Prasugrel

Uses

Prasugrel is used to reduce the rate of thrombotic cardiovascular (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 is also used to associated treatment for these conditions: Cardiovascular Events

How Prasugrel works

Prasugrel is an thienopyridine and a prodrug which inhibits ADP receptors by irreversibly acting on the P2Y12 receptor on platelets. The active metabolite of prasugrel prevents binding of adenosine diphosphate (ADP) to its platelet receptor, impairing the ADP-mediated activation of the glycoprotein GPIIb/IIIa complex. Prasugrel is proposed to have a similar mechanism of action to clopidogrel.

Dosage

Prasugrel dosage

Prasugrel should be initiated with a single 60 mg loading dose and then continued at 10mg once a day. Patients taking Prasugrel should also take aspirin (75 mg to 325 mg) daily. Prasugrel may be administered with or without food.

In patients with acute coronary syndrome (ACS) who are managed with PCI, premature discontinuation of any antiplatelet agent, including Prasugrel, could result in an increased risk of thrombosis, myocardial infarction or death due to the patient's underlying disease. A treatment of up to 12 months is recommended, unless the discontinuation of Prasugrel is clinically indicated.

In case of patients weighing ≤ 60 kg or patient’s ≥ 75 years old, Prasugrel should be given as a single 60 mg loading dose and then continued at a 5 mg once-daily dose.

Toxicity

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

Precaution

General Risk of Bleeding: Thienopyridines, including Prasugrel, increase the risk of bleeding. Prasugrel should not be used in patients with active bleeding, prior TIA or stroke

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.

Propensity to bleed (e.g., recent trauma, recent surgery, recent or recurrent gastrointestinal (GI) bleeding, active peptic ulcer disease, or severe hepatic impairment): Prasugrel should be used with caution.

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. Do not start Prasugrel in patients likely to undergo urgent CABG.

Discontinuation of Prasugrel: Discontinue thienopyridines, including Prasugrel, for active bleeding, elective surgery, stroke, or TIA.

Interaction

Coadministration of prasugrel and warfarin increases the risk of bleeding. Coadministration of Prasugrel and NSAIDs (used chronically) may increase the risk of bleeding. Prasugrel can be administered with drugs that are inducers or inhibitors of cytochrome P450 enzymes. Prasugrel can be administered with aspirin (75 mg to 325 mg/day), heparin, GPIIb/IIIa inhibitors, statins, digoxin, and drugs that elevate gastric pH, including proton pump inhibitors and H2 blockers.

Food Interaction

• Avoid herbs and supplements with anticoagulant/antiplatelet activity. Examples include garlic, ginger, bilberry, danshen, piracetam, and ginkgo biloba.
• Take with or without food.

Prasugrel Drug Interaction

Major: apixabanModerate: aspirin, aspirin, omega-3 polyunsaturated fatty acidsUnknown: ubiquinone, sacubitril / valsartan, empagliflozin, insulin glargine, atorvastatin, metoprolol, metoprolol, nitroglycerin, ranolazine, levothyroxine, insulin degludec, acetaminophen, cyanocobalamin, ascorbic acid, cholecalciferol, cetirizine

Prasugrel Disease Interaction

Major: bleeding, coronary and cerebral vascular diseaseModerate: renal/liver disease

Volume of Distribution

44-68L

Elimination Route

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 to 1.5 hours. Prasugrel may be administered with or without food.

Half Life

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

Clearance

Apparent clearance = 112 - 166 L/hr

Elimination Route

Approximately 68% of the orally 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.

Pregnancy & Breastfeeding use

Pregnancy Category B. There are no adequate and well-controlled studies of Prasugrel use in pregnant women. Prasugrel should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

It is not known whether Prasugrel is excreted in human milk. Because many drugs are excreted in human milk, prasugrel should be used during nursing only if the potential benefit to the mother justifies the potential risk to the nursing infant.

Contraindication

Prasugrel should be avoided in case of hypersensitivity to the active substance or to any of the excipients, active pathological bleeding, and history of stroke or transient ischaemic attack (TIA), severe hepatic impairment.

Special Warning

Pediatric use: Safety and effectiveness in pediatric patients have not been established.

Geriatric Use: The use of Prasugrel in patients ≥75 years of age is generally not recommended because these patients are at greater risk of bleeding, including fatal bleeding, compared to patients <75 years of age. If prescribed, a lower maintenance dose of 5 mg should be used.

Renal Impairment: No dosage adjustment is necessary for patients with renal impairment. There is limited experience in patients with end-stage renal disease

Hepatic Impairment: No dosage adjustment is necessary in patients with mild to moderate hepatic impairment.

Acute Overdose

Overdose of Prasugrel may lead to prolonged bleeding time and subsequent bleeding omplications. No data are available on the reversal of the pharmacological effect of prasugrel; however, if prompt correction of prolonged bleeding time is required, platelet transfusion and/or other blood products may be considered.

Storage Condition

Store in a dry & cool place. Protect from light & moisture. Keep out of the reach of children.

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