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Prasugrel

Pronunciation

Pronunciation: PRA-soo-grel
Class: Aggregation inhibitor

Trade Names

Effient
- Tablet, oral 5 mg
- Tablet, oral 10 mg

Pharmacology

Prasugrel is a thienopyridine class inhibitor of platelet activation and aggregation. It acts by irreversibly binding its active metabolite to the P2Y 12 class of adenosine diphosphate (ADP) receptors on platelets.

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Pharmacokinetics

Absorption

Rapidly absorbed (at least 79% of the dose is absorbed). T max of the active metabolite is approximately 30 min. C max is decreased by 49% and T max is increased to 1.5 h when administered with a high-fat, high-calorie meal.

Distribution

Active metabolite is 98% bound to human serum albumin. Apparent Vd of active metabolite is 44 to 86 L.

Metabolism

Undergoes rapid hydrolysis in the intestine to a thiolactone, which is then converted to the active metabolite, primarily by CYP3A4 and CYP2B6, and to a lesser extent by CYP2C9 and CYP2C19. The active metabolite is metabolized to 2 inactive compounds by S-methylation or conjugation with cysteine.

Elimination

68% excreted in urine; 27% excreted in feces. The half-life of the active metabolite is approximately 7 h. Apparent clearance estimates are 112 to 166 L/h.

Special Populations

Renal Function Impairment

In patients with ESRD, both C max and AUC 0-t last of the active metabolite were approximately half that in healthy patients and in patients with moderate renal impairment.

Hepatic Function Impairment

Pharmacokinetics are similar in patients with mild to moderate hepatic impairment compared with healthy patients; the pharmacokinetics have not been studied in patients with severe hepatic disease.

Elderly

The AUC was 19% higher in patients 75 y and older than in patients younger than 75 y.

Children

Pharmacokinetics and pharmacodynamics have not been evaluated.

Gender

Pharmacokinetics of the active metabolite are similar in men and women.

Race

The AUC was approximately 19% higher in Chinese, Japanese, and Korean subjects than in white subjects.

Body weight

The AUC is approximately 30% to 40% higher in subjects with a body weight of less than 60 kg than in those weighing 60 kg or more.

Smokers

Pharmacokinetics of the active metabolite are similar in smokers and nonsmokers.

Indications and Usage

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 or non–ST elevation MI (NSTEMI); patients with ST elevation MI (STEMI) when managed with primary or delayed PCI.

Contraindications

Active pathological bleeding, such as peptic ulcer or intracranial hemorrhage; prior transient ischemic attack (TIA) or stroke; hypersensitivity to any component of the product.

Dosage and Administration

Acute Coronary Syndrome
Adults weighing 60 kg or more

PO Start with a 60 mg loading dose, then continue at 10 mg once daily, initiating and continuing aspirin (75 to 325 mg/day) in combination with prasugrel.

Adults weighing less than 60 kg

PO Start with a 60 mg loading dose, then continue at 5 mg once daily, initiating and continuing aspirin (75 to 325 mg/day) in combination with prasugrel.

General Advice

  • Administer with or without food.
  • Discontinue prasugrel for active bleeding, elective surgery, stroke, or TIA.
  • Do not break the tablet.

Storage/Stability

Store between 59° and 86°F. Dispense and keep the product in original container.

Drug Interactions

Aspirin

Bleeding time may be increased; however, aspirin 75 to 325 mg daily may be administered with prasugrel.

CYP2B6 substrates (eg, bupropion, cyclophosphamide, nevirapine, propofol)

Prasugrel may decrease exposure to these agents; however, the magnitude of the decrease is not expected to have a clinically important effect on the pharmacokinetics of drugs that are primarily metabolized by CYP2B6.

CYP3A inhibitors (eg, ciprofloxacin, clarithromycin, diltiazem, grapefruit juice, indinavir, ketoconazole, verapamil)

The C max of prasugrel and its metabolite may be decreased; however, the magnitude of the decrease is not expected to have a clinically important effect on the pharmacokinetics of the active metabolite of prasugrel.

Direct factor Xa inhibitors (eg, rivaroxaban)

The risk of bleeding is increased. Avoid coadministration.

Direct thrombin inhibitors (eg, desirudin, dabigatran)

The risk of bleeding is increased. Coadminister desirudin with caution and close clinical monitoring. Coadministration of dabigatran is not recommended.

Drugs that elevate gastric pH (eg, lansoprazole, ranitidine)

Coadministration of ranitidine or lansoprazole with prasugrel may decrease C max of the prasugrel active metabolite without altering the AUC or T max . Prasugrel may be administered with drugs that elevate gastric pH.

Fibrinolytic therapy (eg, tenecteplase)

The risk of bleeding is increased. Use with caution and closely monitor clinical response.

Heparin

The risk of bleeding is increased; however, heparin may be administered with prasugrel.

NSAIDs (eg, celecoxib, naproxen), warfarin

Risk of hemorrhage may be increased. Use with caution.

Adverse Reactions

Cardiovascular

Hypertension (8%); hypotension (4%); atrial fibrillation, bradycardia (3%); stroke (1%).

CNS

Headache (6%); dizziness, fatigue (4%).

GI

Nausea (5%); diarrhea, GI hemorrhage (2%).

Hematologic

Bleeding (14%); epistaxis (6%); leukopenia (3%); anemia (2%); hemoptysis, postprocedural hemorrhage, subcutaneous hematoma (1%); thrombocytopenia, thrombotic thrombocytopenic purpura (postmarketing).

Hypersensitivity

Hypersensitivity reactions including anaphylaxis (postmarketing).

Metabolic

Hypercholesterolemia, hyperlipidemia (7%).

Respiratory

Dyspnea (5%); cough (4%).

Miscellaneous

Back pain (5%); noncardiac chest pain, pain in extremity, peripheral edema, pyrexia, rash (3%); malignancy (2%).

Precautions

Warnings

Bleeding risk

Prasugrel can cause significant, sometimes fatal, bleeding. Do not use in patients with pathological bleeding or a history of TIA or stroke. Use is not generally recommended in patients 75 y and older because of the risk of fatal and intracranial bleeding and uncertain benefit, except in high-risk situations (patients with diabetes or a history of MI). Do not start prasugrel in patients likely to undergo urgent coronary artery bypass graft (CABG) surgery. When possible, discontinue at least 7 days prior to any surgery.

Additional risk factors for bleeding include body weight less than 60 kg, propensity to bleed, and concomitant use of medications that increase the risk of bleeding (eg, warfarin, heparin, fibrinolytic therapy, long term use of NSAIDs). Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, PCI, CABG, or other surgical procedures in the setting of prasugrel. If possible, manage bleeding without discontinuing prasugrel. Discontinuing prasugrel, particularly in the first few weeks after ACS, increases the risk of subsequent CV events.


Monitor

Monitor patient for bleeding or unusual bruising.


Pregnancy

Category B .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Generally, not recommended in patients 75 y and older, except in high-risk situations (ie, diabetes, history of MI).

Hypersensitivity

Hypersensitivity, including angioedema, has been reported.

Hepatic Function

Patients with severe hepatic disease are generally at higher risk of bleeding.

Thrombotic thrombocytopenic purpura

May occur, sometimes after short-term (less than 2 wk) exposure.

TIA/stroke

Patients who experience a stroke or TIA while on prasugrel generally should have therapy discontinued.

Overdosage

Symptoms

Prolonged bleeding with subsequent bleeding complications.

Patient Information

  • Advise patients to read the Medication Guide before starting therapy and with each refill.
  • Advise patient to take prasugrel exactly as prescribed and not to discontinue prasugrel without first discussing it with the health care provider.
  • Inform patient that it may take longer than usual to stop bleeding while taking prasugrel and to report bleeding or unusual bruising to health care provider without delay.
  • Instruct patients to get prompt medical attention if they experience any of the following symptoms that cannot otherwise be explained: extreme skin paleness, fever, neurologic changes, purple skin patches, weakness, or yellowing of the skin or eyes.
  • Inform patients that thrombotic thrombocytopenic purpura is a rare but serious condition that has been reported with prasugrel use.
  • Advise patients to inform health care providers about use of this drug before undergoing surgical or dental procedures, and before any new drug is taken.
  • Inform patients that they may experience hypersensitivity reactions, including rash, angioedema, anaphylaxis, or other manifestations.

Copyright © 2009 Wolters Kluwer Health.

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