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 [seeClinical Studies (14)].

4.1 Active Bleeding

Prasugrel tablets are contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage (ICH) [seeWarnings and Precautions (5.1)andAdverse 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 ( TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibitio Nwith 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 [seeAdverse Reactions (6.1)andClinical Studies (14)].

4.3 Hypersensitivity

Prasugrel tablets are contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to prasugrel or any component of the product [seeAdverse Reactions (6.2)].

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 <5 g/dL), bleeding events were more common on prasugrel than on clopidogrel [seeAdverse Reactions (6.1)]. 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 [seeContraindications (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 [seeAdverse Reactions (6.1),Use in Specific Populations (8.5),Clinical Pharmacology (12.3), andClinical Studies (14)].
• CABG or other surgical procedure [seeWarnings and Precautions (5.2)].
• Body weight <60 kg. Consider a lower (5 mg) maintenance dose [seeDosage and Administration (2),Adverse Reactions (6.1), andUse 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) [seeAdverse Reactions (6.1)andUse 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 [seeDrug 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.

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 [seeAdverse Reactions (6.1)]. 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 [seeContraindications (4.1, 4.2) and Warnings and Precautions (5.1)].

5.4 Thrombotic Thrombocytopenic Purpura (TTP)

TTP has been reported with the use of prasugrel. 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 [seeAdverse Reactions (6.2)].

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 [seeContraindications (4.3)andAdverse Reactions (6.2)].

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 (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 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 and 6.3% for clopidogrel. Bleeding was the most common adverse reaction leading to study drug discontinuation for both drugs (2.5% for prasugrel 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 than on clopidogrel, as shown in Table 1.

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) [seeWarnings 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.

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 group and 4.5% in the clopidogrel group (see Table 3). The higher risk for bleeding adverse reactions in patients treated with prasugrel persisted up to 7 days from the most recent dose of study drug.

Bleeding Reported as Adverse Reactions
Hemorrhagic events reported as adverse reactions in TRITON-TIMI 38 were, for prasugrel 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 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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of prasugrel. 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.

1. Blood and lymphatic system disorders —thrombocytopenia, thrombotic thrombocytopenic purpura (TTP) [seeWarnings and Precautions (5.4)andPatient Counseling Information (17)]
2. Immune system disorders —hypersensitivity reactions including anaphylaxis [seeContraindications (4.3)]

7.1 Warfarin

Coadministration of prasugrel and warfarin increases the risk of bleeding [seeWarnings and Precautions (5.1)andClinical Pharmacology (12.3)].

7.2 Nonsteroidal Anti-Inflammatory Drugs

Coadministration of prasugrel and NSAIDs (used chronically) may increase the risk of bleeding [seeWarnings 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 [seeClinical 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 can be administered with drugs that are inducers or inhibitors of cytochrome P450 enzymes [seeClinical Pharmacology (12.3)].

Prasugrel 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 [seeClinical Pharmacology (12.3)].

8.1 Pregnancy

Risk Summary
There are no data with prasugrel use in pregnant women to inform a drug-associated risk. No structural malformations were observed in animal reproductive and developmental toxicology studies when rats and rabbits were administered prasugrel during organogenesis at doses of up to 30 times the recommended therapeutic exposures in humans [see Data]. Due to the mechanism of action of prasugrel, and the associated identified risk of bleeding, consider the benefits and risks of prasugrel and possible risks to the fetus when prescribing prasugrel to a pregnant woman [seeBoxed WarningandWarnings and Precautions (5.1, 5.3)].

The background risk of major birth defects and miscarriage for the indicated population is unknown. The background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.

Data
Animal Data
In embryo-fetal developmental toxicology studies, pregnant 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 prasugrel and any potential adverse effects on the breastfed child from prasugrel or from the underlying maternal condition.

Data
Animal Data
Following a 5 mg/kg oral dose of [ 14C]-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 (prasugrel compared with clopidogrel) was similar across age groups.

Patients ≥75 years of age who received prasugrel 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 prasugrel 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 [seeClinical Studies (14)], use of prasugrel 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 [seeWarnings and Precautions (5.1),Clinical Pharmacology (12.3), andClinical Studies (14)].

8.6 Low Body Weight

In TRITON-TIMI 38, 4.6% of patients treated with prasugrel 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 [seeDosage and Administration (2),Warnings and Precautions (5.1), andClinical 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 [seeDosage and Administration (2)andClinical 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 [seeWarnings and Precautions (5.1)andClinical 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 [seeWarnings and Precautions (5.1)andClinical 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.

10.1 Signs and Symptoms

Platelet inhibition by prasugrel is rapid and irreversible, lasting for the life of the platelet, and is unlikely to be increased in the event of an overdose. In rats, lethality was observed after administration of 2000 mg/kg. Symptoms of acute toxicity in dogs included emesis, increased serum alkaline phosphatase, and hepatocellular atrophy. Symptoms of acute toxicity in rats included mydriasis, irregular respiration, decreased locomotor activity, ptosis, staggering gait, and lacrimation.

10.2 Recommendations about Specific Treatment

Platelet transfusion may restore clotting ability. The prasugrel active metabolite is not likely to be removed by dialysis.

12.1 Mechanism of Action

Prasugrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y 12 class of ADP receptors on platelets.

12.2 Pharmacodynamics

Prasugrel produces inhibition of platelet aggregation to 20 μM or 5 μM ADP, as measured by light transmission aggregometry. Following a 60 mg loading dose of prasugrel, approximately 90% of patients had at least 50% inhibition of platelet aggregation by 1 hour. Maximum platelet inhibition was about 80% (see Figure 2). Mean steady-state inhibition of platelet aggregation was about 70% following 3 to 5 days of dosing at 10 mg daily after a 60 mg loading dose of prasugrel.

Figure 2: Inhibition (Mean ± SD) of 20 μM ADP-induced Platelet Aggregation (IPA) Measured by Light Transmission Aggregometry after Prasugrel 60 mg

Platelet aggregation gradually returns to baseline values over 5 to 9 days after discontinuation of prasugrel, this time course 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.

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 to 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. Prasugrel 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 [seeWarnings and Precautions (5.1)andUse 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) [seeDosage and Administration (2),Warnings and Precautions (5.1),Adverse Reactions (6.1), andUse 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 [seeWarnings and Precautions (5.1)andUse 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 [seeWarnings and Precautions (5.1)andUse 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 [seeDrug 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 [seeDrug 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 was administered without regard to coadministration of a proton pump inhibitor or H 2 blocker [seeDrug 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 [seeDrug 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 [seeDrug 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 [seeDrug Interactions (7.4)].

Warfarin- A significant prolongation of the bleeding time was observed when prasugrel was coadministered with 15 mg of warfarin [seeDrug 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 [seeDrug 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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis
No compound-related tumors were observed in a 2-year rat study with prasugrel at oral doses up to 100 mg/kg/day (>100 times the recommended therapeutic exposures in humans [based on plasma exposures to the major circulating human metabolite]). There was an increased incidence of tumors (hepatocellular adenomas) in mice exposed for 2 years to high doses (>250 times the human metabolite exposure).

Mutagenesis
Prasugrel was not genotoxic in two in vitro tests (Ames bacterial gene mutation test, clastogenicity assay in Chinese hamster fibroblasts) and in one in vivo test (micronucleus test by intraperitoneal route in mice).

Impairment of Fertility
Prasugrel had no effect on fertility of male and female rats at oral doses up to 300 mg/kg/day (80 times the human major metabolite exposure at daily dose of 10 mg prasugrel).

16.1 How Supplied

Prasugrel Tablets USP, 10 mg are beige, elongated hexagonal, film-coated, non-scored tablets debossed with ‘I’ on one side and ‘24’ on the other side.

Unit dose packages of 30 (3 x 10) NDC 60687-883-21

16.2 Storage and Handling

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Keep and dispense only in original container. Do not break the tablet.

FOR YOUR PROTECTION: Do not use if blister is torn or broken.