PRASUGREL Drug Interactions: What You Need to Know

INTERACTIONS Opioids: Decreased exposure to prasugrel. Consider use of parenteral antiplatelet agent ( 7.3 ).

7.1 Warfarin Coadministration of prasugrel tablets and warfarin increases the risk of bleeding <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ]</span> .

7.2 Nonsteroidal Anti-Inflammatory Drugs Coadministration of prasugrel tablets and NSAIDs (used chronically) may increase the risk of bleeding <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> .

7.3 Opioids As with other oral P2Y 12 inhibitors, coadministration of opioid agonists delay and reduce the absorption of prasugrel’s active metabolite presumably because of slowed gastric emptying <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . Consider the use of a parenteral anti-platelet agent in acute coronary syndrome patients requiring coadministration of morphine or other opioid agonists.

7.4 Other Concomitant Medications Prasugrel tablets can be administered with drugs that are inducers or inhibitors of cytochrome P450 enzymes <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . Prasugrel tablets can be administered with aspirin (75 mg to 325 mg per day), heparin, GPIIb/IIIa inhibitors, statins, digoxin, and drugs that elevate gastric pH, including proton pump inhibitors and H 2 blockers <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

Drug Interaction Studies

Potential for Other Drugs to Affect Prasugrel Inhibitors of CYP3A Ketoconazole (400 mg daily), a selective and potent inhibitor of CYP3A4 and CYP3A5, did not affect prasugrel-mediated inhibition of platelet aggregation or the active metabolite’s AUC and T max , but decreased the C max by 34% to 46%. Therefore, CYP3A inhibitors such as verapamil, diltiazem, indinavir, ciprofloxacin, clarithromycin, and grapefruit juice are not expected to have a significant effect on the pharmacokinetics of the active metabolite of prasugrel [see Drug Interactions (7.4) ] . Inducers of Cytochromes P450 Rifampicin (600 mg daily), a potent inducer of CYP3A and CYP2B6 and an inducer of CYP2C9, CYP2C19, and CYP2C8, did not significantly change the pharmacokinetics of prasugrel’s active metabolite or its inhibition of platelet aggregation. Therefore, known CYP3A inducers such as rifampicin, carbamazepine, and other inducers of cytochromes P450 are not expected to have significant effect on the pharmacokinetics of the active metabolite of prasugrel [see Drug Interactions (7.4) ] . Drugs that Elevate Gastric pH Daily coadministration of ranitidine (an H 2 blocker) or lansoprazole (a proton pump inhibitor) decreased the C max of the prasugrel active metabolite by 14% and 29%, respectively, but did not change the active metabolite’s AUC and T max . In TRITON-TIMI 38, prasugrel tablets were administered without regard to coadministration of a proton pump inhibitor or H 2 blocker [see Drug Interactions (7.4) ] .

Statins

Atorvastatin (80 mg daily), a drug metabolized by CYP450 3A4, did not alter the pharmacokinetics of prasugrel’s active metabolite or its inhibition of platelet aggregation [see Drug Interactions (7.4) ] . Heparin A single intravenous dose of unfractionated heparin (100 units/kg) did not significantly alter coagulation or the prasugrel-mediated inhibition of platelet aggregation; however, bleeding time was increased compared with either drug alone [see Drug Interactions (7.4) ] .

Aspirin Aspirin

150 mg daily did not alter prasugrel-mediated inhibition of platelet aggregation; however, bleeding time was increased compared with either drug alone [see Drug Interactions (7.4) ] . Warfarin A significant prolongation of the bleeding time was observed when prasugrel was coadministered with 15 mg of warfarin [see Drug Interactions (7.1) ] . Potential for Prasugrel to Affect Other Drugs In vitro metabolism studies demonstrate that prasugrel’s main circulating metabolites are not likely to cause clinically significant inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A, or induction of CYP1A2 or CYP3A.

Drugs

Metabolized by CYP2B6 Prasugrel is a weak inhibitor of CYP2B6. In healthy subjects, prasugrel decreased exposure to hydroxybupropion, a CYP2B6-mediated metabolite of bupropion, by 23%, an amount not considered clinically significant. Prasugrel is not anticipated to have significant effect on the pharmacokinetics of drugs that are primarily metabolized by CYP2B6, such as halothane, cyclophosphamide, propofol, and nevirapine. Effect on Digoxin The potential role of prasugrel as a Pgp substrate was not evaluated. Prasugrel is not an inhibitor of Pgp, as digoxin clearance was not affected by prasugrel coadministration [see Drug Interactions (7.4) ] .

Morphine

Coadministration of 5 mg intravenous morphine with 60 mg loading dose of prasugrel in healthy adults decreased the C max of prasugrel’s active metabolite by 31% with no change in AUC, T max , or inhibition of ADP-induced platelet aggregation. ADP-induced platelet aggregation was higher up to 2 hours following 60 mg loading dose of prasugrel in stable patients more than 1 year after an ACS who were coadministered morphine. In the patients with a 2-hour delay in the onset of platelet aggregation (5 of 11), T max was delayed and prasugrel active metabolite levels were significantly lower at 30 min (5 vs 120 ng/mL) following coadministration with morphine.

Active pathological bleeding ( 4.1 ) Active pathological bleeding ( 4.1 ) Prior transient ischemic attack or stroke ( 4.2 ) Hypersensitivity to prasugrel or any component of the product ( 4.3 )

4.1 Active Bleeding Prasugrel tablet is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 ) and Adverse Reactions ( 6.1 )]</span> .

4.2 Prior Transient Ischemic Attack or Stroke Prasugrel tablet is contraindicated in patients with a history of prior transient ischemic attack (TIA) or stroke. In TRITON-TIMI 38 ( TR ial to Assess I mprovement in T herapeutic Outcomes by O ptimizing Platelet Inhibitio N with prasugrel), patients with a history of TIA or ischemic stroke (&gt;3 months prior to enrollment) had a higher rate of stroke on prasugrel tablets (6.5%; of which 4.2% were thrombotic stroke and 2.3% were intracranial hemorrhage [ICH]) than on clopidogrel (1.2%; all thrombotic). In patients without such a history, the incidence of stroke was 0.9% (0.2% ICH) and 1.0% (0.3% ICH) with Prasugrel tablets and clopidogrel, respectively. Patients with a history of ischemic stroke within 3 months of screening and patients with a history of hemorrhagic stroke at any time were excluded from TRITON-TIMI 38. Patients who experience a stroke or TIA while on Prasugrel tablets generally should have therapy discontinued <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 ) and Clinical Studies ( 14 )]</span>.

4.3 Hypersensitivity Prasugrel tablet is contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to prasugrel or any component of the product <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> .

AND PRECAUTIONS CABG-related bleeding: Risk increases in patients receiving prasugrel who undergo CABG (5.2) . Discontinuation of prasugrel: Premature discontinuation increases risk of stent thrombosis, MI, and death (5.3) . Thrombotic thrombocytopenic purpura (TTP): TTP has been reported with prasugrel (5.4) . Hypersensitivity: Hypersensitivity including angioedema has been reported with prasugrel including in patients with a history of hypersensitivity reaction to other thienopyridines (5.5) .

5.1 General Risk of Bleeding Thienopyridines, including prasugrel, increase the risk of bleeding. With the dosing regimens used in TRITON-TIMI 38, TIMI (Thrombolysis in Myocardial Infarction) Major (clinically overt bleeding associated with a fall in hemoglobin ≥ 5 g/dL, or intracranial hemorrhage) and TIMI Minor (overt bleeding associated with a fall in hemoglobin of ≥ 3 g/dL but &lt; 5 g/dL), bleeding events were more common on prasugrel than on clopidogrel <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . The bleeding risk is highest initially, as shown in Figure 1 (events through 450 days; inset shows events through 7 days).

Figure

1: Non-CABG-Related TIMI Major or Minor Bleeding Events Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, PCI, CABG, or other surgical procedures even if the patient does not have overt signs of bleeding. Do not use prasugrel in patients with active bleeding, prior TIA or stroke [see Contraindications (4.1, 4.2) ] . Other risk factors for bleeding are: Age ≥ 75 years. Because of the risk of bleeding (including fatal bleeding) and uncertain effectiveness in patients ≥ 75 years of age, use of prasugrel is generally not recommended in these patients, except in high-risk situations (patients with diabetes or history of myocardial infarction) where its effect appears to be greater and its use may be considered [see Adverse Reactions (6.1) , Use in Specific Populations (8.5) , Clinical Pharmacology (12.3) and Clinical Studies (14) ] . CABG or other surgical procedure [see Warnings and Precautions (5.2) ] . Body weight < 60 kg. Consider a lower (5 mg) maintenance dose [see Dosage and Administration (2) , Adverse Reactions (6.1) and Use in Specific Populations (8.6) ] . Propensity to bleed (e.g., recent trauma, recent surgery, recent or recurrent gastrointestinal (GI) bleeding, active peptic ulcer disease, severe hepatic impairment, or moderate to severe renal impairment) [see Adverse Reactions (6.1) and Use in Specific Populations (8.7, 8.8) ] . Medications that increase the risk of bleeding (e.g., oral anticoagulants, chronic use of nonsteroidal anti-inflammatory drugs [NSAIDs], and fibrinolytic agents). Aspirin and heparin were commonly used in TRITON-TIMI 38 [see Drug Interactions (7.1, 7.2, 7.4) and Clinical Studies (14) ] . Thienopyridines inhibit platelet aggregation for the lifetime of the platelet (7 to 10 days), so withholding a dose will not be useful in managing a bleeding event or the risk of bleeding associated with an invasive procedure. Because the half-life of prasugrel’s active metabolite is short relative to the lifetime of the platelet, it may be possible to restore hemostasis by administering exogenous platelets; however, platelet transfusions within 6 hours of the loading dose or 4 hours of the maintenance dose may be less effective.

Figure

1

5.2 Coronary Artery Bypass Graft Surgery-Related Bleeding The risk of bleeding is increased in patients receiving prasugrel who undergo CABG. If possible, prasugrel should be discontinued at least 7 days prior to CABG. Of the 437 patients who underwent CABG during TRITON-TIMI 38, the rates of CABG-related TIMI Major or Minor bleeding were 14.1% in the prasugrel group and 4.5% in the clopidogrel group <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . The higher risk for bleeding events in patients treated with prasugrel persisted up to 7 days from the most recent dose of study drug. For patients receiving a thienopyridine within 3 days prior to CABG, the frequencies of TIMI Major or Minor bleeding were 26.7% (12 of 45 patients) in the prasugrel group, compared with 5.0% (3 of 60 patients) in the clopidogrel group. For patients who received their last dose of thienopyridine within 4 to 7 days prior to CABG, the frequencies decreased to 11.3% (9 of 80 patients) in the prasugrel group and 3.4% (3 of 89 patients) in the clopidogrel group. Do not start prasugrel in patients likely to undergo urgent CABG. CABG-related bleeding may be treated with transfusion of blood products, including packed red blood cells and platelets; however, platelet transfusions within 6 hours of the loading dose or 4 hours of the maintenance dose may be less effective.

5.3 Discontinuation of Prasugrel Discontinue thienopyridines, including prasugrel, for active bleeding, elective surgery, stroke, or TIA. The optimal duration of thienopyridine therapy is unknown. In patients who are managed with PCI and stent placement, premature discontinuation of any antiplatelet medication, including thienopyridines, conveys an increased risk of stent thrombosis, myocardial infarction, and death. Patients who require premature discontinuation of a thienopyridine will be at increased risk for cardiac events. Lapses in therapy should be avoided, and if thienopyridines must be temporarily discontinued because of an adverse event(s), they should be restarted as soon as possible <span class="opacity-50 text-xs">[see Contraindications (4.1, 4.2) and Warnings and Precautions (5.1) ]</span> .

5.4 Thrombotic Thrombocytopenic Purpura (TTP) TTP has been reported with the use of prasugrel. TTP can occur after a brief exposure (&lt; 2 weeks). TTP is a serious condition that can be fatal and requires urgent treatment, including plasmapheresis (plasma exchange). TTP is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes [fragment red blood cells] seen on peripheral smear), neurological findings, renal dysfunction, and fever <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> .

5.5 Hypersensitivity Including Angioedema Hypersensitivity including angioedema has been reported in patients receiving prasugrel, including patients with a history of hypersensitivity reaction to other thienopyridines <span class="opacity-50 text-xs">[see Contraindications (4.3) and Adverse Reactions (6.2) ]</span> .

5.1 General Risk of Bleeding Thienopyridines, including prasugrel, increase the risk of bleeding. With the dosing regimens used in TRITON-TIMI 38, TIMI (Thrombolysis in Myocardial Infarction) Major (clinically overt bleeding associated with a fall in hemoglobin ≥ 5 g/dL, or intracranial hemorrhage) and TIMI Minor (overt bleeding associated with a fall in hemoglobin of ≥ 3 g/dL but &lt; 5 g/dL), bleeding events were more common on prasugrel than on clopidogrel <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . The bleeding risk is highest initially, as shown in Figure 1 (events through 450 days; inset shows events through 7 days).

Figure

1: Non-CABG-Related TIMI Major or Minor Bleeding Events Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, PCI, CABG, or other surgical procedures even if the patient does not have overt signs of bleeding. Do not use prasugrel in patients with active bleeding, prior TIA or stroke [see Contraindications (4.1, 4.2) ] . Other risk factors for bleeding are: Age ≥ 75 years. Because of the risk of bleeding (including fatal bleeding) and uncertain effectiveness in patients ≥ 75 years of age, use of prasugrel is generally not recommended in these patients, except in high-risk situations (patients with diabetes or history of myocardial infarction) where its effect appears to be greater and its use may be considered [see Adverse Reactions (6.1) , Use in Specific Populations (8.5) , Clinical Pharmacology (12.3) and Clinical Studies (14) ] . CABG or other surgical procedure [see Warnings and Precautions (5.2) ] . Body weight < 60 kg. Consider a lower (5 mg) maintenance dose [see Dosage and Administration (2) , Adverse Reactions (6.1) and Use in Specific Populations (8.6) ] . Propensity to bleed (e.g., recent trauma, recent surgery, recent or recurrent gastrointestinal (GI) bleeding, active peptic ulcer disease, severe hepatic impairment, or moderate to severe renal impairment) [see Adverse Reactions (6.1) and Use in Specific Populations (8.7, 8.8) ] . Medications that increase the risk of bleeding (e.g., oral anticoagulants, chronic use of nonsteroidal anti-inflammatory drugs [NSAIDs], and fibrinolytic agents). Aspirin and heparin were commonly used in TRITON-TIMI 38 [see Drug Interactions (7.1, 7.2, 7.4) and Clinical Studies (14) ] . Thienopyridines inhibit platelet aggregation for the lifetime of the platelet (7 to 10 days), so withholding a dose will not be useful in managing a bleeding event or the risk of bleeding associated with an invasive procedure. Because the half-life of prasugrel’s active metabolite is short relative to the lifetime of the platelet, it may be possible to restore hemostasis by administering exogenous platelets; however, platelet transfusions within 6 hours of the loading dose or 4 hours of the maintenance dose may be less effective.

Figure

1

5.4 Thrombotic Thrombocytopenic Purpura (TTP) TTP has been reported with the use of prasugrel. TTP can occur after a brief exposure (&lt; 2 weeks). TTP is a serious condition that can be fatal and requires urgent treatment, including plasmapheresis (plasma exchange). TTP is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes [fragment red blood cells] seen on peripheral smear), neurological findings, renal dysfunction, and fever <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> .