PRASUGREL

Prasugrel tablets, USP contain prasugrel, a thienopyridine class inhibitor of platelet activation and aggregation mediated by the P2Y 12 ADP receptor. Prasugrel tablets are formulated as the hydrochloride salt, a racemate, which is chemically designated as 5-[(1RS)-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate hydrochloride. Prasugrel hydrochloride has the molecular formula C 20 H 20 FNO 3 S•HCl representing a molecular weight of 409.90. The chemical structure of prasugrel hydrochloride is: Prasugrel hydrochloride, USP is a white to light brown crystalline solid. It is soluble at pH 2, slightly soluble at pH 3 to 4, and practically insoluble at pH 6 to 7.5. It also dissolves freely in methanol and is slightly soluble in 1- and 2-propanol and acetone. It is practically insoluble in diethyl ether and ethyl acetate. Prasugrel tablets are available for oral administration as 5 mg or 10 mg capsule shaped, film-coated, unscored tablets, debossed on each side. Each yellow 5 mg tablet is manufactured with 5.49 mg prasugrel hydrochloride, equivalent to 5 mg prasugrel and each brown 10 mg tablet with 10.98 mg prasugrel hydrochloride, equivalent to 10 mg of prasugrel. Other ingredients include crospovidone, glyceryl dibehenate, hypromellose, lactose monohydrate, mannitol, pregelatinized starch (corn), sucrose stearic acid esters, titanium dioxide, triacetin and yellow iron oxide. The 5 mg tablets also contain FD&C Yellow No. 6 Aluminum Lake. The 10 mg tablets also contain black iron oxide and red iron oxide. Meets USP Dissolution Test 2. Prasugrel Hydrochloride Structural Formula

Prasugrel tablets are a P2Y 12 platelet inhibitor indicated for the reduction of thrombotic cardiovascular events (including stent thrombosis) in patients with acute coronary syndrome who are to be managed with percutaneous coronary intervention (PCI) as follows: Patients with unstable angina or non-ST-elevation myocardial infarction (NSTEMI) ( 1.1 ). Patients with ST-elevation myocardial infarction (STEMI) when managed with either primary or delayed PCI ( 1.1 ). 1.1 Acute Coronary Syndrome Prasugrel tablets are indicated to reduce the rate of thrombotic CV events (including stent thrombosis) in patients with acute coronary syndrome (ACS) who are to be managed with percutaneous coronary intervention (PCI) as follows: Patients with unstable angina (UA) or non-ST-elevation myocardial infarction (NSTEMI). Patients with ST-elevation myocardial infarction (STEMI) when managed with primary or delayed PCI. Prasugrel tablets have been shown to reduce the rate of a combined endpoint of cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke compared to clopidogrel. The difference between treatments was driven predominantly by MI, with no difference on strokes and little difference on CV death [see Clinical Studies (14) ] .

Initiate prasugrel tablets treatment as a single 60 mg oral loading dose and then continue at 10 mg orally once daily. Patients taking prasugrel tablets should also take aspirin (75 mg to 325 mg) daily [see Drug Interactions (7.4) and Clinical Pharmacology (12.3) ] . Prasugrel tablets may be administered with or without food [see Clinical Pharmacology (12.3) and Clinical Studies (14) ] . Timing of Loading Dose: In the clinical trial that established the efficacy and safety of prasugrel tablets, the loading dose of prasugrel tablets was not administered until coronary anatomy was established in UA/NSTEMI patients and in STEMI patients presenting more than 12 hours after symptom onset. In STEMI patients presenting within 12 hours of symptom onset, the loading dose of prasugrel tablets was administered at the time of diagnosis, although most received prasugrel tablets at the time of PCI [see Clinical Studies (14) ] . For the small fraction of patients that required urgent CABG after treatment with prasugrel tablets, the risk of significant bleeding was substantial. Although it is generally recommended that antiplatelet therapy be administered promptly in the management of ACS because many cardiovascular events occur within hours of initial presentation, in a trial of 4033 NSTEMI patients, no clear benefit was observed when prasugrel tablets loading dose was administered prior to diagnostic coronary angiography compared to at the time of PCI; however, risk of bleeding was increased with early administration in patients undergoing PCI or early CABG. Dosing in Low Weight Patients: Compared to patients weighing ≥ 60 kg, patients weighing < 60 kg have an increased exposure to the active metabolite of prasugrel and an increased risk of bleeding on a 10 mg once daily maintenance dose. Consider lowering the maintenance dose to 5 mg in patients < 60 kg. The effectiveness and safety of the 5 mg dose have not been prospectively studied [see Warnings and Precautions (5.1) , Adverse Reactions (6.1) , and Clinical Pharmacology (12.3) ] . Initiate treatment with a single 60 mg oral loading dose ( 2 ). Continue at 10 mg once daily with or without food. Consider 5 mg once daily for patients < 60 kg ( 2 ). Patients should also take aspirin (75 mg to 325 mg) daily ( 2 ).

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 tablets are contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage (ICH) [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ] . 4.2 Prior Transient Ischemic Attack or Stroke Prasugrel tablets are 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 (> 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 [see Adverse Reactions (6.1) and Clinical Studies (14) ] . 4.3 Hypersensitivity Prasugrel tablets are contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to prasugrel or any component of the product [see Adverse Reactions (6.2) ] .

The following serious adverse reactions are also discussed elsewhere in the labeling: Bleeding [see Boxed Warning and Warnings and Precautions (5.1 , 5.2) ] Thrombotic Thrombocytopenic Purpura [see Warnings and Precautions (5.4) ] Hypersensitivity Including Angioedema [see Warnings and Precautions (5.5) ] Bleeding, including life-threatening and fatal bleeding, is the most commonly reported adverse reaction ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Safety in patients with ACS undergoing PCI was evaluated in a clopidogrel-controlled study, TRITON-TIMI 38, in which 6741 patients were treated with prasugrel tablets (60 mg loading dose and 10 mg once daily) for a median of 14.5 months (5802 patients were treated for over 6 months; 4136 patients were treated for more than 1 year). The population treated with prasugrel tablets was 27 to 96 years of age, 25% female, and 92% Caucasian. All patients in the TRITON-TIMI 38 study were to receive aspirin. The dose of clopidogrel in this study was a 300 mg loading dose and 75 mg once daily. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with the rates observed in other clinical trials of another drug and may not reflect the rates observed in practice. Drug Discontinuation The rate of study drug discontinuation because of adverse reactions was 7.2% for prasugrel tablets and 6.3% for clopidogrel. Bleeding was the most common adverse reaction leading to study drug discontinuation for both drugs (2.5% for prasugrel tablets and 1.4% for clopidogrel). Bleeding Bleeding Unrelated to CABG Surgery In TRITON-TIMI 38, overall rates of TIMI Major or Minor bleeding adverse reactions unrelated to coronary artery bypass graft surgery (CABG) were significantly higher on prasugrel tablets than on clopidogrel, as shown in Table 1. Table 1: Non-CABG-Related Bleeding Patients may be counted in more than one row. (TRITON-TIMI 38) Prasugrel Tablets (%) (N = 6741) Clopidogrel (%) (N = 6716) TIMI Major or Minor bleeding 4.5 3.4 TIMI Major bleeding See 5.1 for definition. 2.2 1.7 Life-threatening 1.3 0.8 Fatal 0.3 0.1 Symptomatic intracranial hemorrhage (ICH) 0.3 0.3 Requiring inotropes 0.3 0.1 Requiring surgical intervention 0.3 0.3 Requiring transfusion (≥ 4 units) 0.7 0.5 TIMI Minor bleeding 2.4 1.9 Figure 1 demonstrates non-CABG-related TIMI Major or Minor bleeding. The bleeding rate is highest initially, as shown in Figure 1 (inset: Days 0 to 7) [see Warnings and Precautions (5.1) ] . Bleeding by Weight and Age In TRITON-TIMI 38, non-CABG-related TIMI Major or Minor bleeding rates in patients with the risk factors of age ≥ 75 years and weight < 60 kg are shown in Table 2. Table 2: Bleeding Rates for Non-CABG-Related Bleeding by Weight and Age (TRITON-TIMI 38) Major/Minor Fatal Prasugrel Tablets 10 mg prasugrel tablets maintenance dose (%) Clopidogrel 75 mg clopidogrel maintenance dose (%) Prasugrel Tablets (%) Clopidogrel (%) Weight < 60 kg (N = 308 prasugrel tablets, N = 356 clopidogrel) 10.1 6.5 0.0 0.3 Weight ≥ 60 kg (N = 6373 prasugrel tablets, N = 6299 clopidogrel) 4.2 3.3 0.3 0.1 Age < 75 years (N = 5850 prasugrel tablets, N = 5822 clopidogrel) 3.8 2.9 0.2 0.1 Age ≥ 75 years (N = 891 prasugrel tablets, N = 894 clopidogrel) 9.0 6.9 1.0 0.1 Bleeding Related to CABG In TRITON-TIMI 38, 437 patients who received a thienopyridine underwent CABG during the course of the study. The rate of CABG-related TIMI Major or Minor bleeding was 14.1% for the prasugrel tablets group and 4.5% in the clopidogrel group (see Table 3). The higher risk for bleeding adverse reactions in patients treated with prasugrel tablets persisted up to 7 days from the most recent dose of study drug. Table 3: CABG-Related Bleeding Patients may be counted in more than one row. (TRITON-TIMI 38) Prasugrel Tablets (%) (N = 213) Clopidogrel (%) (N = 224) TIMI Major or Minor bleeding 14.1 4.5 TIMI Major bleeding 11.3 3.6 Fatal 0.9 0 Reoperation 3.8 0.5 Transfusion of ≥ 5 units 6.6 2.2 Intracranial hemorrhage 0 0 TIMI Minor bleeding 2.8 0.9 Bleeding Reported as Adverse Reactions Hemorrhagic events reported as adverse reactions in TRITON-TIMI 38 were, for prasugrel tablets and clopidogrel, respectively: epistaxis (6.2%, 3.3%), gastrointestinal hemorrhage (1.5%, 1.0%), hemoptysis (0.6%, 0.5%), subcutaneous hematoma (0.5%, 0.2%), post-procedural hemorrhage (0.5%, 0.2%), retroperitoneal hemorrhage (0.3%, 0.2%), pericardial effusion/hemorrhage/tamponade (0.3%, 0.2%), and retinal hemorrhage (0.0%, 0.1%). Malignancies During TRITON-TIMI 38, newly diagnosed malignancies were reported in 1.6% and 1.2% of patients treated with prasugrel and clopidogrel, respectively. The sites contributing to the differences were primarily colon and lung. In another Phase 3 clinical study of ACS patients not undergoing PCI, in which data for malignancies were prospectively collected, newly diagnosed malignancies were reported in 1.8% and 1.7% of patients treated with prasugrel and clopidogrel, respectively. The site of malignancies was balanced between treatment groups except for colorectal malignancies. The rates of colorectal malignancies were 0.3% prasugrel, 0.1% clopidogrel and most were detected during investigation of GI bleed or anemia. It is unclear if these observations are causally related, are the result of increased detection because of bleeding, or are random occurrences. Other Adverse Events In TRITON-TIMI 38, common and other important nonhemorrhagic adverse events were, for prasugrel tablets and clopidogrel, respectively: severe thrombocytopenia (0.06%, 0.04%), anemia (2.2%, 2.0%), abnormal hepatic function (0.22%, 0.27%), allergic reactions (0.36%, 0.36%), and angioedema (0.06%, 0.04%). Table 4 summarizes the adverse events reported by at least 2.5% of patients. Table 4: Non-Hemorrhagic Treatment Emergent Adverse Events Reported by at Least 2.5% of Patients in Either Group Prasugrel Tablets (%) (N = 6741) Clopidogrel (%) (N = 6716) Hypertension 7.5 7.1 Hypercholesterolemia/Hyperlipidemia 7.0 7.4 Headache 5.5 5.3 Back pain 5.0 4.5 Dyspnea 4.9 4.5 Nausea 4.6 4.3 Dizziness 4.1 4.6 Cough 3.9 4.1 Hypotension 3.9 3.8 Fatigue 3.7 4.8 Noncardiac chest pain 3.1 3.5 Atrial fibrillation 2.9 3.1 Bradycardia 2.9 2.4 Leukopenia (< 4 x 10 9 WBC WBC = white blood cell /L) 2.8 3.5 Rash 2.8 2.4 Pyrexia 2.7 2.2 Peripheral edema 2.7 3.0 Pain in extremity 2.6 2.6 Diarrhea 2.3 2.6 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of prasugrel tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: thrombocytopenia, thrombotic thrombocytopenic purpura (TTP) [see Warnings and Precautions (5.4) and Patient Counseling Information (17) ] Immune System Disorders: hypersensitivity reactions including anaphylaxis [see Contraindications (4.3) ]

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 [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ] . 7.2 Nonsteroidal Anti-Inflammatory Drugs Coadministration of prasugrel tablets and NSAIDs (used chronically) may increase the risk of bleeding [see Warnings and Precautions (5.1) ] . 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 [see Clinical Pharmacology (12.3) ] . 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 [see Clinical Pharmacology (12.3) ] . 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 [see Clinical Pharmacology (12.3) ] . 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.