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 [see Drug Interactions (7.4) and Clinical Pharmacology (12.3)]. Effient may be administered with or without food [see Clinical Pharmacology (12.3) and Clinical Studies (14)].

Effient 5-mg is available as a yellow, elongated hexagonal, film-coated, non-scored tablet debossed with "5121" on one side and 3 parallel arched lines followed by a "5" on the other side.

Effient 10-mg is available as a beige, elongated hexagonal, film-coated, non-scored tablet debossed with "5123" on one side and 3 parallel arched lines followed by a "10" on the other side.

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

• Bleeding [see Boxed Warning and Warnings and Precautions (5.1, 5.2)]
• Thrombotic Thrombocytopenic Purpura [see Warnings and Precautions (5.4)]
• Hypersensitivity Including Angioedema [see Warnings and Precautions (5.5)]

Effient contains prasugrel, a thienopyridine class inhibitor of platelet activation and aggregation mediated by the P2Y12 ADP receptor. Effient is formulated as the hydrochloride salt, a racemate, which is chemically designated as 5-[(1RS)-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate hydrochloride. Prasugrel hydrochloride has the empirical formula C20H20FNO3S•HCl representing a molecular weight of 409.90. The chemical structure of prasugrel hydrochloride is:

Prasugrel hydrochloride is a white to practically white solid. It is soluble at pH 2, slightly soluble at pH 3 to 4, and practically insoluble at pH 6 to 7.5. It also dissolves freely in methanol and is slightly soluble in 1- and 2-propanol and acetone. It is practically insoluble in diethyl ether and ethyl acetate.

Effient is available for oral administration as 5-mg or 10-mg elongated hexagonal, film-coated, non-scored tablets, debossed on each side. Each yellow 5-mg tablet is manufactured with 5.49 mg prasugrel hydrochloride, equivalent to 5-mg prasugrel and each beige 10-mg tablet with 10.98 mg prasugrel hydrochloride, equivalent to 10-mg of prasugrel.

Other ingredients include mannitol, hypromellose, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, sucrose stearate, and glyceryl behenate. The color coatings contain lactose, hypromellose, titanium dioxide, triacetin, iron oxide yellow, and iron oxide red (only in Effient 10-mg tablet).

The clinical evidence for the effectiveness of Effient is derived from the TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel) study, a 13,608-patient, multicenter, international, randomized, double-blind, parallel-group study comparing Effient to a regimen of clopidogrel, each added to aspirin and other standard therapy, in patients with ACS (UA, NSTEMI, or STEMI) who were to be managed with PCI. Randomization was stratified for UA/NSTEMI and STEMI.

Patients with UA/NSTEMI presenting within 72 hours of symptom onset were to be randomized after undergoing coronary angiography. Patients with STEMI presenting within 12 hours of symptom onset could be randomized prior to coronary angiography. Patients with STEMI presenting between 12 hours and 14 days of symptom onset were to be randomized after undergoing coronary angiography. Patients underwent PCI, and for both UA/NSTEMI and STEMI patients, the loading dose was to be administered anytime between randomization and 1 hour after the patient left the catheterization lab. If patients with STEMI were treated with thrombolytic therapy, randomization could not occur until at least 24 hours (for tenecteplase, reteplase, or alteplase) or 48 hours (for streptokinase) after the thrombolytic was given.

Patients were randomized to receive Effient (60-mg loading dose followed by 10-mg once daily) or clopidogrel (300-mg loading dose followed by 75-mg once daily), with administration and follow-up for a minimum of 6 months (actual median 14.5 months). Patients also received aspirin (75-mg to 325-mg once daily). Other therapies, such as heparin and intravenous glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors, were administered at the discretion of the treating physician. Oral anticoagulants, other platelet inhibitors, and chronic NSAIDs were not allowed.

The primary outcome measure was the composite of cardiovascular death, nonfatal MI, or nonfatal stroke in the UA/NSTEMI population. Success in this group allowed analysis of the same endpoint in the overall ACS and STEMI populations. Nonfatal MIs included both MIs detected solely through analysis of creatine kinase muscle-brain (CK-MB) changes and clinically apparent (investigator-reported) MIs.

The patient population was 92% Caucasian, 26% female, and 39% ≥65 years of age. The median time from symptom onset to study drug administration was 7 hours for patients with STEMI and 30 hours for patients with UA/NSTEMI. Approximately 99% of patients underwent PCI. The study drug was administered after the first coronary guidewire was placed in approximately 75% of patients.

Effient significantly reduced total endpoint events compared to clopidogrel (see Table 5 and Figure 3). The reduction of total endpoint events was driven primarily by a decrease in nonfatal MIs, both those occurring early (through 3 days) and later (after 3 days). Approximately 40% of MIs occurred peri-procedurally and were detected solely by changes in CK-MB. Administration of the clopidogrel loading dose in TRITON-TIMI 38 was delayed relative to the placebo-controlled trials that supported its approval for ACS. Effient produced higher rates of clinically significant bleeding than clopidogrel in TRITON-TIMI 38 [see Adverse Reactions (6.1)]. Choice of therapy requires balancing these differences in outcome.

The treatment effect of Effient was apparent within the first few days, and persisted to the end of the study (see Figure 3). The inset shows results over the first 7 days.

Figure 3: Time to first event of CV death, MI, or stroke (TRITON-TIMI 38).

The Kaplan-Meier curves (see Figure 3) show the primary composite endpoint of CV death, nonfatal MI, or nonfatal stroke over time in the UA/NSTEMI and STEMI populations. In both populations, the curves separate within the first few hours. In the UA/NSTEMI population, the curves continue to diverge throughout the 15 month follow-up period. In the STEMI population, the early separation was maintained throughout the 15 month follow-up period, but there was no progressive divergence after the first few weeks.

Effient reduced the occurrence of the primary composite endpoint compared to clopidogrel in both the UA/NSTEMI and STEMI populations (see Table 5). In patients who survived an on-study myocardial infarction, the incidence of subsequent events was also lower in the Effient group.

The effect of Effient in various subgroups is shown in Figures 4 and 5. Results are generally consistent across pre-specified subgroups, with the exception of patients with a history of TIA or stroke [see Contraindications (4.2)]. The treatment effect was driven primarily by a reduction in nonfatal MI. The effect in patients ≥75 years of age was also somewhat smaller, and bleeding risk is higher in these individuals [see Adverse Reactions (6.1)]. See below for analyses of patients ≥75 years of age with risk factors.

Figure 4: Subgroup analyses for time to first event of CV death, MI, or stroke (HR and 95% CI; TRITON-TIMI 38) – UA/NSTEMI Patients.

Figure 5: Subgroup analyses for time to first event of CV death, MI, or stroke (HR and 95% CI; TRITON-TIMI 38) – STEMI Patients.

Effient is generally not recommended in patients ≥75 years of age, except in high-risk situations (diabetes mellitus or prior MI) where its effect appears to be greater and its use may be considered. These recommendations are based on subgroup analyses (see Table 6) and must be interpreted with caution, but the data suggest that Effient reduces ischemic events in such patients.

There were 50% fewer stent thromboses (95% C.I. 32% - 64%; p<0.001) reported among patients randomized to Effient (0.9%) than among patients randomized to clopidogrel (1.8%). The difference manifested early and was maintained through one year of follow-up. Findings were similar with bare metal and drug-eluting stents.

In TRITON-TIMI 38, prasugrel reduced ischemic events (mainly nonfatal MIs) and increased bleeding events [see Adverse Reactions (6.1)] relative to clopidogrel. The findings are consistent with the intended greater inhibition of platelet aggregation by prasugrel at the doses used in the study [see Clinical Pharmacology (12.2)]. There is, however, an alternative explanation: both prasugrel and clopidogrel are pro-drugs that must be metabolized to their active moieties. Whereas the pharmacokinetics of prasugrel's active metabolite are not known to be affected by genetic variations in CYP2B6, CYP2C9, CYP2C19, or CYP3A5, the pharmacokinetics of clopidogrel's active metabolite are affected by CYP2C19 genotype, and approximately 30% of Caucasians are reduced-metabolizers. Moreover, certain proton pump inhibitors, widely used in the ACS patient population and used in TRITON-TIMI 38, inhibit CYP2C19, thereby decreasing formation of clopidogrel's active metabolite. Thus, reduced-metabolizer status and use of proton pump inhibitors may diminish clopidogrel's activity in a fraction of the population, and may have contributed to prasugrel's greater treatment effect and greater bleeding rate in TRITON-TIMI 38. The extent to which these factors were operational, however, is unknown.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Administration

• Advise patients not to break Effient tablets.
• Remind patients not to discontinue Effient without first discussing it with the physician who prescribed Effient [see Warnings and Precautions (5.3)].
• Inform patients to keep Effient in the container in which it comes, and keep the container closed tightly with the gray cylinder (desiccant) inside.

Bleeding

Inform patients that they:

• will bruise and bleed more easily.
• will take longer than usual to stop bleeding.
• should report any unanticipated, prolonged, or excessive bleeding, or blood in their stool or urine [see Warnings and Precautions (5.1)].

Thrombotic Thrombocytopenic Purpura

• Inform patients that TTP is a rare but serious condition that has been reported with Effient.
• Instruct patients to get prompt medical attention if they experience symptoms of TTP that cannot otherwise be explained [see Warnings and Precautions (5.4)].

Hypersensitivity

Inform patients that they may have hypersensitivity reactions and to seek immediate medical attention if any signs and symptoms of a hypersensitivity reaction occur. Patients who have had hypersensitivity reactions to other thienopyridines may have hypersensitivity reactions to Effient.

Invasive Procedures

Instruct patients to:

• inform physicians and dentists that they are taking Effient before any invasive procedure is scheduled [see Warnings and Precautions (5.1)].
• tell the doctor performing the invasive procedure to talk to the prescribing health care professional before stopping Effient.

Concomitant Medications

Ask patients to list all prescription medications, over-the-counter medications, or dietary supplements they are taking or plan to take so the physician knows about other treatments that may affect bleeding risk (e.g., warfarin and NSAIDs) [see Drug Interactions (7.1, 7.2)].

Effient® is a registered trademark of Eli Lilly and Company.

Manufactured by Eli Lilly and Company, Indianapolis, IN, 46285, USA

Marketed by Daiichi Sankyo, Inc. and Lilly USA, LLC

Copyright © 2009, 2019, Daiichi Sankyo, Inc. and Eli Lilly and Company. All rights reserved.

EFF-0005-USPI-20190328

MEDICATION GUIDE

Effient® (Ef′-fee-ent)

(prasugrel) tablets

Read this Medication Guide before you start taking Effient and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your doctor about your medical condition or your treatment.

What is the most important information I should know about Effient?

• Effient is used to lower your chance of having a heart attack or other serious problems with your heart or blood vessels. But, Effient can cause bleeding, which can be serious, and sometimes lead to death. You should not start to take Effient if it is likely that you will have heart bypass surgery (coronary artery bypass graft surgery or CABG) right away. You have a higher risk of bleeding if you take Effient and then have heart bypass surgery.
• Do not take Effient if you:
  • currently have abnormal bleeding, such as stomach or intestinal bleeding, or bleeding in your head
  • have had a stroke or “mini-stroke” (also known as transient ischemic attack or TIA)
  • are allergic to prasugrel or any of the ingredients in Effient. See the end of this Medication Guide for a list of ingredients in Effient.
• Get medical help right away if you think you may be having a stroke or TIA. Symptoms that you may be having a stroke or TIA include:
  • sudden slurring of speech,
  • sudden weakness or numbness in one part of your body,
  • sudden blurry vision, or sudden severe headache.
• If you have a stroke or TIA while taking Effient, your doctor will probably stop your Effient. Follow your doctor's instructions about stopping Effient. Do not stop taking Effient unless your doctor tells you to.
• Before having any surgery, you should talk to your doctor about stopping Effient. If possible, Effient should be stopped at least 1 week (7 days) before any surgery, as instructed by the doctor who prescribed Effient for you.

Your risk of bleeding while taking Effient may be higher if you also:

• have had trauma, such as an accident or surgery
• have stomach or intestine bleeding that is recent or keeps coming back, or you have a stomach ulcer
• have severe liver problems
• have moderate to severe kidney problems
• weigh less than 132 pounds
• take other medicines that increase your risk of bleeding, including:
  • warfarin sodium (Coumadin*, Jantoven*)
  • a medicine that contains heparin
  • other medicines to prevent or treat blood clots
  • regular daily use of non-steroidal anti-inflammatory drugs (NSAIDs)

Tell your doctor if you take any of these medicines. Ask your doctor if you are not sure if your medicine is one listed above.

• Effient increases your risk of bleeding because it lessens the ability of your blood to clot. While you take Effient:
  • you will bruise and bleed more easily
  • you are more likely to have nose bleeds
  • it will take longer for any bleeding to stop
• Call your doctor right away if you have any of these signs or symptoms of bleeding:
  • unexpected bleeding or bleeding that lasts a long time
  • bleeding that is severe or you cannot control
  • pink or brown urine
  • red or black stool (looks like tar)
  • bruises that happen without a known cause or get larger
  • cough up blood or blood clots
  • vomit blood or your vomit looks like “coffee grounds”
• Do not stop taking Effient without talking to the doctor who prescribes it for you. People who are treated with angioplasty and have a stent, and stop taking Effient too soon, have a higher risk of a blood clot in the stent, having a heart attack, or dying. If you must stop Effient because of bleeding, your risk of a heart attack may be higher. See “What are the possible side effects of Effient?” for more information about side effects.

What is Effient?

Effient is a prescription medicine used to treat people who:

• have had a heart attack or severe chest pain that happens when your heart does not get enough oxygen, and
• have been treated with a procedure called “angioplasty” (also called balloon angioplasty).

Effient is used to lower your chance of having another serious problem with your heart or blood vessels, such as another heart attack, a stroke, blood clots in your stent, or death.

Platelets are blood cells that help with normal blood clotting. Effient helps prevent platelets from sticking together and forming a clot that can block an artery or a stent.

It is not known if Effient is safe and works in children.

What should I tell my doctor before taking Effient?

Effient may not be right for you. Tell your doctor about all of your medical conditions, including if you:

• have any bleeding problems
• have had a stroke or “mini-stroke” (also known as transient ischemic attack or TIA)
• are allergic to any medicines, including clopidogrel (Plavix*) or ticlopidine hydrochloride (Ticlid*)
• have a history of stomach ulcers, colon polyps, diverticulosis
• have liver problems
• have kidney problems
• have had any recent severe injury or surgery
• plan to have surgery or a dental procedure. See “What is the most important information I should know about Effient?”
• pregnant, or are planning to get pregnant. It is not known if Effient will harm your baby.
• if you are breast-feeding. It is not known if Effient passes into your breast-milk. You and your doctor should decide if you will take Effient or breast-feed. You should not do both without talking with your doctor.

Tell all of your doctors and dentists that you are taking Effient. They should talk to the doctor who prescribed Effient for you, before you have any surgery or invasive procedure.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Certain medicines may increase your risk of bleeding. See “What is the most important information I should know about Effient?”

Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine.

How should I take Effient?

• Take Effient exactly as prescribed by your doctor.
• Take Effient one time each day.
• You can take Effient with or without food.
• Do not split Effient tablets.
• Take Effient with aspirin as instructed by your doctor.
• Your doctor will decide how long you should take Effient. Do not stop taking Effient without first talking to the doctor who prescribed it for you. See “What is the most important information I should know about Effient?”
• If you miss a dose, take Effient as soon as you remember. If it is almost time for your next dose, skip the missed dose. Just take the next dose at your regular time. Do not take two doses at the same time unless your doctor tells you to.
• If you take too much Effient, call your local emergency room or poison control center right away.
• Call your doctor or healthcare provider right away if you fall or injure yourself, especially if you hit your head. Your doctor or healthcare provider may need to check you.

What are the possible side effects of Effient?

Effient can cause serious side effects, including:

• See “What is the most important information I should know about Effient?”
• A blood clotting problem called Thrombotic Thrombocytopenic Purpura (TTP). TTP can happen with Effient, sometimes after a short time (less than 2 weeks). TTP is a blood clotting problem where blood clots form in blood vessels and can happen all over the body. TTP needs to be treated in a hospital right away, because you may die. Get medical help right away if you have any of these symptoms and they cannot be explained by another medical condition:
  • purplish spots called purpura on the skin or mucous membranes (such as on the mouth) due to bleeding under the skin
  • paleness or jaundice (a yellowish color of the skin or eyes)
  • feeling tired or weak
  • fever
  • fast heart rate or feeling short of breath
  • headache, speech changes, confusion, coma, stroke, or seizure
  • low amount of urine or urine that is pink-tinged or has blood in it
  • stomach area (abdominal) pain, nausea, vomiting, or diarrhea
  • visual changes
• Serious allergic reactions. Serious allergic reactions can happen with Effient, or if you have had a serious allergic reaction to the medicine clopidogrel (Plavix*) or ticlopidine (Ticlid*). Get medical help right away if you get any of these symptoms of a severe allergic reaction while taking Effient.
  • swelling or hives of your face, lips, in or around your mouth, or throat
  • trouble breathing or swallowing
  • chest pain or pressure
  • dizziness or fainting

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all of the possible side effects of Effient. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects.

You may report side effects to FDA at 1-800-FDA-1088.

How should I store Effient?

• Keep Effient at room temperature between 59°F to 86°F (15°C to 30°C).
• Keep and dispense only in original container.
• Keep the container closed tightly with the gray cylinder inside.
• Protect Effient from moisture.

Keep Effient and all medicines out of the reach of children.

General Information about Effient

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Effient for a condition for which it was not prescribed. Do not give your Effient to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide summarizes the most important information about Effient. If you would like more information about Effient, talk with your doctor or pharmacist. For more information, call 1-800-545-5979 or go to the following website: www.effient.com

What are the ingredients in Effient?

Active Ingredient: prasugrel

Inactive Ingredients: mannitol, hypromellose, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, sucrose stearate, and glyceryl behenate. The color coatings contain lactose, hypromellose, titanium dioxide, triacetin, iron oxide yellow, and iron oxide red (only in Effient 10 mg tablet).

Effient® is a registered trademark of Eli Lilly and Company.

Revised: March 28, 2019

Manufactured by Eli Lilly and Company, Indianapolis, IN, 46285, USA

Marketed by Daiichi Sankyo, Inc. and Lilly USA, LLC

This Medication Guide has been approved by the U.S. Food and Drug Administration.

*The brands listed are trademarks of their respective owners and are not trademarks of Daiichi Sankyo, Inc. or Eli Lilly and Company.

Copyright © 2009, 2019 Daiichi Sankyo, Inc. and Eli Lilly and Company. All rights reserved.

EFF-0002-MG-20190328

PACKAGE LABEL – Effient 5 mg 30 Tablets

30 Tablets

NDC 0002-5121-30

Effient ®

(prasugrel) tablets

5 mg

Rx only

Keep and dispense only in original container. Keep container closed and do not remove desiccant from bottle.

Dispense accompanying Medication Guide to each patient.

effient.com

Daiichi Sankyo/Lilly

PACKAGE LABEL – Effient 10 mg 30 Tablets

30 Tablets

NDC 0002-5123-30

Effient ®

(prasugrel) tablets

10 mg

Rx only

Keep and dispense only in original container. Keep container closed and do not remove desiccant from bottle.

Dispense accompanying Medication Guide to each patient.

effient.com

Daiichi Sankyo/Lilly