Product Name
:
SURFENT
Chemical Name
:
Prasugrel ( HCl )
Therapeutic Category
:
Cardiovascular drugs
Pharmacologic Category
:
Antiplatelet Agent - Antiplatelet Agent, Thienopyridine
Pharmaceutical Form
:
Tablets
Composition
:
Prasugrel ( HCl ) 5mg / 10mg
Dosing
 
Dosing: Adult
Acute coronary syndrome managed with PCI: Oral: Loading dose: 60 mg administered promptly (as soon as coronary anatomy is known or before if risk for bleeding is low and need for CABG considered unlikely) and no later than 1 hour after PCI; Maintenance dose: 10 mg once daily (in combination with aspirin 81-325 mg/day). Note: In patients weighing <60 kg, the manufacturer suggests to consider decreasing maintenance dose to 5 mg once daily; however, prospective clinical trial data does not exist to support this recommendation and may place some patients at risk of thrombotic complications (eg, stent thrombosis); consider use of full dose while monitoring closely for bleeding complications or administration of an alternative agent (eg, clopidogrel).
Duration of prasugrel (in combination with aspirin) after stent placement: Premature interruption of therapy may result in stent thrombosis with subsequent fatal and nonfatal MI. With STEMI, prasugrel for at least 12 months regardless of stent type (ie, either bare metal or drug eluting stent) is recommended (Kushner, 2009). With UA/NSTEMI, at least 12 months of prasugrel regardless of stent type is recommended and for up to 15 months unless the risk of bleeding outweighs the benefits (Wright, 2011). In either setting, a duration >15 months may be considered in patients with DES placement (Kushner, 2009; Wright 2011).

Dosing: Geriatric

Refer to adult dosing. Patients ≥75 years: Use not recommended; may be considered in high-risk situations (eg, patients with diabetes or history of MI).

Dosing: Renal Impairment

No dosage adjustment necessary.

Dosing: Hepatic Impairment

No dosage adjustment necessary for mild-to-moderate hepatic impairment; use in severe hepatic impairment has not been evaluated.
Use
 
Reduces rate of thrombotic cardiovascular events (eg, stent thrombosis) in patients who are to be managed with percutaneous coronary intervention (PCI) for unstable angina, non-ST-segment elevation MI, or ST-elevation MI (STEMI)
Adverse Reactions
 
As with all drugs which may affect hemostasis, bleeding is associated with prasugrel. Hemorrhage may occur at virtually any site. Risk is dependent on multiple variables, including patient susceptibility and concurrent use of multiple agents which alter hemostasis.
2% to 10%:
Cardiovascular: Hypertension (8%), hypotension (4%), atrial fibrillation (3%), bradycardia (3%), noncardiac chest pain (3%), peripheral edema (3%)
Central nervous system: Headache (6%), dizziness (4%), fatigue (4%), fever (3%), extremity pain (3%)
Dermatologic: Rash (3%)
Endocrine & metabolic: Hypercholesterolemia/hyperlipidemia (7%)
Gastrointestinal: Nausea (5%), diarrhea (2%), gastrointestinal hemorrhage (2%)
Hematologic: Leukopenia (3%), anemia (2%)
Neuromuscular & skeletal: Back pain (5%)
Respiratory: Epistaxis (6%), dyspnea (5%), cough (4%)
<2% (Limited to important or life-threatening): Allergic reaction, angioedema, hematoma, hemoptysis, hemorrhage (postprocedural, retinal, retroperitoneal), liver function (abnormal), thrombocytopenia
Contraindications
 
Active pathological bleeding such as peptic ulcer disease (PUD) or intracranial hemorrhage; history of transient ischemic attack (TIA) or stroke
Warnings / Precautions Drug
 
Boxed warnings:
• Bleeding: See “Concerns related to adverse effects
• Coronary artery bypass graft surgery: See “Other warnings/precautions”
• Elderly: See “Special populations”
Concerns related to adverse effects:
• Bleeding: [U.S. Boxed Warning]: May cause significant or fatal bleeding. Use is contraindicated in patients with active pathological bleeding or history of TIA or stroke. Additional risk factors for bleeding include age ≥75 years, propensity to bleed (eg, recent trauma or surgery, recent or recurrent GI bleeding, active PUD, severe hepatic impairment), body weight <60 kg, CABG or other surgical procedure, concomitant use of medications that increase risk of bleeding (eg, warfarin, NSAIDs). Bleeding should be suspected if patient becomes hypotensive after undergoing recent coronary angiography, PCI, CABG, or other surgical procedure even if overt signs of bleeding do not exist; if possible, do not discontinue prasugrel. Management of bleeding episodes includes the use of PRBCs and platelet transfusion.
• Thrombotic thrombocytopenic purpura (TTP): Cases of thrombotic thrombocytopenic purpura (usually occurring within the first 2 weeks of therapy), resulting in some fatalities, have been reported with other thienopyridines; urgent plasmapheresis is required.
Disease-related concerns:
• Hepatic impairment: No dosage adjustment is necessary in patients with mild-to-moderate hepatic impairment; use with caution in patients with severe hepatic impairment (patients not studied and may be at higher risk of bleeding).
• Renal impairment: No dosage adjustment is necessary; use with caution in patients with end-stage renal disease (experience is limited).
Concurrent drug therapy issues:
• Anticoagulants: Use with caution in patients receiving oral anticoagulants (eg, warfarin); bleeding risk is increased.
• NSAIDs: Use with caution in patients chronically receiving NSAIDs; bleeding risk is increased.
• Fibrinolytics: Use with caution in patients receiving fibrinolytics; bleeding risk is increased.
Special populations:
• Elderly: [U.S. Boxed Warning]: In patients ≥75 years of age, use is not recommended due to increased risk of fatal and intracranial bleeding and uncertain benefit; use may be considered in high-risk situations (eg, patients with diabetes or history of MI).
• Low-weight patients: In patients weighing <60 kg, risk of bleeding increased; consider lower maintenance dose.
Other warnings/precautions:
• Coronary artery bypass graft surgery: [U.S. Boxed Warning]: Discontinue ≥7 days prior to coronary artery bypass graft (CABG) surgery; increased risk of bleeding; do not initiate therapy in patients likely to undergo CABG.
• Drug discontinuation: Discontinue therapy for active bleeding, elective surgery, stroke, or TIA; reinitiate therapy as soon as possible unless patient suffers stroke or TIA where subsequent use is contraindicated; if possible, manage bleeding without discontinuing therapy since premature discontinuation of treatment may cause increased risk for cardiac adverse events; lapses in treatment should be avoided.
Interactions
 
Anticoagulants: Antiplatelet Agents may enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Antiplatelet Agents: May enhance the anticoagulant effect of other Antiplatelet Agents. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease serum concentrations of the active metabolite(s) of Prasugrel. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of Antiplatelet Agents. An increased risk of bleeding may occur. Nonsteroidal Anti-Inflammatory Agents may diminish the cardioprotective effect of Antiplatelet Agents. This interaction is likely specific to aspirin, and not to other antiplatelet agents. Risk C: Monitor therapy
Ranitidine: May decrease serum concentrations of the active metabolite(s) of Prasugrel. Risk C: Monitor therapy
Thrombolytic Agents: Antiplatelet Agents may enhance the anticoagulant effect of Thrombolytic Agents. Risk C: Monitor therapy
Pregnancy
 
B
Pregnancy Implications
There are no adequate and well-controlled studies in pregnant women. Use during pregnancy only if the benefits justify the risk to the fetus.
Lactation
 
Excretion in breast milk unknown/consider risk:benefit
Mechanism of Action
 
Prasugrel 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. Platelet aggregation returns to baseline within 5-9 days of discontinuation.
Pharmacodynamics / Kinetics
 
Onset of action: Inhibition of platelet aggregation (IPA): Dose dependent: 60 mg loading dose: <30 minutes; median time to reach 20% IPA: 30 minutes (Brandt, 2007)
Peak effect: Time to maximal IPA: Dose-dependent: Note: Degree of IPA based on adenosine diphosphate (ADP) concentration used during light aggregometry: 60 mg loading dose: Occurs 4 hours post administration; mean IPA (ADP 5 μmol/L): 78.8%: mean IPA (ADP 20 micromole/L): 84.1%
Duration of effect: >3 days; platelet aggregation gradually returns to baseline values over 5-9 days after discontinuation; reflective of new platelet production
Absorption: Rapid; ≥79%
Distribution: Vd: 44-68 L
Protein binding: Active metabolite: ~98%
Metabolism: Rapid intestinal and serum metabolism via esterase-mediated hydrolysis to a thiolactone (inactive), which is then converted, via CYP450-mediated (primarily CYP3A4 and CYP2B6) oxidation, to an active metabolite (R-138727)
Half-life elimination: Active metabolite: ~7 hours (range 2-15 hours)
Time to peak, plasma: Active metabolite: ~30 minutes (peak plasma levels begin to decrease at ~24 hours); with high-fat/high-calorie meal: 1.5 hours
Excretion: Urine (~68% inactive metabolites); feces (27% inactive metabolites