Prasugrel

Prasugrel is an anticoagulant agent belonging to the P2Y12 platelet inhibitors.

Prasugrel is a P2Y12 platelet inhibitor used to reduce the risk of thrombotic cardiovascular events in unstable angina or non-ST-elevation myocardial infarction (NSTEMI), and in patients with STEMI when managed with either primary or delayed PCI.

Prasugrel is rapidly absorbed from the GI tract. The time to peak plasma concentration is approximately 30 min. The Plasma protein binding of Prasugrel is approximately 98%. 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. Via urine (approx 68%) and feces (approx 27%). Elimination half-life: Approx 7.4 hr. 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.

Prasugrel shows common side effects like Dizziness, excessive tiredness, pain in the back, arms, or legs, cough, Fever, weakness, paleness, purple patches on the skin, yellowing of the skin or eyes, shortness of breath, slow, fast, or irregular heartbeat, headache, confusion, seizures, slow or difficult speech, sudden weakness of an arm or leg, stomach pain, nausea, vomiting, diarrhea, decreased urination, rash, swelling of the eyes, face, mouth, lips, tongue, throat, arms, hands, feet, ankles, or lower legs.

Prasugrel is available in the form of an Oral Tablet.

Prasugrel is available in India, the US, the UK, Singapore, Australia, and Japan.

Prasugrel belonging to the P2Y12 platelet inhibitor, acts as an anticoagulant agent.

Prasugrel, an inhibitor of platelet activation and aggregation, is a prodrug that is metabolized to both active (R-138727) and inactive metabolites. The active metabolite irreversibly blocks the P2Y₁₂ component of ADP receptors on the platelet, which prevents activation of the GPIIb/IIIa receptor complex, thereby reducing platelet activation and aggregation.

The Data on the Onset of action of Prasugrel is not available.

The Duration of Action for Prasugrel in the body is approximately 5-9 days.

The Tmax was found within 30-90 minutes following the administration of Prasugrel.

Prasugrel is available in the form of an Oral Tablet.

Prasugrel tablet is taken orally usually once daily.

Prasugrel is antiplatelet which is used to prevent clots in blood vessels. It can be taken in combination with other antiplatelets for better action. It is not recommended in patients with bleeding disorders.

Prasugrel is an anticoagulant agent belonging to the P2Y12 platelet inhibitor.

Prasugrel inhibits platelet activation and aggregation. The active metabolite irreversibly blocks the P2Y₁₂ component of adenosine diphosphate (ADP) receptors on the platelet, which prevents activation of the GPIIb/IIIa receptor complex, thereby reducing platelet activation and aggregation.

Prasugrel is approved for use in the following clinical indications

• Acute coronary syndrome (non-ST-elevation myocardial infarction, unstable angina, or ST-elevation myocardial infarction) managed by percutaneous coronary intervention

Prasugrel is indicated to reduce the rate of thrombotic cardiovascular (CV) events (including stent thrombosis) in patients with the 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 has 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 in strokes and little difference in CV death.

• Acute coronary syndrome (non-ST-elevation myocardial infarction, unstable angina, or ST-elevation myocardial infarction) managed by percutaneous coronary intervention

Loading dose:

Oral: 60 mg once before PCI in combination with aspirin and a parenteral anticoagulant; followed by maintenance dosing. If coronary angiography is planned soon after diagnosis, it is reasonable to delay the initial loading dose until after coronary anatomy is known.

Maintenance dose:

Oral: ≥60 kg:

10 mg once daily in combination with aspirin beginning the day after PCI.

Oral: <60 kg:

5 mg once daily in combination with aspirin beginning the day after PCI. An alternative P2Y₁₂ inhibitor may be considered if bleeding is a major concern.

Prasugrel is available in various strengths as 5mg and 10mg.

Prasugrel is available in the form of Oral Tablets.

Avoid herbs and supplements with anticoagulant/antiplatelet activity. Examples include garlic, ginger, bilberry, danshen, piracetam, and ginkgo Biloba.

Prasugrel is contraindicated in patients with

• Active Bleeding

Prasugrel is contraindicated in patients with active pathological bleeding such as a peptic ulcer or intracranial hemorrhage.

• Prior Transient Ischemic Attack or Stroke

Prasugrel is 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 Inhibition with Prasugrel), patients with a history of TIA or ischemic stroke (> 3 months prior to enrollment) had a higher rate of stroke on Prasugrel (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 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 generally should have therapy discontinued.

• Hypersensitivity

Prasugrel is contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to prasugrel or any component of the product.

• Bleeding

May cause significant, sometimes fatal, bleeding. Do not use prasugrel in patients with active pathological bleeding or a history of TIA or stroke. Additional risk factors for bleeding include body weight <60 kg, propensity to bleed (eg, recent trauma, recent surgery, recent or recurrent GI bleeding, active peptic ulcer disease, severe hepatic impairment, or moderate to severe renal impairment), 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 cardiovascular events. Management of bleeding episodes includes the use of PRBCs and platelet transfusion.

• Hypersensitivity

Hypersensitivity, including angioedema, has been reported, in patients with a previous history of thienopyridine hypersensitivity. Because of structural similarities, cross-reactivity is possible among the thienopyridines (clopidogrel, prasugrel, and ticlopidine); use with caution or avoid in patients with a previous history of thienopyridine hypersensitivity. The use of prasugrel is contraindicated in patients with hypersensitivity (eg, anaphylaxis) to prasugrel.

• 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. The higher risk for bleeding events in patients treated with Prasugrel persisted up to 7 days from the most recent dose of the 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 a 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.

• 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 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.

• Thrombotic Thrombocytopenic Purpura

Thrombotic thrombocytopenic purpura (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.

It is not known whether Prasugrel is excreted in human milk; however, metabolites of Prasugrel were found in rat 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.

Prasugrel is recommended in pregnant women only if necessary. The benefits and risks should be considered before receiving Prasugrel.

Avoid herbs and supplements with anticoagulant/antiplatelet activity. Examples include garlic, ginger, bilberry, danshen, piracetam, and ginkgo Biloba.

• Common Adverse effects

Hypertension, hypotension, atrial fibrillation, bradycardia, peripheral edema, Headache, dizziness, fatigue, noncardiac chest pain, Skin rash, Hypercholesterolemia, hyperlipidemia, Nausea, diarrhea, gastrointestinal hemorrhage, Leukopenia, anemia, minor hemorrhage, major hemorrhage, Back pain, limb pain, Epistaxis, dyspnea, cough, Fever.

• Rare Adverse effects

Abnormal hepatic function tests, anaphylaxis, angioedema, hematoma, hemoptysis, hemorrhage (requiring inotropes or transfusion), hypersensitivity reaction, intracranial hemorrhage (symptomatic), re-operation due to bleeding, thrombocytopenia, thrombotic thrombocytopenic purpura.

• Warfarin

Coadministration of Effient and warfarin increases the risk of bleeding.

• Nonsteroidal Anti-Inflammatory Drugs

Coadministration of Effient and NSAIDs (used chronically) may increase the risk of bleeding.

• Opioids

As with other oral P2Y₁₂ inhibitors, coadministration of opioid agonists delay and reduces the absorption of prasugrel’s active metabolite presumably because of slowed gastric emptying. Consider the use of a parenteral anti-platelet agent in acute coronary syndrome patients requiring coadministration of morphine or other opioid agonists.

• Other Concomitant Medications

Effient can be administered with drugs that are inducers or inhibitors of cytochrome P450 enzymes.

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 H₂ blockers.

The common side effect of Prasugrel include the following

• Common

Dizziness, excessive tiredness, pain in the back, arms, or legs, cough.

• Rare

Fever, weakness, paleness, purple patches on the skin, yellowing of the skin or eyes, shortness of breath, slow, fast, or irregular heartbeat, headache, confusion, seizures, slow or difficult speech, sudden weakness of an arm or leg, stomach pain, nausea, vomiting, diarrhea, decreased urination, rash, swelling of the eyes, face, mouth, lips, tongue, throat, arms, hands, feet, ankles, or lower legs.

• Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies of Prasugrel use in pregnant women. Reproductive and developmental toxicology studies in rats and rabbits at doses of up to 30 times the recommended therapeutic exposures in humans (based on plasma exposures to the major circulating human metabolite) revealed no evidence of fetal harm; however, animal studies are not always predictive of human response. Prasugrel should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

• Nursing Mothers

It is not known whether Prasugrel is excreted in human milk; however, metabolites of Prasugrel were found in rat 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.

• Pediatric Use

As per FDA, the safety and effectiveness in pediatric patients have not been established.

• 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 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, the 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.

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.

Management:

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

Pharmacodynamic

Prasugrel is a thienopyridine ADP receptor inhibitor that inhibits platelet aggregation by irreversibly binding to P2Y12 receptors.

Pharmacokinetics

• Absorption

Rapidly absorbed from the GI tract. The time to peak plasma concentration is approximately 30 min.

• Distribution

The Plasma protein binding of Prasugrel is approximately 98%.

• Metabolism and Excretion

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. Via urine (approx. 68%) and feces (approx. 27%). Elimination half-life: Approx 7.4 hr. 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.

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