bleed, which may increase the risk of bleeding associated with prasugrel.
Prasugrel is contraindicated in patients with a hypersensitivity to prasugrel or any component of the product. Hypersensitivity reactions, including angioedema, have been reported in patients receiving prasugrel, including patients with a history of thienopyridine hypersensitivity.
Geriatric patients 75 years of age and older are at increased risk of bleeding; prasugrel use is generally not recommended in this population due to the higher bleeding risk versus younger adults, except for those high-risk patients with diabetes or prior history of myocardial infarction where benefits exceed risks. A post-hoc analysis of the TRITON-TIMI 38 trial identified those patients 75 years of age or older as receiving no net clinical benefit from treatment with prasugrel (HR, 0.99; 95% CI 0.81 to 1.21; p = 0.92). Also, older adults 75 years or older and receiving prasugrel had an increased rate of fatal bleeding events (1%) and symptomatic ICH (0.8%) when compared with those 75 years and older who received clopidogrel (0.1% and 0.3% respectively). High concentrations of the active metabolite of prasugrel may account for the increased bleeding rate and subsequent lack of clinical benefit in these geriatric subjects. In the TRITON-TIMI 38 trial, geriatric patients 75 years and older had a mean exposure (AUC) to the active metabolite that was 19% higher than adults less than 75 years of age. According to the Beers Criteria, prasugrel is considered a potentially inappropriate medication (PIM) in older adults; use cautiously in adults 75 years of age and older due to an increased risk of bleeding, although the benefit in high-risk older adults (e.g., those with prior myocardial infarction or diabetes) may offset the risk when used for the FDA-approved indication of acute coronary syndrome managed with percutaneous coronary intervention.
General dosing information
Switching from another P2Y12 inhibitor to prasugrel:
-Switching from intravenous cangrelor:-Discontinue cangrelor and immediately administer prasugrel 60 mg PO loading dose, then prasugrel 10 mg PO once daily.
-Switching from clopidogrel:
--Within 30 days of the index event: Discontinue clopidogrel and administer prasugrel 60 mg PO loading dose irrespective of the timing of the last clopidogrel dose, then prasugrel 10 mg PO once daily starting 24 hours after the last clopidogrel dose.
-More than 30 days from the index event: Discontinue clopidogrel and administer prasugrel 10 mg PO once daily 24 hours after the last clopidogrel dose.
-Switching from ticagrelor:-Within 30 days of index event: Discontinue ticagrelor and administer prasugrel 60 mg PO loading dose 24 hours after the last ticagrelor dose, then prasugrel 10 mg PO once daily.
-More than 30 days from the index event: Discontinue ticagrelor and administer prasugrel 60 mg PO loading dose 24 hours after the last ticagrelor dose, then prasugrel 10 mg PO once daily.
Switching from prasugrel to another P2Y12 Inhibitor:
-Bridging to intravenous cangrelor:-Discontinue prasugrel and initiate cangrelor 0.75 mcg/kg/minute (without a bolus dose) 3 to 4 days after the last administered prasugrel dose. Consider platelet function testing to determine time to initiate cangrelor infusion.
-Switching to clopidogrel:
--Within 30 days of index event and without bleeding or bleeding concerns: Discontinue prasugrel and administer clopidogrel 600 mg PO loading dose 24 hours after the last prasugrel dose, then clopidogrel 75 mg PO once daily.
-Within 30 days of index event and with bleeding or bleeding concerns: Discontinue prasugrel and consider switching directly to clopidogrel maintenance dose of 75 mg PO once daily 24 hours after the last prasugrel dose.
-More than 30 days from the index event: Discontinue prasugrel and administer clopidogrel 75 mg PO once daily starting 24 hours after the last prasugrel dose.
-Switching to ticagrelor:-Within 30 days of the index event: Discontinue prasugrel and administer ticagrelor 180 mg PO loading dose 24 hours after the last prasugrel dose, then ticagrelor 90 mg PO twice daily.
-More than 30 days of the index event: Discontinue prasugrel and administer ticagrelor 90 mg PO twice daily starting 24 hours after the last prasugrel dose.
For arterial thromboembolism prophylaxis (including stent thrombosis) in persons with acute coronary syndrome (i.e., unstable angina, acute myocardial infarction, NSTEMI, or acute myocardial infarction, STEMI) who are to be managed with percutaneous coronary intervention (PCI):
Oral dosage:
Adults weighing 60 kg or more: 60 mg PO loading dose, then 10 mg PO once daily in combination with aspirin. Although it is generally recommended that antiplatelet therapy be promptly administered in the management of ACS as many cardiovascular events occur within hours of initial presentation, no clear benefit was observed when prasugrel was administered prior to diagnostic coronary angiography compared to at the time of PCI; however, bleeding risk was increased with early administration in patients undergoing PCI or early CABG.
Adults weighing less than 60 kg: 60 mg PO loading dose, then 5 mg PO once daily in combination with aspirin. Compared to persons weighing 60 kg or more, those weighing less than 60 kg have an increased exposure to the active metabolite of prasugrel and an increased risk of bleeding when given 10 mg/day. The safety and effectiveness of the 5 mg dose have not been prospectively studied. Although it is generally recommended that antiplatelet therapy be promptly administered in the management of ACS as many cardiovascular events occur within hours of initial presentation, no clear benefit was observed when prasugrel was administered prior to diagnostic coronary angiography compared to at the time of PCI; however, bleeding risk was increased with early administration in patients undergoing PCI or early CABG.
For myocardial infarction prophylaxis* in moderate- or high-risk persons with coronary artery disease*:
Oral dosage:
Adults older than 75 years or weighing less than 60 kg: 5 mg PO once daily in combination with low-dose aspirin.
Adults 18 to 75 years weighing 60 kg or more: 10 mg PO once daily in combination with low-dose aspirin.
Maximum Dosage Limits:
-Adults
10 mg/day PO; 60 mg PO as a single loading dose.
-Elderly
< 75 years: 10 mg/day PO; 60 mg PO as a single loading dose.
>= 75 years: 10 mg/day PO; 60 mg PO as a single loading dose; generally not recommended.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Mild impairment (Child-Pugh class A, total score of 5 or 6) or moderate impairment (Child-Pugh class B, total score of 7-9): No dosage adjustment needed.
Severe impairment (Child-Pugh class C, total score > 10): No specific guidelines are available. Use with caution as patients with severe hepatic disease may be at increased risk of bleeding.
Patients with Renal Impairment Dosing
No dosage adjustment needed in patients with renal impairment; there is limited experience in patients with end-stage renal disease. Patients with moderate to severe renal impairment are at increased risk of bleeding.
*non-FDA-approved indication
Abciximab: (Moderate) Concomitant use of platelet glycoprotein IIb/IIIa inhibitors (i.e., abciximab, eptifibatide, or tirofiban) with an ADP receptor antagonist (i.e., clopidogrel, prasugrel, ticagrelor, or ticlopidine) may be associated with an increased risk of bleeding.
Abrocitinib: (Contraindicated) Concurrent use with prasugrel is contraindicated during the first 3 months of abrocitinib therapy due to an increased risk of bleeding with thrombocytopenia.
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Although indicated for concomitant use, both prasugrel and aspirin are associated with bleeding. Aspirin 150 mg did not alter prasugrel-mediated inhibition of platelet aggregation; however, bleeding time was increased compared to either drug alone. Monitor for bleeding during concomitant therapy.
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Although indicated for concomitant use, both prasugrel and aspirin are associated with bleeding. Aspirin 150 mg did not alter prasugrel-mediated inhibition of platelet aggregation; however, bleeding time was increased compared to either drug alone. Monitor for bleeding during concomitant therapy.
Acetaminophen; Aspirin: (Moderate) Although indicated for concomitant use, both prasugrel and aspirin are associated with bleeding. Aspirin 150 mg did not alter prasugrel-mediated inhibition of platelet aggregation; however, bleeding time was increased compared to either drug alone. Monitor for bleeding during concomitant therapy.
Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Although indicated for concomitant use, both prasugrel and aspirin are associated with bleeding. Aspirin 150 mg did not alter prasugrel-mediated inhibition of platelet aggregation; however, bleeding time was increased compared to either drug alone. Monitor for bleeding during concomitant therapy.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Acetaminophen; Codeine: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Acetaminophen; Hydrocodone: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Acetaminophen; Ibuprofen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Acetaminophen; Oxycodone: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Ado-Trastuzumab emtansine: (Moderate) Use caution if coadministration of platelet inhibitors with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
Alfentanil: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Alteplase: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution.
Aminolevulinic Acid: (Minor) Agents, such as platelet inhibitors, that decrease clotting could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
Amlodipine; Celecoxib: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Anagrelide: (Moderate) Although anagrelide inhibits platelet aggregation at high doses, there is a potential additive risk for bleeding if anagrelide is given in combination with other agents that effect hemostasis such as ADP receptor antagonists including clopidogrel, prasugrel, ticagrelor, or ticlopidine.
Antithrombin III: (Moderate) Concomitant use of prasugrel and other agents that may affect hemostasis, such as anticoagulants, may be associated with an increased risk of bleeding.
Antithymocyte Globulin: (Moderate) An increased risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia, such as antithymocyte globulin. Platelet inhibitors should be used cautiously in patients with thrombocytopenia following the administration of antithymocyte globulin or other drugs that cause significant thrombocytopenia due to the increased risk of bleeding.
Apixaban: (Major) The concomitant use of apixaban and platelet inhibitors (e.g, aspirin) may increase the risk of bleeding. In the ARISTOTLE trial (comparative trial of apixaban and warfarin in patients with nonvalvular atrial fibrillation), concomitant use of aspirin increased the bleeding risk of apixaban from 1.8%/year to 3.4%/year. If given concomitantly, patients should be educated about the signs and symptoms of bleeding and be instructed to report them immediately or go to an emergency room.
Argatroban: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., clopidogrel, platelet glycoprotein IIb/IIIa inhibitors, ticlopidine, etc.) in combination with argatroban.
Aspirin, ASA: (Moderate) Although indicated for concomitant use, both prasugrel and aspirin are associated with bleeding. Aspirin 150 mg did not alter prasugrel-mediated inhibition of platelet aggregation; however, bleeding time was increased compared to either drug alone. Monitor for bleeding during concomitant therapy.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Although indicated for concomitant use, both prasugrel and aspirin are associated with bleeding. Aspirin 150 mg did not alter prasugrel-mediated inhibition of platelet aggregation; however, bleeding time was increased compared to either drug alone. Monitor for bleeding during concomitant therapy.
Aspirin, ASA; Caffeine: (Moderate) Although indicated for concomitant use, both prasugrel and aspirin are associated with bleeding. Aspirin 150 mg did not alter prasugrel-mediated inhibition of platelet aggregation; however, bleeding time was increased compared to either drug alone. Monitor for bleeding during concomitant therapy.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Although indicated for concomitant use, both prasugrel and aspirin are associated with bleeding. Aspirin 150 mg did not alter prasugrel-mediated inhibition of platelet aggregation; however, bleeding time was increased compared to either drug alone. Monitor for bleeding during concomitant therapy.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Although indicated for concomitant use, both prasugrel and aspirin are associated with bleeding. Aspirin 150 mg did not alter prasugrel-mediated inhibition of platelet aggregation; however, bleeding time was increased compared to either drug alone. Monitor for bleeding during concomitant therapy. (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Although indicated for concomitant use, both prasugrel and aspirin are associated with bleeding. Aspirin 150 mg did not alter prasugrel-mediated inhibition of platelet aggregation; however, bleeding time was increased compared to either drug alone. Monitor for bleeding during concomitant therapy.
Aspirin, ASA; Dipyridamole: (Moderate) Although indicated for concomitant use, both prasugrel and aspirin are associated with bleeding. Aspirin 150 mg did not alter prasugrel-mediated inhibition of platelet aggregation; however, bleeding time was increased compared to either drug alone. Monitor for bleeding during concomitant therapy. (Moderate) Because dipyridamole is a platelet inhibitor, there is a potential additive risk for bleeding if dipyridamole is given in combination with other agents that affect hemostasis such as ADP receptor antagonists including clopidogrel, prasugrel, ticagrelor, or ticlopidine.
Aspirin, ASA; Omeprazole: (Moderate) Although indicated for concomitant use, both prasugrel and aspirin are associated with bleeding. Aspirin 150 mg did not alter prasugrel-mediated inhibition of platelet aggregation; however, bleeding time was increased compared to either drug alone. Monitor for bleeding during concomitant therapy.
Aspirin, ASA; Oxycodone: (Moderate) Although indicated for concomitant use, both prasugrel and aspirin are associated with bleeding. Aspirin 150 mg did not alter prasugrel-mediated inhibition of platelet aggregation; however, bleeding time was increased compared to either drug alone. Monitor for bleeding during concomitant therapy. (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Belladonna; Opium: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Benzhydrocodone; Acetaminophen: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Betrixaban: (Major) Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if betrixaban and platelet inhibitors are used concomitantly. Coadministration of betrixaban and platelet inhibitors may increase the risk of bleeding.
Bexarotene: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including bexarotene.
Bivalirudin: (Moderate) When used as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI), bivalirudin is intended for use with aspirin (300 to 325 mg/day PO) and has been studied only in patients receiving concomitant aspirin. Generally, an additive risk of bleeding may be seen in patients receiving other platelet inhibitors (other than aspirin). In clinical trials in patients undergoing PTCA, patients receiving bivalirudin with heparin, warfarin, or thrombolytics had increased risks of major bleeding events compared to those receiving bivalirudin alone. According to the manufacturer, the safety and effectiveness of bivalirudin have not been established when used in conjunction with platelet inhibitors other than aspirin. However, bivalirudin has been safely used as an alternative to heparin in combination with provisional use of platelet glycoprotein IIb/IIIa inhibitors during angioplasty (REPLACE-2). In addition, two major clinical trials have evaluated the use of bivalirudin in patients receiving streptokinase following acute myocardial infarction (HERO-1, HERO-2). Based on the these trials, bivalirudin may be considered an alternative to heparin therapy for use in combination with streptokinase for ST-elevation MI. Bivalirudin has not been sufficiently studied in combination with other more specific thrombolytics.
Bupivacaine; Meloxicam: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Although indicated for concomitant use, both prasugrel and aspirin are associated with bleeding. Aspirin 150 mg did not alter prasugrel-mediated inhibition of platelet aggregation; however, bleeding time was increased compared to either drug alone. Monitor for bleeding during concomitant therapy. (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Cangrelor: (Major) Do not administer prasugrel until the cangrelor infusion is discontinued. The expected antiplatelet effect of a 60 mg loading dose of prasugrel will be blocked if administered during the cangrelor infusion. Prasugrel therapy should be initiated immediately after cangrelor discontinuation.
Caplacizumab: (Major) Avoid concomitant use of caplacizumab and platelet inhibitors when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Celecoxib: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Celecoxib; Tramadol: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying. (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Chlorambucil: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as chlorambucil.
Chlorpheniramine; Codeine: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Chlorpheniramine; Hydrocodone: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Cilostazol: (Moderate) Carefully monitor patients for signs and symptoms of bleeding during coadministration of cilostazol and prasugrel. Both agents are platelet inhibitors; therefore, concomitant use may increase the risk of bleeding. Platelet aggregation returns to normal within 96 hours of discontinuing cilostazol.
Citalopram: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving prasugrel. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
Cladribine: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Clofarabine: (Moderate) Due to the thrombocytopenic effects of antineoplastics an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Clopidogrel: (Moderate) Because clopidogrel and prasugrel inhibit platelet aggregation, a potential additive risk for bleeding exists if the drugs are given in combination. Patients should be instructed to monitor for signs and symptoms of bleeding and to promptly report any bleeding events.
Codeine: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Codeine; Guaifenesin: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Codeine; Phenylephrine; Promethazine: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Codeine; Promethazine: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Collagenase: (Moderate) Cautious use of injectable collagenase by patients taking platelet inhibitors is advised. The efficacy and safety of administering injectable collagenase to a patient taking a platelet inhibitor within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
Dabigatran: (Moderate) Concomitant use of prasugrel and other agents that may affect hemostasis, such as anticoagulants, may be associated with an increased risk of bleeding.
Dalteparin: (Moderate) Based on the mechanism of actions of prasugrel and unfractionated heparin or low-molecular weight heparins (LMWHs), patients receiving these medications in combination may be at increased risk of bleeding. The concurrent use of prasugrel and a single 100 unit/kg intravenous dose of heparin did not disrupt coagulation or the inhibition of platelet aggregation; however, the bleeding time increased compared with monotherapy of either medication. Use caution when administering prasugrel with medications that may increase the risk of bleeding, such as unfractionated heparin or LMWH.
Danazol: (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with platelet inhibitors.
Dasatinib: (Moderate) Monitor for evidence of bleeding if coadministration of dasatinib and prasugrel is necessary. Dasatinib can cause serious and fatal bleeding. Concomitant platelet inhibitors may increase the risk of hemorrhage.
Defibrotide: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like platelet inhibitors is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue antithrombotic agents prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Deoxycholic Acid: (Moderate) Use deoxycholic acid with caution in patients receiving platelet inhibitors. Excessive bruising or bleeding may occur in and around the treatment area.
Desvenlafaxine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with a platelet inhibitor and to promptly report any bleeding events to the practitioner.
Diclofenac: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Diclofenac; Misoprostol: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Diflunisal: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Diphenhydramine; Ibuprofen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Diphenhydramine; Naproxen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Dipyridamole: (Moderate) Because dipyridamole is a platelet inhibitor, there is a potential additive risk for bleeding if dipyridamole is given in combination with other agents that affect hemostasis such as ADP receptor antagonists including clopidogrel, prasugrel, ticagrelor, or ticlopidine.
Duloxetine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with a platelet inhibitor and to promptly report any bleeding events to the practitioner.
Edoxaban: (Major) Coadministration of edoxaban and platelet inhibitors should be avoided due to an increased risk of bleeding during concurrent use. Occasionally, short-term coadministration may be necessary in patients transitioning to and from edoxaban. Long-term coadminstration is not recommended. Promptly evaluate any signs or symptoms of blood loss in patients on concomitant therapy.
Elexacaftor; tezacaftor; ivacaftor: (Moderate) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as prasugrel. Ivacaftor is an inhibitor of CYP3A and a weak inhibitor of CYP2C9; prasugrel is metabolized by CYP3A and CYP2C9. Co-administration of ivacaftor with CYP3A and CYP2C9 substrates, such as prasugrel, can theoretically increase prasugrel exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Enoxaparin: (Major) Whenever possible, discontinue agents which may enhance the risk of hemorrhage, including prasugrel, before initiation of enoxaparin therapy. If coadministration is essential, conduct close clinical and laboratory monitoring.
Eptifibatide: (Moderate) Concomitant use of platelet glycoprotein IIb/IIIa inhibitors (i.e., abciximab, eptifibatide, or tirofiban) with an ADP receptor antagonist (i.e., clopidogrel, prasugrel, ticagrelor, or ticlopidine) may be associated with an increased risk of bleeding.
Escitalopram: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving prasugrel. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
Etodolac: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Fenoprofen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Fentanyl: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Moderate) Because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with other platelet inhibitors. Theoretically, the risk of bleeding may be increased.
Fludarabine: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Fluoxetine: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving prasugrel. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
Flurbiprofen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Fluvoxamine: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving prasugrel. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
Fondaparinux: (Moderate) Concomitant use of prasugrel and other agents that may affect hemostasis, such as anticoagulants, may be associated with an increased risk of bleeding.
Garlic, Allium sativum: (Moderate) Use together with caution. Garlic produces clinically significant antiplatelet effects, and a risk for bleeding may occur if platelet inhibitors are given in combination with garlic.
Ginger, Zingiber officinale: (Moderate) Ginger inhibits thromboxane synthetase, a platelet aggregation inducer, and is a prostacyclin agonist so additive bleeding may occur if platelet inhibitors are given in combination with ginger, zingiber officinale.
Ginkgo, Ginkgo biloba: (Moderate) Monitor for signs or symptoms of bleeding with coadministration of ginkgo biloba and platelet inhibitors as an increased bleeding risk may occur. Although data are mixed, ginkgo biloba is reported to inhibit platelet aggregation and several case reports describe bleeding complications with ginkgo biloba, with or without concomitant drug therapy.
Guaifenesin; Hydrocodone: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Heparin: (Moderate) Based on the mechanism of actions of prasugrel and unfractionated heparin or low-molecular weight heparins (LMWHs), patients receiving these medications in combination may be at increased risk of bleeding. The concurrent use of prasugrel and a single 100 unit/kg intravenous dose of heparin did not disrupt coagulation or the inhibition of platelet aggregation; however, the bleeding time increased compared with monotherapy of either medication. Use caution when administering prasugrel with medications that may increase the risk of bleeding, such as unfractionated heparin or LMWH.
Homatropine; Hydrocodone: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Hydrocodone: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Hydrocodone; Ibuprofen: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying. (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Hydrocodone; Pseudoephedrine: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Hydromorphone: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Ibritumomab Tiuxetan: (Major) During and after therapy, avoid the concomitant use of Yttrium (Y)-90 ibrutumomab tiuxetan with drugs that interfere with platelet function such as platelet inhibitors; the risk of bleeding may be increased. If coadministration with platelet inhibitors is necessary, monitor platelet counts more frequently for evidence of thrombocytopenia.
Ibrutinib: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as prasugrel may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
Ibuprofen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Ibuprofen; Famotidine: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Ibuprofen; Oxycodone: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying. (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Ibuprofen; Pseudoephedrine: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Icosapent ethyl: (Moderate) Icosapent ethyl is an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA). Because omega-3 fatty acids inhibit platelet aggregation, caution is advised when icosapent ethyl is used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 36 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant icosapent ethyl therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with prasugrel, a CYP3A substrate, as prasugrel toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
Iloprost: (Moderate) When used concurrently with platelet inhibitors, inhaled iloprost may increase the risk of bleeding.
Indomethacin: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Inotersen: (Moderate) Use caution with concomitant use of inotersen and ADP receptor antagonists due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of ADP receptor antagonists in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Intravenous Lipid Emulsions: (Moderate) Because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with other platelet inhibitors. Theoretically, the risk of bleeding may be increased.
Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with prasugrel may result in increased serum concentrations of prasugrel. Prasugrel is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
Ivacaftor: (Moderate) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as prasugrel. Ivacaftor is an inhibitor of CYP3A and a weak inhibitor of CYP2C9; prasugrel is metabolized by CYP3A and CYP2C9. Co-administration of ivacaftor with CYP3A and CYP2C9 substrates, such as prasugrel, can theoretically increase prasugrel exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Ketoprofen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Ketorolac: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Levomilnacipran: (Moderate) Carefully monitor patients for signs and symptoms of bleeding during coadministration of levomilnacipran and platelet inhibitors. Serotonin-norepinephrine reuptake inhibitors (SNRIs) affect platelet activation; therefore, concomitant use may increase the risk of bleeding.
Levorphanol: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Lomustine, CCNU: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as lomustine.
Lumacaftor; Ivacaftor: (Moderate) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as prasugrel. Ivacaftor is an inhibitor of CYP3A and a weak inhibitor of CYP2C9; prasugrel is metabolized by CYP3A and CYP2C9. Co-administration of ivacaftor with CYP3A and CYP2C9 substrates, such as prasugrel, can theoretically increase prasugrel exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Meclofenamate Sodium: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Mefenamic Acid: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Meloxicam: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Meperidine: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Mercaptopurine, 6-MP: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Methadone: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Methoxsalen: (Minor) Agents that affect platelet function, such as platelet inhibitors, could decrease the efficacy of methoxsalen when used during photodynamic therapy.
Methylsulfonylmethane, MSM: (Moderate) Increased effects from concomitant anticoagulant drugs including increased bruising or blood in the stool have been reported in patients taking methylsulfonylmethane, MSM. Although these effects have not been confirmed in published medical literature or during clinical studies, clinicians should consider using methylsulfonylmethane, MSM with caution in patients who are taking anticoagulants or antiplatelets including clopidogrel until data confirming the safety of these drug combinations are available. During one of the available, published clinical trials in patients with osteoarthritis, those patients with bleeding disorders or using anticoagulants or antiplatelets were excluded from enrollment. Patients who choose to consume methylsulfonylmethane, MSM while receiving clopidogrel should be observed for increased bleeding.
Milnacipran: (Moderate) Carefully monitor patients for signs and symptoms of bleeding during coadministration of milnacipran and platelet inhibitors. Serotonin-norepinephrine reuptake inhibitors (SNRIs) affect platelet activation; therefore, concomitant use may increase the risk of bleeding.
Morphine: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Morphine; Naltrexone: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Mycophenolate: (Moderate) Platelet Inhibitors inhibit platelet aggregation and should be used cautiously in patients with thrombocytopenia, as mycophenolate can also cause thrombocytopenia.
Nabumetone: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Naproxen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Naproxen; Esomeprazole: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Naproxen; Pseudoephedrine: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Nelarabine: (Moderate) Due to the thrombocytopenic effects of nelarabine, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Nonsteroidal antiinflammatory drugs: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Obinutuzumab: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
Olanzapine; Fluoxetine: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving prasugrel. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
Oliceridine: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Opiate Agonists: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Oxaprozin: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Oxycodone: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Oxymorphone: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Paroxetine: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving prasugrel. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
Pentosan: (Moderate) Concomitant use of prasugrel and other agents that may affect hemostasis, such as anticoagulants, may be associated with an increased risk of bleeding.
Pentostatin: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Pentoxifylline: (Moderate) A potential additive risk for bleeding exists if platelet inhibitors are given in combination with other agents that affect hemostasis such as pentoxifylline.
Photosensitizing agents (topical): (Minor) Agents, such as platelet inhibitors, that decrease clotting could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
Piroxicam: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Platelet Glycoprotein IIb/IIIa Inhibitors: (Moderate) Concomitant use of platelet glycoprotein IIb/IIIa inhibitors (i.e., abciximab, eptifibatide, or tirofiban) with an ADP receptor antagonist (i.e., clopidogrel, prasugrel, ticagrelor, or ticlopidine) may be associated with an increased risk of bleeding.
Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Moderate) Prasterone is contraindicated for use in patients with active deep vein thrombosis, pulmonary embolism or history of these conditions. Prasterone is also contraindicated in patients with active arterial thromboembolic disease (for example, stroke and myocardial infarction), or a history of these conditions. Thus, patients receiving anticoagulation due to a history of these conditions are not candidates for prasterone treatment. DHEA is converted to androgens and estrogens within the human body and thus may affect hemostasis via androgenic or estrogenic effects. Estrogens increase the production of clotting factors VII, VIII, IX, and X. Androgens, such as testosterone, increase the synthesis of several anticoagulant and fibrinolytic proteins. Because of the potential effects on coagulation, patients receiving prasterone or DHEA concurrently with preventative anticoagulants (e.g., warfarin or heparin) or other platelet inhibitors, including aspirin, ASA should be monitored for side effects or the need for dosage adjustments.
Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Moderate) Prasterone is contraindicated for use in patients with active deep vein thrombosis, pulmonary embolism or history of these conditions. Prasterone is also contraindicated in patients with active arterial thromboembolic disease (for example, stroke and myocardial infarction), or a history of these conditions. Thus, patients receiving anticoagulation due to a history of these conditions are not candidates for prasterone treatment. DHEA is converted to androgens and estrogens within the human body and thus may affect hemostasis via androgenic or estrogenic effects. Estrogens increase the production of clotting factors VII, VIII, IX, and X. Androgens, such as testosterone, increase the synthesis of several anticoagulant and fibrinolytic proteins. Because of the potential effects on coagulation, patients receiving prasterone or DHEA concurrently with preventative anticoagulants (e.g., warfarin or heparin) or other platelet inhibitors, including aspirin, ASA should be monitored for side effects or the need for dosage adjustments.
Purine analogs: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Remifentanil: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Reteplase, r-PA: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution.
Rivaroxaban: (Major) Avoid concurrent administration of platelet inhibitors such as prasugrel with rivaroxaban unless the benefit outweighs the risk of increased bleeding. An increase in bleeding time to 45 minutes was observed in 2 drug interaction studies where another platelet inhibitor and rivaroxaban (15 mg single dose) were coadministered in healthy subjects. In the first study, the increase in bleeding time to 45 minutes was observed in approximately 45% of patients. Approximately 30% of patients in the second study had the event. The change in bleeding time was approximately twice the maximum increase seen with either drug alone. No change in the pharmacokinetic parameters of either drug were noted.
Selective serotonin reuptake inhibitors: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving prasugrel. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
Selumetinib: (Moderate) Closely monitor for bleeding if coadministration of selumetinib and platelet inhibitors is necessary as concurrent use may increase the bleeding risk; adjust the platelet inhibitor dose as appropriate. Selumetinib contains vitamin E which can inhibit platelet aggregation.
Sertraline: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving prasugrel. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
Sufentanil: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Sulindac: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Sumatriptan; Naproxen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Tapentadol: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Tenecteplase: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution.
Tezacaftor; Ivacaftor: (Moderate) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as prasugrel. Ivacaftor is an inhibitor of CYP3A and a weak inhibitor of CYP2C9; prasugrel is metabolized by CYP3A and CYP2C9. Co-administration of ivacaftor with CYP3A and CYP2C9 substrates, such as prasugrel, can theoretically increase prasugrel exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Thioguanine, 6-TG: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Thrombolytic Agents: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution.
Tirofiban: (Moderate) Concomitant use of platelet glycoprotein IIb/IIIa inhibitors (i.e., abciximab, eptifibatide, or tirofiban) with an ADP receptor antagonist (i.e., clopidogrel, prasugrel, ticagrelor, or ticlopidine) may be associated with an increased risk of bleeding.
Tolmetin: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Tramadol: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Tramadol; Acetaminophen: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Trazodone: (Moderate) Platelet aggregation may be impaired by trazodone due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking trazodone concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
Treprostinil: (Moderate) Monitor patients for signs and symptoms of bleeding if treprostinil is administered with prasugrel. Treprostinil inhibits platelet aggregation; prasugrel is a platelet inhibitor. Coadministration increases the risk of bleeding.
Venlafaxine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with a platelet inhibitor and to promptly report any bleeding events to the practitioner.
Verteporfin: (Moderate) Use caution if coadministration of verteporfin with platelet inhibitors is necessary due to the risk of decreased verteporfin efficacy. Verteporfin is a light-activated drug. Once activated, local damage to neovascular endothelium results in a release of procoagulant and vasoactive factors resulting in platelet aggregation, fibrin clot formation, and vasoconstriction. Concomitant use of drugs that decrease platelet aggregation could decrease the efficacy of verteporfin therapy.
Vilazodone: (Moderate) Patients should be instructed to monitor for signs and symptoms of bleeding while taking vilazodone concurrently with salicylates or other platelet inhibitors and to promptly report any bleeding events to the practitioner. Platelet aggregation may be impaired by vilazodone due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., aspirin, cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors).
Vorapaxar: (Moderate) Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as ADP receptor antagonists including clopidogrel, prasugrel, ticagrelor, or ticlopidine.
Vorinostat: (Moderate) Carefully monitor patients for signs and symptoms of bleeding during coadministration of prasugrel and vorinostat. Due to the thrombocytopenic effects of vorinostat, an additive risk of bleeding may occur in patients taking platelet inhibitors.
Vortioxetine: (Moderate) Platelet aggregation may be impaired by vortioxetine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Bleeding events related to drugs that inhibit serotonin reuptake have ranged from ecchymosis to life-threatening hemorrhages. Patients should be instructed to monitor for signs and symptoms of bleeding while taking vortioxetine concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
Warfarin: (Moderate) The potential for bleeding is increased when prasugrel and oral anticoagulants, such as warfarin, are coadministered. According to the manufacturer, a significant prolongation of the bleeding time was observed when prasugrel was administered with 15 mg of warfarin. Avoid coadministration of prasugrel and warfarin when possible; monitor for bleeding if prasugrel is given concurrently with warfarin.
Prasugrel is a thienopyridine compound that inhibits adenosine diphosphate (ADP) induced platelet aggregation. Prasugrel, similar to clopidogrel, is an inactive prodrug and requires hepatic conversion to an active metabolite; however unlike clopidogrel, this activation is a rapid single-step process. The active metabolite irreversibly binds and antagonizes the platelet P2Y12 receptor for the life of the platelet, thus preventing ADP binding. With ADP unable to bind to the platelet, activation of glycoprotein IIb/IIIa (GIIb/IIIa) complex is impaired. Because the GIIb/IIIa complex is the major platelet receptor for fibrinogen, fibrinogen binding and ultimately platelet aggregation is also impaired.
Prasugrel is an orally administered inactive prodrug requiring conversion to an active metabolite.
Inhibition of platelet aggregation (IPA) from two dosing regimens (40 mg load with 7.5 mg maintenance and 60 mg load with 15 mg maintenance) was studied over 21 days in a phase I trial. In this trial, both loading doses were effective at rapidly inhibiting platelet aggregation with peak platelet inhibition occurring within 60-90 minutes and remaining consistent throughout the 24 hour period. Twenty-four hours after the loading dose, maintenance doses were initiated. The IPA for each dose reached steady state between days 7 and 14 with the 15 mg dose achieving significantly higher platelet inhibition (day 14 through 21). According to the manufacturer, a 60 mg loading dose will achieve 50% inhibition of platelets after 1 hour in 90% of patients. In addition, mean steady state IPA of 70% will occur in 3-5 days following the recommended 60 mg loading and 10 mg daily maintenance dose. The effectiveness of prasugrel at inhibiting platelet aggregation was compared with clopidogrel in a phase II clinical trial. In this trial, prasugrel was more potent and had a more rapid onset than clopidogrel. The inhibition of platelet aggregation (IPA with 20 mcmol/L ADP) following a loading dose of 60 mg prasugrel versus 600 mg clopidogrel was 30% and 4% respectively after 30 minutes, 74% and 31% after 6 hours, and 69% and 32% after 24 hours. After discontinuation of prasugrel, platelet aggregation returns to pretreatment levels in 5-9 days. This delayed in activity is a result of the time to produce new platelets as prasugrel binding is irreversible.
Affected cytochrome P450 isoenzymes:
Prasugrel is a substrate for CYP3A4, CYP2B6, CYP2C9, and CYP2C19 as well as a weak inhibitor of CYP2B6. Based on studies in healthy subjects, prasugrel is not expected to affect the pharmacokinetics of medications with CYP2B6 mediated metabolism. In addition, inhibitors of CYP3A4 and inducers of CYP3A4, CYP2B6, CYP2C9, CYP2C19, and CYP2C8 have not significantly affected the pharmacokinetics of the active metabolite of prasugrel. Prasugrel is not an inhibitor of PGP; it is not yet known if prasugrel is a PGP substrate. Prasugrel may be administered with medications that are inducers or inhibitors of the cytochrome P450 enzymes.
-Route-Specific Pharmacokinetics
Oral Route
Prasugrel is extensively (>= 79%) and rapidly absorbed with peak plasma concentrations occurring within 30 minutes. Prasugrel may be administered without regard to food as exposure (AUC) is not affected by meals; however, peak plasma concentrations may be decreased and time to peak plasma concentrations may be increased following a high fat, high caloric meal. After oral absorption, hydrolysis by intestinal carboxylesterases and subsequent oxidation by hepatic cytochrome P450 enzymes, primarily CYP3A4 and CYP2B6 and to a lesser extent CYP2C9 and CYP2C19, convert prasugrel into the active metabolite. The active metabolite is 98% bound to human albumin and has an estimated volume of distribution ranging from 44-68 L. The active metabolite has an elimination half live of approximately 7 hours (range 2-15 hours) with clearance occurring via a secondary metabolism to two inactive compounds. These inactive compounds are then excreted in the urine (68%) and feces (27%).
-Special Populations
Geriatric
The use of prasugrel has been studied in the elderly population. In the TRITON-TIMI 38 trial, patients >= 75 years of age were found to have no net benefit and to be at an increased risk of fatal bleeding (1%) and symptomatic intracranial bleeding (0.8%) when compared with clopidogrel treated patients (0.1% and 0.3% respectively). In this trial, patients >= 75 years of age had a mean exposure to the active metabolite that was 19% higher than in patients < 75 years. In a study in subjects with stable atherosclerosis, the mean exposure to the prasugrel active metabolite was approximately half in subjects >= 75 years old taking a 5 mg maintenance dose compared with subjects 45-64 years old taking a 10 mg maintenance dose. The manufacturer recommends avoiding prasugrel in patients >= 75 years of age, except for high risk patients such as diabetics or patients with a history of myocardial infarction where benefit is apparently increased.
Ethnic Differences
In clinical trials with prasugrel, exposure to the active metabolite is 19% higher in the Asian population (Chinese, Japanese, and Korean) than in the White, African, or Hispanic populations. The manufacturer has not recommended dose adjustments based on ethnicity.
Other
Low Body Weight
Patients with low body weight (< 60 kg) were at an increased risk of bleeding with no net clinical benefit. According to the manufacturer of prasugrel, patients weighing < 60 kg have an increased exposure to the active metabolite (30-40% higher) compared with patients weighing >= 60 kg. The manufacturer recommends lowering the maintenance dose to 5 mg daily. Although the safety and efficacy of the 5 mg dose have not been prospectively studied, a study in subjects with stable atherosclerosis found the AUC of the active metabolite to be approximately 38% lower in subjects < 60 kg taking 5 mg than in subjects >= 60 kg taking 10 mg.