Effient Drug Information

Acute Coronary Syndrome Effient ® is indicated 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 (UA) or non-ST-elevation myocardial infarction (NSTEMI). 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 (MI), or nonfatal stroke compared to clopidogrel. The difference between treatments was driven predominantly by MI, with no difference on strokes and little difference on CV death .

Initiate Effient treatment as a single 60 mg oral loading dose and then continue at 10 mg orally once daily. Patients taking Effient should also take aspirin (75 mg to 325 mg) daily . Effient may be administered with or without food . Initiate treatment with a single 60 mg oral loading dose. Continue at 10 mg once daily with or without food.

Consider 5 mg once daily for patients <60 kg. Patients should also take aspirin (75 mg to 325 mg) daily. Timing of Loading Dose In the clinical trial that established the efficacy and safety of Effient, the loading dose of Effient was not administered until coronary anatomy was established in UA/NSTEMI patients and in STEMI patients presenting more than 12 hours after symptom onset.

In STEMI patients presenting within 12 hours of symptom onset, the loading dose of Effient was administered at the time of diagnosis, although most received Effient at the time of PCI . For the small fraction of patients that required urgent CABG after treatment with Effient, the risk of significant bleeding was substantial. Although it is generally recommended that antiplatelet therapy be administered promptly in the management of ACS because many cardiovascular events occur within hours of initial presentation, in a trial of 4033 NSTEMI patients, no clear benefit was observed when Effient loading dose was administered prior to diagnostic coronary angiography compared to at the time of PCI; however, risk of bleeding was increased with early administration in patients undergoing PCI or early CABG. Dosing in Low Weight Patients Compared to patients weighing ≥60 kg, patients weighing <60 kg have an increased exposure to the active metabolite of prasugrel and an increased risk of bleeding on a 10 mg once daily maintenance dose. Consider lowering the maintenance dose to 5 mg in patients <60 kg.

The effectiveness and safety of the 5 mg dose have not been prospectively studied .

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 Patients may be counted in more than one row. (TRITON-TIMI 38) Effient (%) (N=6741) Clopidogrel (%) (N=6716) TIMI Major or Minor bleeding 4.5

TIMI Major bleeding See 5.1 for definition. 2.2 1.7 Life-threatening 1.3 0.8

Fatal 0.3

Symptomatic intracranial hemorrhage (ICH) 0.3 0.3 Requiring inotropes 0.3 0.1 Requiring surgical

intervention 0.3

Requiring transfusion (≥4 units) 0.7 0.5

TIMI Minor bleeding 2.4

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) Major/Minor Fatal Effient 10 mg Effient maintenance dose (%) Clopidogrel 75 mg clopidogrel maintenance dose (%) Effient (%) Clopidogrel (%) Weight <60 kg (N=308 Effient, N=356 clopidogrel) 10.1 6.5 0.0

Weight ≥60 kg (N=6373 Effient, N=6299 clopidogrel) 4.2 3.3 0.3 0.1 Age

<75 years (N=5850 Effient, N=5822 clopidogrel) 3.8 2.9 0.2

Age ≥75 years (N=891 Effient, N=894 clopidogrel) 9.0 6.9 1.0 0.1 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 Patients may be counted in more than one row. (TRITON-TIMI 38) Effient (%) (N=213) Clopidogrel (%) (N=224) TIMI Major or Minor bleeding 14.1

TIMI Major bleeding 11.3 3.6 Fatal 0.9 0 Reoperation 3.8 0.5 Transfusion

of ≥5 units 6.6

Intracranial hemorrhage 0 0

TIMI Minor bleeding 2.8

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 nonhemorrhagic 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 Effient (%) (N=6741) Clopidogrel (%) (N=6716) Hypertension 7.5

Nausea 4.6 4.3 Dizziness 4.1 4.6 Cough 3.9 4.1 Hypotension 3.9 3.8

Fatigue 3.7

Noncardiac chest pain 3.1 3.5 Atrial fibrillation 2.9 3.1 Bradycardia 2.9 2.4

Leukopenia (<4 × 10 9 WBC WBC = white blood cell /L) 2.8

Rash 2.8 2.4 Pyrexia 2.7 2.2 Peripheral edema 2.7 3.0 Pain in

extremity 2.6

Diarrhea 2.3 2.6 6.2 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

Nonsteroidal Anti-Inflammatory Drugs Coadministration of Effient and

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

Opioids As with other oral P2Y 12 inhibitors, coadministration 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 H 2 blockers .

Pregnancy Risk Summary There are no data with Effient use in pregnant women to inform a drug-associated risk. No structural malformations were observed in animal reproductive and developmental toxicology studies when rats and rabbits were administered prasugrel during organogenesis at doses of up to 30 times the recommended therapeutic exposures in humans. Due to the mechanism of action of Effient, and the associated identified risk of bleeding, consider the benefits and risks of Effient and possible risks to the fetus when prescribing Effient to a pregnant woman . The background risk of major birth defects and miscarriage for the indicated population is unknown.

The background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies. Data Animal Data In embryo-fetal developmental toxicology studies, pregnant rats and rabbits received prasugrel at maternally toxic oral doses equivalent to more than 40 times the human exposure. A slight decrease in fetal body weight was observed, but there were no structural malformations in either species.

In prenatal and postnatal rat studies, maternal treatment with prasugrel had no effect on the behavioral or reproductive development of the offspring at doses greater than 150 times the human exposure.

Pediatric Use Safety and effectiveness in pediatric patients have not been established. In a randomized, placebo-controlled trial, the primary objective of reducing the rate of vaso-occlusive crisis (painful crisis or acute chest syndrome) in pediatric patients, aged 2 to less than 18 years, with sickle cell anemia was not met.

Active Bleeding Effient is contraindicated in patients with active pathological bleeding such

as peptic ulcer or intracranial hemorrhage (ICH) .

Prior Transient Ischemic Attack or Stroke Effient is contraindicated in patients with

a history of prior transient ischemic attack (TIA) or stroke. In TRITON-TIMI 38 ( TR ial to Assess I mprovement in T herapeutic Outcomes by O ptimizing Platelet Inhibitio N with Prasugrel), patients with a history of TIA or ischemic stroke (>3 months prior to enrollment) had a higher rate of stroke on Effient (6.5%; of which 4.2% were thrombotic stroke and 2.3% were intracranial hemorrhage ) 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 Effient 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 Effient generally should have therapy discontinued .

Hypersensitivity Effient is contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to prasugrel

or any component of the product .

Signs and 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.

Recommendations about Specific Treatment Platelet transfusion may restore clotting ability.

The prasugrel active metabolite is not likely to be removed by dialysis.