Prasugrel

Prasugrel is part of the drug class:

• Platelet aggregation inhibitors excl. heparin

Medicines can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of prasugrel there are no specific foods that you must exclude from your diet when receiving prasugrel.

Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Prasugrel is usually given together with aspirin. Follow your doctor's instructions about how much aspirin to take and for how long.

Prasugrel can be taken with or without food.

Because prasugrel keeps your blood from coagulating (clotting) to prevent unwanted blood clots, this medicine can also make it easier for you to bleed, even from a minor injury such as a fall or a bump on the head. Contact your doctor or seek emergency medical attention if you fall or hit your head, or have any bleeding that will not stop.

If you need surgery or dental work, tell the surgeon or dentist ahead of time that you are using prasugrel. You may need to stop using the medicine for a short time before surgery to prevent excessive bleeding.

Do not stop taking prasugrel unless your doctor tells you to. If you stop taking this medicine too soon you could have life-threatening medical problems such as a blood clot or a heart attack.

Store at room temperature away from moisture and heat. Keep the tablets in their original container, along with the packet or canister of moisture-absorbing preservative. Keep the bottle tightly closed when not in use.

Contraindications

• Active pathological bleeding (e.g., peptic ulcer, intracranial hemorrhage).1

• History of stroke or TIA.1

Warnings/Precautions

Warnings

Risk of serious, sometimes fatal bleeding.1 2 6 10 Major and minor bleeding events, including life-threatening and fatal bleeding reported more frequently in patients receiving prasugrel than those who received clopidogrel in pivotal clinical study.1 2 6 10

Greater risk of bleeding observed in patients ≥75 years of age, those weighing < 60 kg, and those with prior stroke or TIA.1 2 Additional risk factors include recent trauma, recent surgery (e.g., CABG), recent or recurrent GI bleeding, active peptic ulcer disease, severe hepatic impairment, and concurrent use of drugs that increase risk of bleeding (e.g., oral anticoagulants, NSAIAs, thrombolytic agents).1

Do not use in patients who are actively bleeding and/or who have a history of stroke or TIA.1 17 18 Not recommended in patients likely to undergo emergent CABG.1 (See Coronary Artery Bypass Grafting Surgery under Cautions.)

Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, PCI, CABG, or any other surgical procedure, even if there are no overt manifestations of bleeding.1

If possible, manage bleeding without discontinuing prasugrel; premature discontinuance is associated with an increased risk of subsequent cardiovascular events.1 (See Discontinuance of Therapy under Cautions.) May treat bleeding with platelet transfusions; however, transfusions within 6 hours of a loading dose or 4 hours of a maintenance dose may be less effective.1 Withholding a dose not likely to resolve or prevent bleeding.1

Higher incidence of stroke (thrombotic and hemorrhagic) and no evidence of clinical benefit reported among patients with a history of stroke or TIA receiving prasugrel compared with clopidogrel in TRITON-TIMI 38 study.1 2 Use not recommended in patients with a history of stroke or TIA; in general, discontinue prasugrel in those who experience such cerebrovascular events during therapy.1 18

Increased risk of bleeding in patients who undergo CABG surgery.1 2 (See Bleeding under Cautions.) CABG-related major and minor bleeding events occurred substantially more frequently in patients who received prasugrel versus clopidogrel in pivotal clinical study.1 2

Discontinue prasugrel at least 7 days prior to CABG.1 Do not initiate in patients who are likely to undergo urgent CABG.1 May treat CABG-related bleeding with blood product transfusions (e.g., packed RBCs, platelets).1

Discontinue prasugrel in patients who develop active bleeding, stroke, or TIA during therapy.1 Temporarily discontinue drug at least 7 days prior to elective surgery.1 70

In general, avoid premature discontinuance of thienopyridine treatment because of the subsequent increased risk of ischemic complications.1 6 45

Premature discontinuance of antiplatelet therapy in patients with intracoronary stents, particularly drug-eluting stents, associated with increased risk of stent thrombosis, MI, and/or death.43 44 45 46 47 48 49 54 At least 12 months of dual-drug antiplatelet therapy is recommended following placement of coronary artery stent (bare-metal or drug-eluting).993 994 1010 An even longer duration (up to 30 months) of dual-drug antiplatelet therapy may be beneficial in reducing stent thrombosis and other cardiovascular events; however, such prolonged therapy was associated with increased bleeding and an unexpected finding of increased all-cause mortality.1019 1020 FDA continuing to evaluate these findings.1019

Advise patients to never discontinue such therapy without first consulting their prescribing clinician, even if instructed to do so by another health-care professional.1 45 (See Advice to Patients.) If prasugrel must be temporarily discontinued because of an adverse event, reinstitute therapy as soon as possible.1

Reported rarely with use of other thienopyridine derivatives, sometimes after brief exposure (<2 weeks); potentially fatal.1 31 Characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes on peripheral blood smear), neurologic findings, renal dysfunction, and fever.1 31 Requires urgent treatment (e.g., plasmapheresis).1

Specific Populations

Category B.1

Distributed into milk in rats; not known whether distributed into human milk.1 Use during nursing only if potential benefits outweigh risks.1

Safety and efficacy not established in pediatric patients.1

Geriatric patients, particularly those ≥75 years of age, appear to be at greater risk of bleeding (including fatal bleeding) with prasugrel therapy compared with younger patients.1 Fatal bleeding and symptomatic intracranial hemorrhage occurred more often in patients ≥75 years of age receiving prasugrel compared with that in clopidogrel-treated patients in a large clinical study.1

In general, avoid use in patients ≥75 years of age, but may consider use in certain geriatric patients with high-risk conditions (e.g., diabetes, previous MI) in whom a greater net clinical benefit has been demonstrated.1 5 18 70

In patients with mild to moderate hepatic impairment (Child-Pugh class A or B), inhibition of platelet aggregation was similar to that of healthy individuals.1 Not specifically studied in patients with severe hepatic impairment; such patients generally are at higher risk of bleeding.1

Inhibition of platelet aggregation similar in patients with moderate renal impairment (Clcr of 30–50 mL/minute) and healthy individuals.1

Patients with low body weight (< 60 kg) have increased exposure to the active metabolite of prasugrel and appear to be at increased risk of bleeding.1 (See Bleeding under Cautions.)

Common Adverse Effects

Bleeding, including life-threatening and fatal bleeding events.1 2

Metabolized principally by CYP3A4 and CYP2B6; to a lesser extent by CYP2C9 and CYP2C19.1 13 14 22 23 30 Not likely to inhibit CYP isoenzymes 1A2, 2C9, 2C19, 2D6 or 3A4 nor induce isoenzymes 1A2 or 3A4.1 13 Weak inhibitor of CYP2B6.1 25

Does not inhibit P-glycoprotein (Pgp) transport system.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Clinically important interactions mediated by CYP enzymes unlikely.1 13 25

CYP3A4 inhibitors: No substantial effect on systemic exposure or antiplatelet activity of prasugrel’s active metabolite.1 22

CYP3A4 inducers: Not expected to substantially alter pharmacokinetic or pharmacodynamic response to prasugrel.1 25

Drugs metabolized by CYP2B6: Potential for increased plasma concentrations and exposure to concomitantly administered drug; however, clinically important interactions not expected because of weak inhibition of CYP2B6.1 25

Other Antiplatelet or Antithrombotic Agents

Manufacturer states that prasugrel may be administered concomitantly with aspirin, heparin, and GP IIb/IIIa-receptor inhibitors.1 While evidence from drug interaction studies with other antiplatelet or antithrombotic agents generally is lacking, increased risk of bleeding likely with concomitant use of such agents.13 14

Specific Drugs or Foods

Use prasugrel as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take with or without food.
• To gain the most benefit, do not miss doses.
• Keep taking this medicine as you have been told by your doctor or other health care provider, even if you feel well.
• Do not split or break tablet.
• Take aspirin as you have been told by your doctor.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses unless told to do so by your doctor.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of bleeding like throwing up blood or throw up that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; vaginal bleeding that is not normal; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop.
• Trouble swallowing.
• Chest pain or pressure.
• Dizziness or passing out.
• Very bad headache.
• Purple patches on the skin or mouth.
• Very bad and sometimes deadly blood problems like thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) have happened with prasugrel in some people. Call your doctor right away if you feel very tired or weak or have any bruising or bleeding; dark urine or yellow skin or eyes; pale skin; change in the amount of urine passed; change in eyesight; change in strength on 1 side is greater than the other, trouble speaking or thinking, or change in balance; or fever.

• Store at room temperature.
• Store in the original container. Do not take out the antimoisture cube or packet.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

(PRA soo grel)

Duration of effect: Platelet aggregation gradually returns to baseline values over 5-9 days after discontinuation; reflective of new platelet production

Half-Life Elimination

Half-life elimination: Active metabolite: ~7 hours (range: 2-15 hours)

Protein Binding

Active metabolite: ~98%

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

Acute coronary syndrome (ACS): Oral:

Percutaneous coronary intervention (PCI) for ACS: Loading dose: 60 mg administered promptly (as soon as coronary anatomy is known) and no later than 1 hour after PCI; Maintenance dose: 10 mg once daily (in combination with aspirin) (ACCF/AHA [O’Gara, 2013]; AHA/ACC [Amsterdam 2014]; Levine 2011). For patients with STEMI, a loading dose may also be administered if PCI is performed >24 hours after treatment with a fibrin-specific thrombolytic (ie, alteplase, reteplase, tenecteplase) (ACCF/AHA [O’Gara, 2013]).

Maintenance dosing in low body weight (ie, <60 kg) individuals: Due to a higher incidence of bleeding in patients weighing <60 kg, a maintenance dose of 5 mg once daily may be considered. In aspirin-treated patients weighing <60 kg (mean: 56.4 ± 3.7 kg) with stable coronary artery disease, the use of prasugrel 5 mg once daily was shown to reduce platelet reactivity to a similar extent as prasugrel 10 mg administered once daily to patients >60 kg (mean: 84.7 ± 14.9 kg); clinical events were not evaluated (Erlinge 2012). In patients with ACS (medically managed) treated with aspirin, a 5 mg daily maintenance dose (after a 30 mg loading dose) in patients <60 kg did not demonstrate a significant difference in the composite primary end point of death from cardiovascular causes, MI, or stroke compared to patients >60 kg treated with a 10 mg maintenance dose; bleeding risk was not increased (Roe 2012).

Duration of prasugrel (in combination with aspirin) after stent placement: Premature interruption of therapy may result in stent thrombosis, MI, and death. According to the ACC/AHA Duration of Dual Antiplatelet Therapy (DAPT) guidelines, at least 12 months of a P2Y12 inhibitor (eg, prasugrel) is recommended for those with ACS receiving either stent type (bare metal [BMS] or drug eluting stent [DES]). The DAPT score may be useful in determining whether to prolong or extend DAPT in patients with stent placement (Yeh 2016). In addition, in patients with DES placement with a high risk of bleeding or significant overt bleeding on DAPT, it may be reasonable to discontinue prasugrel after 6 months of therapy instead (ACC/AHA [Levine 2016]).

Conversion from clopidogrel to prasugrel: Beginning 24 hours after the last clopidogrel dose (loading or maintenance), may initiate prasugrel 10 mg once daily or a 60 mg loading dose followed in 24 hours with 10 mg once daily (Angiolillo 2010; Payne 2008; Wiviott 2007).

No dosage adjustment necessary; use caution in moderate to severe impairment (patients are generally at higher risk of bleeding).

Hemodialysis: Not dialyzable (NCS/SCCM [Frontera 2016])

Prasugrel can cause significant, sometimes fatal, bleeding. Do not use prasugrel in patients with active pathological bleeding or a history of transient ischemic attack (TIA) or stroke.

In patients ≥75 years, prasugrel is generally not recommended because of the increased risk of fatal and intracranial bleeding and uncertain benefit, except in high-risk situations (patients with diabetes or a history of myocardial infarction [MI]) in which its effect appears to be greater and its use may be considered.

Do not start prasugrel in patients likely to undergo urgent coronary artery bypass graft (CABG) surgery. When possible, discontinue prasugrel at least 7 days prior to any surgery.

Additional risk factors for bleeding include body weight <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 nonsteroidal anti-inflammatory drugs [NSAIDs]).

Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (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 acute coronary syndrome (ACS), increases the risk of subsequent cardiovascular events.

Adverse events have not been observed in animal reproduction studies. Information related to use during pregnancy is limited (Tello-Montoliu, 2012).