3) ] . effient 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) ] .

ar 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) ] .

] . 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 effient 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 effient 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 (7-10 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 effient who undergo cabg. if possible, effient 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 effient group and 4.5% in the clopidogrel group [see adverse reactions (6.1) ] . the higher risk for bleeding events in patients treated with effient 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 effient 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 effient 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 effient discontinue thienopyridines, including effient, 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 [see contraindications (4.1 , 4.2) and warnings and precautions (5.1) ] . 5.4 thrombotic thrombocytopenic purpura (ttp) ttp has been reported with the use of effient. ttp can occur after a brief exposure (<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 [see adverse reactions (6.2) ] . 5.5 hypersensitivity including angioedema hypersensitivity including angioedema has been reported in patients receiving effient, including patients with a history of hypersensitivity reaction to other thienopyridines [see contraindications (4.3) and adverse reactions (6.2) ] .

inistered at the time of diagnosis, although most received effient at the time of pci [see clinical studies (14) ] . for the small fraction of patients that required urgent cabg after treatment with effient, 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 effient 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) ] .

e, 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 effient and 6.3% for clopidogrel. bleeding was the most common adverse reaction leading to study drug discontinuation for both drugs (2.5% for effient 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 effient 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) effient (%) (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 effient 10 mg effient maintenance dose (%) clopidogrel 75 mg clopidogrel maintenance dose (%) effient (%) clopidogrel (%) weight <60 kg (n=308 effient, n=356 clopidogrel) 10.1 6.5 0.0 0.3 weight ≥60 kg (n=6373 effient, n=6299 clopidogrel) 4.2 3.3 0.3 0.1 age <75 years (n=5850 effient, n=5822 clopidogrel) 3.8 2.9 0.2 0.1 age ≥75 years (n=891 effient, 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 effient group and 4.5% in the clopidogrel group (see table 3 ). the higher risk for bleeding adverse reactions in patients treated with effient 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) effient (%) (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 effient 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 effient 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 effient (%) (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 × 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 effient. 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) ]

3) ] . effient 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) ] .

nant rats and rabbits received prasugrel at maternally toxic oral doses equivalent to more than 40 times the human exposure. a slight decrease in fetal body weight was observed, but there were no structural malformations in either species. in prenatal and postnatal rat studies, maternal treatment with prasugrel had no effect on the behavioral or reproductive development of the offspring at doses greater than 150 times the human exposure. 8.2 lactation risk summary there is no information regarding the presence of prasugrel in human milk, the effects on the breastfed infant, or the effects on milk production. metabolites of prasugrel were found in rat milk [see data ] . the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for effient and any potential adverse effects on the breastfed child from effient or from the underlying maternal condition. data animal data following a 5 mg/kg oral dose of [ 14 c]-prasugrel to lactating rats, metabolites of prasugrel were detected in the maternal milk and blood. 8.4 pediatric use safety and effectiveness in pediatric patients have not been established. in a randomized, placebo-controlled trial, the primary objective of reducing the rate of vaso-occlusive crisis (painful crisis or acute chest syndrome) in pediatric patients, aged 2 to less than 18 years, with sickle cell anemia was not met. 8.5 geriatric use in triton-timi 38, 38.5% of patients were ≥65 years of age and 13.2% were ≥75 years of age. the risk of bleeding increased with advancing age in both treatment groups, although the relative risk of bleeding (effient compared with clopidogrel) was similar across age groups. patients ≥75 years of age who received effient 10 mg had an increased risk of fatal bleeding events (1.0%) compared to patients who received clopidogrel (0.1%). in patients ≥75 years of age, symptomatic intracranial hemorrhage occurred in 7 patients (0.8%) who received effient and in 3 patients (0.3%) who received clopidogrel. because of the risk of bleeding, and because effectiveness is uncertain in patients ≥75 years of age [see clinical studies (14) ] , use of effient is generally not recommended in these patients, except in high-risk situations (diabetes and past history of myocardial infarction) where its effect appears to be greater and its use may be considered [see warnings and precautions (5.1) , clinical pharmacology (12.3) , and clinical studies (14) ] . 8.6 low body weight in triton-timi 38, 4.6% of patients treated with effient had body weight <60 kg. individuals with body weight <60 kg had an increased risk of bleeding and an increased exposure to the active metabolite of prasugrel [see dosage and administration (2) , warnings and precautions (5.1) , and clinical pharmacology (12.3) ] . 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 dosage and administration (2) and clinical pharmacology (12.3) ] . 8.7 renal impairment no dosage adjustment is necessary for patients with renal impairment. there is limited experience in patients with end-stage renal disease, but such patients are generally at higher risk of bleeding [see warnings and precautions (5.1) and clinical pharmacology (12.3) ] . 8.8 hepatic impairment no dosage adjustment is necessary in patients with mild to moderate hepatic impairment (child-pugh class a and b). the pharmacokinetics and pharmacodynamics of prasugrel in patients with severe hepatic disease have not been studied, but such patients are generally at higher risk of bleeding [see warnings and precautions (5.1) and clinical pharmacology (12.3) ] . 8.9 metabolic status in healthy subjects, patients with stable atherosclerosis, and patients with acs receiving prasugrel, there was no relevant effect of genetic variation in cyp2b6, cyp2c9, cyp2c19, or cyp3a5 on the pharmacokinetics of prasugrel's active metabolite or its inhibition of platelet aggregation.

prasugrel at maternally toxic oral doses equivalent to more than 40 times the human exposure. a slight decrease in fetal body weight was observed, but there were no structural malformations in either species. in prenatal and postnatal rat studies, maternal treatment with prasugrel had no effect on the behavioral or reproductive development of the offspring at doses greater than 150 times the human exposure.

e being a reflection of new platelet production rather than pharmacokinetics of prasugrel. discontinuing clopidogrel 75 mg and initiating a prasugrel 10 mg maintenance dose with or without a prasugrel 60 mg loading dose results in a decrease of 14 percentage points in maximum platelet aggregation (mpa) by day 7. this decrease in mpa is not greater than that typically produced by a 10 mg maintenance dose of prasugrel alone. the relationship between inhibition of platelet aggregation and clinical activity has not been established. figure 2 5 mg in low body weight patients in patients with stable coronary artery disease, mean platelet inhibition in subjects <60 kg taking 5 mg prasugrel was similar to that of subjects ≥60 kg taking 10 mg prasugrel. the relationship between inhibition of platelet aggregation and clinical activity has not been established. 12.3 pharmacokinetics prasugrel is a prodrug and is rapidly metabolized to a pharmacologically active metabolite and inactive metabolites. the active metabolite has an elimination half-life of about 7 hours (range 2-15 hours). healthy subjects, patients with stable atherosclerosis, and patients undergoing pci show similar pharmacokinetics. absorption and binding following oral administration, ≥79% of the dose is absorbed. the absorption and metabolism are rapid, with peak plasma concentrations (c max ) of the active metabolite occurring approximately 30 minutes after dosing. the active metabolite's exposure (auc) increases slightly more than proportionally over the dose range of 5 to 60 mg. repeated daily doses of 10 mg do not lead to accumulation of the active metabolite. in a study of healthy subjects given a single 15 mg dose, the auc of the active metabolite was unaffected by a high-fat, high-calorie meal, but c max was decreased by 49% and t max was increased from 0.5 to 1.5 hours. effient can be administered without regard to food. the active metabolite is bound about 98% to human serum albumin. metabolism and elimination prasugrel is not detected in plasma following oral administration. it is rapidly hydrolyzed in the intestine to a thiolactone, which is then converted to the active metabolite by a single step, primarily by cyp3a4 and cyp2b6 and to a lesser extent by cyp2c9 and cyp2c19. the estimates of apparent volume of distribution of prasugrel's active metabolite ranged from 44 to 68 l and the estimates of apparent clearance ranged from 112 to 166 l/hr in healthy subjects and patients with stable atherosclerosis. the active metabolite is metabolized to two inactive compounds by s-methylation or conjugation with cysteine. the major inactive metabolites are highly bound to human plasma proteins. approximately 68% of the prasugrel dose is excreted in the urine and 27% in the feces as inactive metabolites. specific populations geriatric patients in a study of 32 healthy subjects between the ages of 20 and 80 years, age had no significant effect on pharmacokinetics of prasugrel's active metabolite or its inhibition of platelet aggregation. in triton-timi 38, the mean exposure (auc) of the active metabolite was 19% higher in patients ≥75 years of age than in patients <75 years of age. in a study in subjects with stable atherosclerosis, the mean exposure (auc) to the active metabolite of prasugrel in subjects ≥75 years old taking a 5 mg maintenance dose was approximately half that seen in subjects 45 to 64 years old taking a 10 mg maintenance dose [see warnings and precautions (5.1) and use in specific populations (8.5) ] . body weight the mean exposure (auc) to the active metabolite is approximately 30 to 40% higher in subjects with a body weight of <60 kg than in those weighing ≥60 kg. in a study in subjects with stable atherosclerosis, the auc of the active metabolite on average was 38% lower in subjects <60 kg taking 5 mg (n=34) than in subjects ≥60 kg taking 10 mg (n=38) [see dosage and administration (2) , warnings and precautions (5.1) , adverse reactions (6.1) , and use in specific populations (8.6) ] . male and female patients pharmacokinetics of prasugrel's active metabolite is similar in men and women. racial or ethnic groups exposure in subjects of african and hispanic descent is similar to that in caucasians. in clinical pharmacology studies, after adjusting for body weight, the auc of the active metabolite was approximately 19% higher in chinese, japanese, and korean subjects than in caucasian subjects. smoking pharmacokinetics of prasugrel's active metabolite is similar in smokers and nonsmokers. patients with renal impairment pharmacokinetics of prasugrel's active metabolite and its inhibition of platelet aggregation is similar in patients with moderate renal impairment (crcl=30 to 50 ml/min) and healthy subjects. in patients with end-stage renal disease, exposure to the active metabolite (both c max and auc (0-t last )) was about half that in healthy controls and patients with moderate renal impairment [see warnings and precautions (5.1) and use in specific populations (8.7) ] . patients with hepatic impairment pharmacokinetics of prasugrel's active metabolite and inhibition of platelet aggregation was similar in patients with mild to moderate hepatic impairment compared to healthy subjects. the pharmacokinetics and pharmacodynamics of prasugrel's active metabolite in patients with severe hepatic disease have not been studied [see warnings and precautions (5.1) and use in specific populations (8.8) ] . 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, effient was 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. 12.5 pharmacogenomics there is no relevant effect of genetic variation in cyp2b6, cyp2c9, cyp2c19, or cyp3a5 on the pharmacokinetics of prasugrel's active metabolite or its inhibition of platelet aggregation.

hours. effient can be administered without regard to food. the active metabolite is bound about 98% to human serum albumin. metabolism and elimination prasugrel is not detected in plasma following oral administration. it is rapidly hydrolyzed in the intestine to a thiolactone, which is then converted to the active metabolite by a single step, primarily by cyp3a4 and cyp2b6 and to a lesser extent by cyp2c9 and cyp2c19. the estimates of apparent volume of distribution of prasugrel's active metabolite ranged from 44 to 68 l and the estimates of apparent clearance ranged from 112 to 166 l/hr in healthy subjects and patients with stable atherosclerosis. the active metabolite is metabolized to two inactive compounds by s-methylation or conjugation with cysteine. the major inactive metabolites are highly bound to human plasma proteins. approximately 68% of the prasugrel dose is excreted in the urine and 27% in the feces as inactive metabolites. specific populations geriatric patients in a study of 32 healthy subjects between the ages of 20 and 80 years, age had no significant effect on pharmacokinetics of prasugrel's active metabolite or its inhibition of platelet aggregation. in triton-timi 38, the mean exposure (auc) of the active metabolite was 19% higher in patients ≥75 years of age than in patients <75 years of age. in a study in subjects with stable atherosclerosis, the mean exposure (auc) to the active metabolite of prasugrel in subjects ≥75 years old taking a 5 mg maintenance dose was approximately half that seen in subjects 45 to 64 years old taking a 10 mg maintenance dose [see warnings and precautions (5.1) and use in specific populations (8.5) ] . body weight the mean exposure (auc) to the active metabolite is approximately 30 to 40% higher in subjects with a body weight of <60 kg than in those weighing ≥60 kg. in a study in subjects with stable atherosclerosis, the auc of the active metabolite on average was 38% lower in subjects <60 kg taking 5 mg (n=34) than in subjects ≥60 kg taking 10 mg (n=38) [see dosage and administration (2) , warnings and precautions (5.1) , adverse reactions (6.1) , and use in specific populations (8.6) ] . male and female patients pharmacokinetics of prasugrel's active metabolite is similar in men and women. racial or ethnic groups exposure in subjects of african and hispanic descent is similar to that in caucasians. in clinical pharmacology studies, after adjusting for body weight, the auc of the active metabolite was approximately 19% higher in chinese, japanese, and korean subjects than in caucasian subjects. smoking pharmacokinetics of prasugrel's active metabolite is similar in smokers and nonsmokers. patients with renal impairment pharmacokinetics of prasugrel's active metabolite and its inhibition of platelet aggregation is similar in patients with moderate renal impairment (crcl=30 to 50 ml/min) and healthy subjects. in patients with end-stage renal disease, exposure to the active metabolite (both c max and auc (0-t last )) was about half that in healthy controls and patients with moderate renal impairment [see warnings and precautions (5.1) and use in specific populations (8.7) ] . patients with hepatic impairment pharmacokinetics of prasugrel's active metabolite and inhibition of platelet aggregation was similar in patients with mild to moderate hepatic impairment compared to healthy subjects. the pharmacokinetics and pharmacodynamics of prasugrel's active metabolite in patients with severe hepatic disease have not been studied [see warnings and precautions (5.1) and use in specific populations (8.8) ] . 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, effient was 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.

loading dose was to be administered anytime between randomization and 1 hour after the patient left the catheterization lab. if patients with stemi were treated with thrombolytic therapy, randomization could not occur until at least 24 hours (for tenecteplase, reteplase, or alteplase) or 48 hours (for streptokinase) after the thrombolytic was given. patients were randomized to receive effient (60 mg loading dose followed by 10 mg once daily) or clopidogrel (300 mg loading dose followed by 75 mg once daily), with administration and follow-up for a minimum of 6 months (actual median 14.5 months). patients also received aspirin (75 mg to 325 mg once daily). other therapies, such as heparin and intravenous glycoprotein iib/iiia (gpiib/iiia) inhibitors, were administered at the discretion of the treating physician. oral anticoagulants, other platelet inhibitors, and chronic nsaids were not allowed. the primary outcome measure was the composite of cardiovascular death, nonfatal mi, or nonfatal stroke in the ua/nstemi population. success in this group allowed analysis of the same endpoint in the overall acs and stemi populations. nonfatal mis included both mis detected solely through analysis of creatine kinase muscle-brain (ck-mb) changes and clinically apparent (investigator-reported) mis. the patient population was 92% caucasian, 26% female, and 39% ≥65 years of age. the median time from symptom onset to study drug administration was 7 hours for patients with stemi and 30 hours for patients with ua/nstemi. approximately 99% of patients underwent pci. the study drug was administered after the first coronary guidewire was placed in approximately 75% of patients. effient significantly reduced total endpoint events compared to clopidogrel (see figure 3 and table 5 ). the reduction of total endpoint events was driven primarily by a decrease in nonfatal mis, both those occurring early (through 3 days) and later (after 3 days). approximately 40% of mis occurred peri-procedurally and were detected solely by changes in ck-mb. administration of the clopidogrel loading dose in triton-timi 38 was delayed relative to the placebo-controlled trials that supported its approval for acs. effient produced higher rates of clinically significant bleeding than clopidogrel in triton-timi 38 [see adverse reactions (6.1) ] . choice of therapy requires balancing these differences in outcome. the treatment effect of effient was apparent within the first few days, and persisted to the end of the study (see figure 3 ). the inset shows results over the first 7 days. figure 3: time to first event of cv death, mi, or stroke (triton-timi 38) the kaplan-meier curves (see figure 3 ) show the primary composite endpoint of cv death, nonfatal mi, or nonfatal stroke over time in the ua/nstemi and stemi populations. in both populations, the curves separate within the first few hours. in the ua/nstemi population, the curves continue to diverge throughout the 15-month follow-up period. in the stemi population, the early separation was maintained throughout the 15-month follow-up period, but there was no progressive divergence after the first few weeks. effient reduced the occurrence of the primary composite endpoint compared to clopidogrel in both the ua/nstemi and stemi populations (see table 5 ). in patients who survived an on-study myocardial infarction, the incidence of subsequent events was also lower in the effient group. table 5: patients with outcome events (cv death, mi, stroke) in triton-timi 38 patients with events from kaplan-meier analysis effient (%) clopidogrel (%) relative risk reduction (%) rrr = (1-hazard ratio) × 100%. values with a negative relative risk reduction indicate a relative risk increase. (95% ci) p-value ua/nstemi n=5044 n=5030 cv death, nonfatal mi, or nonfatal stroke 9.3 11.2 18.0 (7.3, 27.4) 0.002 cv death 1.8 1.8 2.1 (-30.9, 26.8) 0.885 nonfatal mi 7.1 9.2 23.9 (12.7, 33.7) <0.001 nonfatal stroke 0.8 0.8 2.1 (-51.3, 36.7) 0.922 stemi n=1769 n=1765 cv death, nonfatal mi, or nonfatal stroke 9.8 12.2 20.7 (3.2, 35.1) 0.019 cv death 2.4 3.3 26.2 (-9.4, 50.3) 0.129 nonfatal mi 6.7 8.8 25.4 (5.2, 41.2) 0.016 nonfatal stroke 1.2 1.1 -9.7 (-104.0, 41.0) 0.77 the effect of effient in various subgroups is shown in figures 4 and 5. results are generally consistent across pre-specified subgroups, with the exception of patients with a history of tia or stroke [see contraindications (4.2) ] . the treatment effect was driven primarily by a reduction in nonfatal mi. the effect in patients ≥75 years of age was also somewhat smaller, and bleeding risk is higher in these individuals [see adverse reactions (6.1) ] . see below for analyses of patients ≥75 years of age with risk factors. figure 4: subgroup analyses for time to first event of cv death, mi, or stroke (hr and 95% ci; triton-timi 38) – ua/nstemi patients figure 5: subgroup analyses for time to first event of cv death, mi, or stroke (hr and 95% ci; triton-timi 38) – stemi patients effient is generally not recommended in patients ≥75 years of age, except in high-risk situations (diabetes mellitus or prior mi) where its effect appears to be greater and its use may be considered. these recommendations are based on subgroup analyses (see table 6 ) and must be interpreted with caution, but the data suggest that effient reduces ischemic events in such patients. table 6: subgroup analyses for time to first event of cv death, mi, or stroke: patients < or ≥75 years of age, ± diabetes, ± prior history of mi, all acs patient population effient clopidogrel hazard ratio (95% ci) n % with events n % with events age ≥75 diabetes – yes 249 14.9 234 21.8 0.64 (0.42, 0.97) diabetes – no 652 16.4 674 15.3 1.1 (0.83, 1.43) age <75 diabetes – yes 1327 10.8 1336 14.8 0.72 (0.58, 0.89) diabetes – no 4585 7.8 4551 9.5 0.82 (0.71, 0.94) age ≥75 prior mi – yes 220 17.3 212 22.6 0.72 (0.47, 1.09) prior mi – no 681 15.6 696 15.2 1.05 (0.80, 1.37) age <75 prior mi – yes 1006 12.2 996 15.4 0.78 (0.62, 0.99) prior mi – no 4906 7.7 4891 9.7 0.78 (0.68, 0.90) there were 50% fewer stent thromboses (95% c.i. 32% - 64%; p<0.001) reported among patients randomized to effient (0.9%) than among patients randomized to clopidogrel (1.8%). the difference manifested early and was maintained through one year of follow-up. findings were similar with bare metal and drug-eluting stents. in triton-timi 38, prasugrel reduced ischemic events (mainly nonfatal mis) and increased bleeding events [see adverse reactions (6.1) ] relative to clopidogrel. the findings are consistent with the intended greater inhibition of platelet aggregation by prasugrel at the doses used in the study [see clinical pharmacology (12.2) ] . there is, however, an alternative explanation: both prasugrel and clopidogrel are prodrugs that must be metabolized to their active moieties. whereas the pharmacokinetics of prasugrel's active metabolite is not known to be affected by genetic variations in cyp2b6, cyp2c9, cyp2c19, or cyp3a5, the pharmacokinetics of clopidogrel's active metabolite is affected by cyp2c19 genotype, and approximately 30% of caucasians are reduced metabolizers. moreover, certain proton pump inhibitors, widely used in the acs patient population and used in triton-timi 38, inhibit cyp2c19, thereby decreasing formation of clopidogrel's active metabolite. thus, reduced-metabolizer status and use of proton pump inhibitors may diminish clopidogrel's activity in a fraction of the population, and may have contributed to prasugrel's greater treatment effect and greater bleeding rate in triton-timi 38. the extent to which these factors were operational, however, is unknown. figure 3 figure 4 figure 5

nd precautions (5.4) ] . hypersensitivity inform patients that they may have hypersensitivity reactions and to seek immediate medical attention if any signs and symptoms of a hypersensitivity reaction occur. patients who have had hypersensitivity reactions to other thienopyridines may have hypersensitivity reactions to effient. invasive procedures instruct patients to: inform physicians and dentists that they are taking effient before any invasive procedure is scheduled [see warnings and precautions (5.1) ] . tell the doctor performing the invasive procedure to talk to the prescribing healthcare professional before stopping effient. concomitant medications ask patients to list all prescription medications, over-the-counter medications, or dietary supplements they are taking or plan to take so the physician knows about other treatments that may affect bleeding risk (e.g., warfarin and nsaids) [see drug interactions (7.1 , 7.2) ].