Side Effects of Effient (prasugrel)

Effient (prasugrel) is a thienopyridine anti-platelet drug used to reduce blood clots and the rate of thrombotic cardiovascular events (including stent thrombosis) in patients with acute coronary syndrome who are to be managed with percutaneous coronary intervention as follows:

• patients with unstable angina or non-ST-elevation myocardial infarction (NSTEMI), and
• patients with ST-elevation myocardial infarction (STEMI) when managed with primary or delayed PCI.

Effient has been shown to reduce the rate of a combined endpoint of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke compared to clopidogrel.

Common side effects of Effient include

• an increased risk of bleeding,
• headache,
• dizziness,
• back pain,
• minor chest pain,
• tired feeling,
• fatigue,
• nausea,
• cough,
• high or low blood pressure,
• shortness of breath,
• slow heart rate,
• rash,
• fever,
• swelling or pain in the extremities, and diarrhea.

Serious side effects of Effient include

• thrombotic thrombocytopenic purpura and
• hypersensitivity including angioedema.

Drug interactions of Effient include warfarin, because coadministration of Effient and warfarin increases the risk of bleeding. Coadministration of Effient and nonsteroidal anti-inflammatory drugs (NSAIDs) (used chronically) may increase the risk of bleeding.

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

It is unknown if Effient is excreted in breast milk. Because many drugs are excreted in human milk, Effient should be used during breastfeeding only if the potential benefit to the mother justifies the potential risk to the nursing infant.

General Risk of Bleeding

Thienopyridines, including Effient, increase the risk of bleeding. With the dosing regimens used in TRITON-TIMI 38, TIMI (Thrombolysis in Myocardial Infarction) Major (clinically overt bleeding associated with a fall in hemoglobin ≥ 5 g/dL, or intracranial hemorrhage) and TIMI Minor (overt bleeding associated with a fall in hemoglobin of ≥ 3 g/dL but < 5 g/dL) bleeding events were more common on Effient than on clopidogrel.

Do not use Effient in patients with active bleeding, prior TIA or stroke. Other risk factors for bleeding are:

• Age ≥ 75 years. Because of the risk of bleeding (including fatal bleeding) and uncertain effectiveness in patients ≥75 years of age, use of Effient 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.
• CABG or other surgical procedure.
• Body weight < 60 kg. Consider a lower (5 mg) maintenance dose.
• Propensity to bleed (e.g., recent trauma, recent surgery, recent or recurrent gastrointestinal (GI) bleeding, active peptic ulcer disease, or severe hepatic impairment).
• Medications that increase the risk of bleeding (e.g., oral anticoagulants, chronic use of non-steroidal anti-inflammatory drugs [NSAIDs], and fibrinolytic agents). Aspirin and heparin were commonly used in TRITON-TIMI 38.

Thienopyridines inhibit platelet aggregation for the lifetime of the platelet (7-10 days), so withholding a dose will not be useful in managing a bleeding event or the risk of bleeding associated with an invasive procedure.

Because the half-life of prasugrel’s active metabolite is short relative to the lifetime of the platelet, it may be possible to restore hemostasis by administering exogenous platelets; however, platelet transfusions within 6 hours of the loading dose or 4 hours of the maintenance dose may be less effective.

Coronary Artery Bypass Graft Surgery-Related Bleeding

• The risk of bleeding is increased in patients receiving Effient who undergo CABG.
• If possible, Effient 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 Effient group and 4.5% in the clopidogrel group.
• The higher risk for bleeding events in patients treated with Effient persisted up to 7 days from the most recent dose of 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 Effient 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 Effient in patients likely to undergo urgent CABG.
  CABG-related bleeding may be treated with 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 Effient

• Discontinue thienopyridines, including Effient, 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 a 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 Effient. 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.

Hypersensitivity Including Angioedema

• Hypersensitivity including angioedema has been reported in patients receiving Effient, including patients with a history of hypersensitivity reaction to other thienopyridines.

The following serious adverse reactions are also discussed elsewhere in the labeling:

• Bleeding
• Thrombotic Thrombocytopenic Purpura
• Hypersensitivity Including Angioedema

Clinical Trials Experience

• Safety in patients with ACS undergoing PCI was evaluated in a clopidogrel-controlled study, TRITON-TIMI 38, in which 6741 patients were treated with Effient (60-mg loading dose and 10-mg once daily) for a median of 14.5 months (5802 patients were treated for over 6 months; 4136 patients were treated for more than 1 year).
• The population treated with Effient was 27 to 96 years of age, 25% female, and 92% Caucasian.
• All patients in the TRITON-TIMI 38 study were to receive aspirin.
• The dose of clopidogrel in this study was a 300-mg loading dose and 75-mg once daily.
• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with the rates observed in other clinical trials of another drug and may not reflect the rates observed in practice.

Drug Discontinuation

• The rate of study drug discontinuation because of adverse reactions was 7.2% for Effient and 6.3% for clopidogrel. Bleeding was the most common adverse reaction leading to study drug discontinuation for both drugs (2.5% for Effient and 1.4% for clopidogrel).

Bleeding

Bleeding Unrelated To CABG Surgery

In TRITON-TIMI 38, overall rates of TIMI Major or Minor bleeding adverse reactions unrelated to coronary artery bypass graft surgery (CABG) were significantly higher on Effient than on clopidogrel, as shown in Table 1.

Table 1: Non-CABG-Related Bleeding^a (TRITON-TIMI 38)

Figure 1 demonstrates non-CABG related TIMI Major or Minor bleeding. The bleeding rate is highest initially, as shown in Figure 1 (inset: Days 0 to 7).

Bleeding By Weight And Age

In TRITON-TIMI 38, non-CABG-related TIMI Major or Minor bleeding rates in patients with the risk factors of age ≥75 years and weight <60 kg are shown in Table 2.

Table 2: Bleeding Rates for Non-CABG-Related Bleeding by Weight and Age (TRITON-TIMI 38)

Bleeding Related To CABG

• In TRITON-TIMI 38, 437 patients who received a thienopyridine underwent CABG during the course of the study. The rate of CABG-related TIMI Major or Minor bleeding was 14.1% for the Effient group and 4.5% in the clopidogrel group (see Table 3).
• The higher risk for bleeding adverse reactions in patients treated with Effient persisted up to 7 days from the most recent dose of study drug.

Table 3: CABG-Related Bleeding^a (TRITON-TIMI 38)

Bleeding Reported As Adverse Reactions

Hemorrhagic events reported as adverse reactions in TRITON-TIMI 38 were, for Effient and clopidogrel, respectively:

• epistaxis (6.2%, 3.3%),
• gastrointestinal hemorrhage (1.5%, 1.0%),
• hemoptysis (0.6%, 0.5%),
• subcutaneous hematoma (0.5%, 0.2%),
• post-procedural hemorrhage (0.5%, 0.2%),
• retroperitoneal hemorrhage (0.3%, 0.2%),
• pericardial effusion/hemorrhage/tamponade (0.3%, 0.2%), and
• retinal hemorrhage (0.0%, 0.1%).

Malignancies

• During TRITON-TIMI 38, newly-diagnosed malignancies were reported in 1.6% and 1.2% of patients treated with prasugrel and clopidogrel, respectively.
• The sites contributing to the differences were primarily colon and lung. In another Phase 3 clinical study of ACS patients not undergoing PCI, in which data for malignancies were prospectively collected, newly-diagnosed malignancies were reported in 1.8% and 1.7% of patients treated with prasugrel and clopidogrel, respectively.
• The site of malignancies was balanced between treatment groups except for colorectal malignancies.
• The rates of colorectal malignancies were 0.3% prasugrel, 0.1% clopidogrel and most were detected during investigation of GI bleed or anemia.
• It is unclear if these observations are causally-related, are the result of increased detection because of bleeding, or are random occurrences.

Other Adverse Events

• In TRITON-TIMI 38, common and other important non-hemorrhagic adverse events were, for Effient and clopidogrel, respectively:
  • severe thrombocytopenia (0.06%, 0.04%),
  • anemia (2.2%, 2.0%),
  • abnormal hepatic function (0.22%, 0.27%),
  • allergic reactions (0.36%, 0.36%), and
  • angioedema (0.06%, 0.04%).
• Table 4 summarizes the adverse events reported by at least 2.5% of patients.

Table 4: Non-Hemorrhagic Treatment Emergent Adverse Events Reported by at Least 2.5% of Patients in Either Group

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Effient. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Blood and lymphatic system disorders - Thrombocytopenia, Thrombotic thrombocytopenic purpura (TTP)
• Immune system disorders - Hypersensitivity reactions including anaphylaxis

Warfarin

• Coadministration of Effient and warfarin increases the risk of bleeding.

Non-Steroidal Anti-Inflammatory Drugs

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

Opioids

• As with other oral P2Y₁₂ inhibitors, co-administration of opioid agonists delay and reduce 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.