PERGUS

Prasugrel, a thienopyridine derivative, is a platelet activation and aggregation inhibitor structurally and pharmacologically related to clopidogrel and ticlopidine.

Similar to clopidogrel, prasugrel is a prodrug that requires enzymatic transformation in the liver to its active metabolite, R-138727.

R-138727 irreversibly binds to P2Y12 type ADP receptors on platelets thus preventing activation of the GPIIb/IIIa receptor complex.

As a result, inhibition of ADP-mediated platelet activation and aggregation occurs.

Prasugrel was developed by Daiichi Sankyo

Co. and is currently marketed in the United States and Canada in cooperation with Eli Lilly and Company for acute coronary syndromes planned for percutaneous coronary intervention (PCI).

FDA approved in 2009.

Indicated in combination with acetylsalicylic acid (ASA) to prevent atherothrombotic events in patients with acute coronary syndrome (ACS) who are to be managed with percutaneous coronary intervention (PCI).

May be used in patients with unstable angina (UA), non-ST elevation myocardial infarction (NSTEMI), ST-elevation myocardial infarction (STEMI) who are to be managed with PCI.

Prasugrel is not recommended in patients 75 years of age or greater, those that weigh<60 kg, and patients with a history of stroke or transient ischemic attack due to increased risk of fatal and intracranial bleeding.

Prasugrel is a thienopyridine

ADP receptor inhibitors which inhibits platelet aggregation by irreversibly binding to P2Y12 receptors.

79% or greater of the dose is absorbed after oral administration.

Absorption and metabolism occur rapidly and peak plasma concentrations (C max ) are reached approximately 30 minutes following oral administration.

Administration with a high fat, high calorie meal did not affect the AUC of the active metabolite in healthy individuals, but the C max was decreased by ~49% and the T max was increased to 0.5-1.5 hours.

Prasugrel may be administered with or without food.

Prasugrel is not detected in plasma following oral administration.

It is rapidly hydrolyzed in the intestine to thiolactone by human carboxylesterase (hCE) 2.

This intermediate is further metabolized to its active metabolite, R-138727, in a single step by cytochrome P450 enzymes in the liver (primarily CYP3A4 and CYP2B6 and to a lesser extent by CYP2C9 and CYP2C19).

The active metabolite is further metabolized by S-methylation or cysteine conjugation to two inactive metabolites.

Unlike clopidogrel, transformation of prasugrel to its active metabolite does not appear to be affected by cytochrome P450 polymorphisms.

Hover over products below to view reaction partners Prasugrel R-95913 R-138727.

Approximately 68% of the Oral administered dose is excreted in urine and 27% in the feces, as inactive metabolites.

The active metabolite is not expected to be removed by dialysis.

The active metabolite has an elimination half-life of about 7.4 hours (range 2-15 hours).

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LD50 (rat) 1,000-2,000 mg/kg; LD50 (rabbit) > 1,000 mg/kg.

Active pathological bleeding Prior transient ischemic attack or stroke Hypersensitivity to prasugrel or any component of the product 4.1 Active Bleeding Prasugrel tablets are contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage (ICH) . 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. 4.3 Hypersensitivity Prasugrel tablets are contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to prasugrel or any component of the product.

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.

Prasugrel tablets may be administered with or without food.

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.

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.

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.

Initiate treatment with a single 60 mg oral loading dose.

Continue at 10 mg once daily with or without food.

Consider 5 mg once daily for patients <60 kg.

Patients should also take aspirin (75 mg to 325 mg) daily.

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) .

Keep and dispense only in original container.

Do not break the tablet.

Do not use if blister is torn or broken.

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.

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.

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 to 4% and of miscarriage is to 20% of clinically recognized pregnancies.

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.

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.

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.

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.

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 to less than 18 years, with sickle cell anemia was not met.

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, 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.