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    ADP (adenosine Diphosphate) Receptor Antagonist Platelet Aggregation Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Thienopyridine platelet aggregation inhibitor
    Used to reduce thrombotic cardiovascular events (including stent thrombosis) in patients with acute coronary syndromes (ACS) being managed with percutaneous coronary intervention (PCI)
    Reduced cardiovascular death, predominantly due to a reduction in the incidence of myocardial infarction

    COMMON BRAND NAMES

    Effient

    HOW SUPPLIED

    Effient/Prasugrel Oral Tab: 5mg, 10mg

    DOSAGE & INDICATIONS

    For arterial thromboembolism prophylaxis (thrombotic cardiovascular events including stent thrombosis) in patients with acute coronary syndrome (i.e., unstable angina, non-ST-elevation myocardial infarction [NSTEMI], or ST-elevation acute myocardial infarction [STEMI]) who are to be managed with percutaneous coronary intervention (PCI).
    Oral dosage
    Adults and Geriatric Adults less than 75 years of age and weighing 60 kg or more

    60 mg PO as a loading dose, then 10 mg PO once daily is recommended; the optimal duration of therapy is not known. Patients should also take aspirin 75 to 325 mg/day PO. 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; however, study data indicate no clear benefit when prasugrel was administered prior to diagnostic coronary angiography compared to at the time of PCI, and bleeding risk was increased with early administration in patients undergoing PCI or early CABG. Prasugrel has been shown to reduce the rate of a combined endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke compared to clopidogrel, with the difference being predominantly due to a reduction in MI, with no difference in stroke and little difference in CV death (composite endpoint, 12.1% [clopidogrel] vs. 9.9% [prasugrel], HR 0.81; CI 0.73 to 0.90, p < 0.001).

    Adults and Geriatric Adults less than 75 years of age and weighing less than 60 kg

    60 mg PO as a loading dose, then consider a lower maintenance dose of 5 mg PO once daily. The optimal duration of therapy is not known. Patients should also take aspirin 75 mg/day to 325 mg/day PO. Compared to patients 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 PO once daily. The safety and efficacy of the 5 mg dose have not been prospectively studied. However, in patients with stable coronary artery disease, mean platelet inhibition was similar in subjects weighing less than 60 kg taking 5 mg prasugrel to that of subjects 60 kg or more taking 10 mg prasugrel. The relationship between inhibition of platelet aggregation and clinical activity has not been established.

    Geriatric 75 years or older

    Use in this population is generally not recommended, except in high-risk patients with a past history of myocardial infarction or diabetes. In the TRITON-TIMI 38 trial, geriatric patients 75 years or older had an increased exposure to the active metabolite (19% higher) and an increased incidence of bleeding with no net benefit. The exceptions were patents with diabetes or a history of myocardial infarction where significant benefit was reported. In such patients, if weight is 60 kg or more: 60 mg PO as a loading dose, then 10 mg PO once daily. If weight is less than 60 kg: 60 mg PO as a loading dose, then consider a lower maintenance dose of 5 mg PO once daily. The optimal duration of therapy is not known. All patients should also take aspirin 75 mg/day to 325 mg/day PO.

    MAXIMUM DOSAGE

    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.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    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.

    Renal Impairment

    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.

    ADMINISTRATION

    Oral Administration

    May be administered with or without food.
    Do not prematurely discontinue therapy.

    Oral Solid Formulations

    Tablets are not scored. 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.

    STORAGE

    Effient:
    - Store and dispense in original container
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Anticoagulant therapy, bleeding, body weight less than 60 kg, coronary artery bypass graft surgery (CABG), GI bleeding, intracranial bleeding, peptic ulcer disease, surgery, trauma

    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.

    Stroke

    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.

    Hepatic disease

    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)

    Thrombotic thrombocytopenic purpura (TTP) has been reported with the use of prasugrel and can occur even after brief exposure (< 2 weeks). TTP is a serious, sometimes fatal, condition that requires urgent treatment (i.e., plasmapheresis). TTP is characterized by thrombocytopenia, microangiopathic hemolytic anemia, neurological findings, renal dysfunction, and fever.

    Abrupt discontinuation

    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.

    Asian patients

    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 Caucasian, 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.

    Children

    Safe and effective use of prasugrel have not been established in children.

    Pregnancy

    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.

    Breast-feeding

    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.

    Renal impairment

    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.

    Thienopyridine hypersensitivity

    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

    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). In addition, 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 and should be used cautiously in adults 75 years of age and older due to an increased risk of bleeding, although the benefit in highest-risk older adults (e.g., those with prior myocardial infarction or diabetes) may offset the risk. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities. According to the OBRA guidelines, platelet inhibitors may cause thrombocytopenia and increase the risk of bleeding. Common side effects of platelet inhibitors include headache, dizziness, and vomiting. Concurrent use with warfarin or NSAIDs may increase the risk of bleeding.

    ADVERSE REACTIONS

    Severe

    bradycardia / Rapid / 2.9-2.9
    atrial fibrillation / Early / 2.9-2.9
    GI bleeding / Delayed / 1.5-1.5
    intracranial bleeding / Delayed / 1.4-1.4
    retroperitoneal bleeding / Delayed / 0.3-0.3
    angioedema / Rapid / 0.1-0.1
    anaphylactoid reactions / Rapid / Incidence not known

    Moderate

    hypertension / Early / 7.5-7.5
    hyperlipidemia / Delayed / 7.0-7.0
    hypercholesterolemia / Delayed / 7.0-7.0
    dyspnea / Early / 4.9-4.9
    hypotension / Rapid / 3.9-3.9
    chest pain (unspecified) / Early / 3.1-3.1
    leukopenia / Delayed / 2.8-2.8
    peripheral edema / Delayed / 2.7-2.7
    bleeding / Early / 2.4-2.4
    anemia / Delayed / 2.2-2.2
    secondary malignancy / Delayed / 1.6-1.6
    hemoptysis / Delayed / 0.6-0.6
    hematoma / Early / 0.5-0.5
    thrombocytopenia / Delayed / 0.3-0.3
    neutropenia / Delayed / 0-0.1

    Mild

    epistaxis / Delayed / 6.2-6.2
    headache / Early / 5.5-5.5
    back pain / Delayed / 5.0-5.0
    nausea / Early / 4.6-4.6
    dizziness / Early / 4.1-4.1
    cough / Delayed / 3.9-3.9
    fatigue / Early / 3.7-3.7
    rash (unspecified) / Early / 2.8-2.8
    fever / Early / 2.7-2.7
    diarrhea / Early / 2.3-2.3

    DRUG INTERACTIONS

    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.
    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.
    Ado-Trastuzumab emtansine: (Major) Use caution if coadministration of platelet inhibitors such as prasugrel with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anti-platelet therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Altretamine: (Moderate) An additive risk of bleeding may occur when platelet inhibitors is used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as altretamine.
    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.
    Anthracyclines: (Moderate) Avoid coadministration if possible. An additive risk of bleeding may occur when platelet inhibitors is used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as anthracyclines. In addition, ticagrelor is a mild CYP3A4 and P-glycoprotein (P-gp) inhibitor; doxorubicin is a major substrate of both CYP3A4 and P-gp. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4 and/or P-gp, resulting in increased concentration and clinical effect of doxorubicin. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Antimetabolites: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antimetabolites.
    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; Butalbital; 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.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (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: (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.
    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.
    Aspirin, ASA; Pravastatin: (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.
    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.
    Bevacizumab: (Moderate) Due to the thrombocytopenic effects of antineoplastics an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    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.
    Cabazitaxel: (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 docetaxel and paclitaxel.
    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.
    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.
    Chondroitin; Glucosamine: (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.
    Cilostazol: (Moderate) Because cilostazol is a platelet aggregation inhibitor, a potential additive risk for bleeding exists if cilostazol is given with other agent that affect hemostasis such as ADP receptor antagonists including clopidogrel, prasugrel, ticagrelor, or ticlopidine. Ticlopidine, in addition to its pharmacodynamic effects, is an inhibitor of the hepatic isoenzyme cytochrome P450 2C19 and thus could decrease the metabolism of cilostazol; a reduction in cilostazol dosage should be considered if the two agents are administered concurrently. Multiple doses of clopidogrel do not significantly increase the steady state plasma concentrations of cilostazol.
    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.
    Cod Liver Oil: (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. (Moderate) Cod liver oil contains vitamin A and may increase the risk of bleeding if coadministered with platelet inhibitors.
    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.
    Danaparoid: (Moderate) Concomitant use of prasugrel and other agents that may affect hemostasis, such as anticoagulants, may be associated with an increased risk of bleeding.
    Danazol: (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with platelet inhibitors.
    Dasatinib: (Moderate) Due to the thrombocytopenic and possible platelet inhibiting effects of dasatinib, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Defibrotide: (Severe) 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.
    Denileukin Diftitox: (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 denileukin difitox.
    Desirudin: (Moderate) Concomitant use of prasugrel and other agents that may affect hemostasis, such as anticoagulants, may be associated with an increased risk of bleeding.
    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.
    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.
    Docetaxel: (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 docetaxel and paclitaxel.
    Drotrecogin Alfa: (Major) Treatment with drotrecogin alfa should be carefully considered in patients who are receiving or have received any platelet inhibitors within 7 days. These patients are at increased risk of bleeding during drotrecogin alfa therapy.
    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.
    Enoxaparin: (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.
    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.
    Estramustine: (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 estramustine.
    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.
    Folate analogs: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    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) Garlic produces clinically significant antiplatelet effects so additive 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: (Major) Use Ginkgo biloba with caution in patients taking platelet inhibitors, as it can produce clinically-significant antiplatelet effects. A compound found in Ginkgo biloba, ginkgolide-B, may act as a selective antagonist of platelet activating factor (PAF). Although a review of Ginkgo biloba in 1992 stated that no known drug interactions exist, spontaneous hyphema has been reported in an elderly male who began taking Ginkgo while stabilized on daily aspirin. After ginkgo was stopped, no further bleeding was noted despite continuing the aspirin therapy. Other clinical data exist that describe spontaneous subdural hematomas associated with chronic Ginkgo biloba ingestion.
    Guarana: (Moderate) Guarana has been shown to possess minor antiplatelet activity and, therefore, concurrent use of guarana and anticoagulants or platelet inhibitors should be avoided.
    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.
    Ibritumomab Tiuxetan: (Moderate) Due to the thrombocytopenic effects of antineoplastics an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Ibrutinib: (Minor) Use caution with concomitant use of ibrutinib and antiplatelet agents such as prasugrel. Bleeding or bruising events occurred in 48% to 63% (grade 3 or 4, 5% to 6%) of patients treated with ibrutinib in clinical trials. The mechanism for bleeding is not well understood, and the risk of hemorrhage may be increased in patients receiving antiplatelet therapy. Closely monitor patients for signs and symptoms 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.
    Ifosfamide: (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 ifosfamide.
    Iloprost: (Moderate) When used concurrently with platelet inhibitors, inhaled iloprost may increase the risk of bleeding.
    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.
    Lepirudin: (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 lepirudin.
    Levomilnacipran: (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 closely monitored for signs and symptoms of bleeding when a platelet inhibitor is administered with an SNRI.
    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.
    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.
    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) 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.
    Mycophenolate: (Moderate) Platelet Inhibitors inhibit platelet aggregation and should be used cautiously in patients with thrombocytopenia, as mycophenolate can also cause thrombocytopenia.
    Nanoparticle Albumin-Bound Paclitaxel: (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 docetaxel and paclitaxel.
    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) NSAIDs can cause GI bleeding, inhibit platelet aggregation, and prolong bleeding time. If NSAIDs are administered with platelet inhibitors, these pharmacodynamic effects may be increased. The manufacturer of clopidogrel advises that caution be used when used in combination with NSAIDs as an increase in occult GI blood loss occurred when clopidogrel was used concomitantly with naproxen
    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.
    Paclitaxel: (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 docetaxel and paclitaxel.
    Pegaspargase: (Moderate) Due to the risk of bleeding and coagulopathy during pegaspargase therapy, patients should receive other agents that may increase the risk of bleeding (e.g., anticoagulants, NSAIDs, platelet inhibitors, or thrombolytic agents) with caution.
    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.
    Phentermine; Topiramate: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates or platelet inhibitors may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Photosensitizing agents: (Minor) Agents, such as platelet inhibitors, that decrease clotting could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    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.
    Porfimer: (Minor) Agents, such as platelet inhibitors, that decrease clotting could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    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.
    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.
    Sodium Hyaluronate, Hyaluronic Acid: (Moderate) Increased bruising or bleeding at the injection site may occur when using hyaluronate sodium with platelet inhibitors especially if used within the 3 weeks prior to the procedure.
    Sorafenib: (Moderate) Due to the thrombocytopenic effects of sorafenib, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Sulfinpyrazone: (Major) Sulfinpyrazone, when used as a uricosuric agent should be avoided when possible with concurrent platelet inhibitors due to potential for additive antiplatelet effects and increased bleeding risk.
    Taxanes: (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 docetaxel and paclitaxel.
    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.
    Tinzaparin: (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.
    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.
    Topiramate: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates or platelet inhibitors may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Trastuzumab: (Moderate) Due to the thrombocytopenic effects of trastuzumab an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    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) When used concurrently with anticoagulants or platelet inhibitors, treprostinil may increase the risk of bleeding.
    Tretinoin, ATRA: (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 tretinoin.
    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: (Minor) Agents, such as platelet inhibitors, that decrease clotting could decrease the efficacy of photosensitizing agents used in photodynamic 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: (Major) Due to the thrombocytopenic effects of vorinostat, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors. Also, torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with anagrelide include vorinostat.
    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.

    PREGNANCY AND LACTATION

    Pregnancy

    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.

    MECHANISM OF ACTION

    Mechanism of Action: 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.

    PHARMACOKINETICS

    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.

    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%).