Drug Detail:Effient (Prasugrel [ pra-soo-grel ])
Drug Class: Platelet aggregation inhibitors
Highlights of Prescribing Information
EFFIENT® (prasugrel) tablets, for oral use
Initial U.S. Approval: 2009
WARNING: BLEEDING RISK
See full prescribing information for complete boxed warning.
- Effient can cause significant, sometimes fatal, bleeding (5.1, 5.2, 6.1).
- Do not use Effient in patients with active pathological bleeding or a history of transient ischemic attack or stroke (4.1, 4.2).
- In patients ≥75 years of age, Effient is generally not recommended, except in high-risk patients (diabetes or prior myocardial infarction [MI]), where its use may be considered (8.5).
- Do not start Effient in patients likely to undergo urgent coronary artery bypass graft surgery (CABG). When possible, discontinue Effient at least 7 days prior to any surgery (5.2).
- Additional risk factors for bleeding include: body weight <60 kg, propensity to bleed, concomitant use of medications that increase the risk of bleeding (5.1).
- Suspect bleeding in any patient who is hypotensive and has recently undergone invasive or surgical procedures (5.1).
- If possible, manage bleeding without discontinuing Effient. Stopping Effient increases the risk of subsequent cardiovascular events (5.3).
Indications and Usage for Effient
Effient is a P2Y12 platelet inhibitor indicated for the reduction of thrombotic cardiovascular events (including stent thrombosis) in patients with acute coronary syndrome who are to be managed with percutaneous coronary intervention (PCI) as follows:
- Patients with unstable angina or non-ST-elevation myocardial infarction (NSTEMI) (1.1).
- Patients with ST-elevation myocardial infarction (STEMI) when managed with either primary or delayed PCI (1.1).
Effient Dosage and Administration
- Initiate treatment with a single 60 mg oral loading dose (2).
- Continue at 10 mg once daily with or without food. Consider 5 mg once daily for patients <60 kg (2).
- Patients should also take aspirin (75 mg to 325 mg) daily (2).
Dosage Forms and Strengths
5 mg and 10 mg tablets (3)
Contraindications
- Active pathological bleeding (4.1)
- Prior transient ischemic attack or stroke (4.2)
- Hypersensitivity to prasugrel or any component of the product (4.3)
Warnings and Precautions
- CABG-related bleeding: Risk increases in patients receiving Effient who undergo CABG (5.2).
- Discontinuation of Effient: Premature discontinuation increases risk of stent thrombosis, MI, and death (5.3).
- Thrombotic thrombocytopenic purpura (TTP): TTP has been reported with Effient (5.4).
- Hypersensitivity: Hypersensitivity including angioedema has been reported with Effient including in patients with a history of hypersensitivity reaction to other thienopyridines (5.5).
Adverse Reactions/Side Effects
Bleeding, including life-threatening and fatal bleeding, is the most commonly reported adverse reaction (6.1).
To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Drug Interactions
Opioids: Decreased exposure to prasugrel. Consider use of parenteral antiplatelet agent (7.3).
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 12/2020
Full Prescribing Information
WARNING: BLEEDING RISK
- Effient can cause significant, sometimes fatal, bleeding [see Warnings and Precautions (5.1, 5.2) and Adverse Reactions (6.1)].
- Do not use Effient in patients with active pathological bleeding or a history of transient ischemic attack (TIA) or stroke [see Contraindications (4.1, 4.2)].
- In patients ≥75 years of age, Effient 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 prior myocardial infarction [MI]) where its effect appears to be greater and its use may be considered [see Use in Specific Populations (8.5)].
- Do not start Effient in patients likely to undergo urgent coronary artery bypass graft surgery (CABG). When possible, discontinue Effient at least 7 days prior to any surgery [see Warnings and Precautions (5.2)].
- Additional risk factors for bleeding include: body weight <60 kg, propensity to bleed, concomitant use of medications that increase the risk of bleeding (e.g., warfarin, heparin, fibrinolytic therapy, chronic use of nonsteroidal anti-inflammatory drugs [NSAIDs]) [see Warnings and Precautions (5.1)].
- 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 Effient [see Warnings and Precautions (5.1)].
- If possible, manage bleeding without discontinuing Effient. Discontinuing Effient, particularly in the first few weeks after acute coronary syndrome, increases the risk of subsequent cardiovascular (CV) events [see Warnings and Precautions (5.3)].
1. Indications and Usage for Effient
1.1 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 [see Clinical Studies (14)].
2. Effient Dosage and Administration
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)].
3. Dosage Forms and Strengths
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.
4. Contraindications
4.1 Active Bleeding
Effient is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage (ICH) [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].
4.2 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 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN 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 [ICH]) 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 [see Adverse Reactions (6.1) and Clinical Studies (14)].
5. Warnings and Precautions
5.1 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 [see Adverse Reactions (6.1)]. The bleeding risk is highest initially, as shown in Figure 1 (events through 450 days; inset shows events through 7 days).
Figure 1: Non-CABG-Related TIMI Major or Minor Bleeding Events |
Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, PCI, CABG, or other surgical procedures even if the patient does not have overt signs of bleeding.
Do not use Effient in patients with active bleeding, prior TIA or stroke [see Contraindications (4.1, 4.2)].
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 [see Adverse Reactions (6.1), Use in Specific Populations (8.5), Clinical Pharmacology (12.3), and Clinical Studies (14)].
- CABG or other surgical procedure [see Warnings and Precautions (5.2)].
- Body weight <60 kg. Consider a lower (5 mg) maintenance dose [see Dosage and Administration (2), Adverse Reactions (6.1), and Use in Specific Populations (8.6)].
- Propensity to bleed (e.g., recent trauma, recent surgery, recent or recurrent gastrointestinal (GI) bleeding, active peptic ulcer disease, severe hepatic impairment, or moderate to severe renal impairment) [see Adverse Reactions (6.1) and Use in Specific Populations (8.7, 8.8)].
- Medications that increase the risk of bleeding (e.g., oral anticoagulants, chronic use of nonsteroidal anti-inflammatory drugs [NSAIDs], and fibrinolytic agents). Aspirin and heparin were commonly used in TRITON-TIMI 38 [see Drug Interactions (7.1, 7.2, 7.4) and Clinical Studies (14)].
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.
5.2 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 [see Adverse Reactions (6.1)]. 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.
5.3 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 [see Contraindications (4.1, 4.2) and Warnings and Precautions (5.1)].
5.4 Thrombotic Thrombocytopenic Purpura (TTP)
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 [see Adverse Reactions (6.2)].
6. Adverse Reactions/Side Effects
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)]
6.1 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.
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.
| Effient (%) (N=6741) | Clopidogrel (%) (N=6716) |
|
|---|---|---|
|
||
| TIMI Major or Minor bleeding | 4.5 | 3.4 |
| TIMI Major bleeding† | 2.2 | 1.7 |
| Life-threatening | 1.3 | 0.8 |
| Fatal | 0.3 | 0.1 |
| Symptomatic intracranial hemorrhage (ICH) | 0.3 | 0.3 |
| Requiring inotropes | 0.3 | 0.1 |
| Requiring surgical intervention | 0.3 | 0.3 |
| Requiring transfusion (≥4 units) | 0.7 | 0.5 |
| TIMI Minor bleeding† | 2.4 | 1.9 |
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) [see Warnings and Precautions (5.1)].
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.
| Major/Minor | Fatal | |||
|---|---|---|---|---|
| Effient*
(%) | Clopidogrel†
(%) | Effient*
(%) | Clopidogrel†
(%) |
|
|
||||
| Weight <60 kg (N=308 Effient, N=356 clopidogrel) | 10.1 | 6.5 | 0.0 | 0.3 |
| 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 | 0.1 |
| 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.
| Effient (%) (N=213) | Clopidogrel (%) (N=224) |
|
|---|---|---|
|
||
| TIMI Major or Minor bleeding | 14.1 | 4.5 |
| TIMI Major bleeding | 11.3 | 3.6 |
| Fatal | 0.9 | 0 |
| Reoperation | 3.8 | 0.5 |
| Transfusion of ≥5 units | 6.6 | 2.2 |
| Intracranial hemorrhage | 0 | 0 |
| TIMI Minor bleeding | 2.8 | 0.9 |
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.
| Effient (%) (N=6741) | Clopidogrel (%) (N=6716) |
|
|---|---|---|
|
||
| Hypertension | 7.5 | 7.1 |
| Hypercholesterolemia/Hyperlipidemia | 7.0 | 7.4 |
| Headache | 5.5 | 5.3 |
| Back pain | 5.0 | 4.5 |
| Dyspnea | 4.9 | 4.5 |
| Nausea | 4.6 | 4.3 |
| Dizziness | 4.1 | 4.6 |
| Cough | 3.9 | 4.1 |
| Hypotension | 3.9 | 3.8 |
| Fatigue | 3.7 | 4.8 |
| Noncardiac chest pain | 3.1 | 3.5 |
| Atrial fibrillation | 2.9 | 3.1 |
| Bradycardia | 2.9 | 2.4 |
| Leukopenia (<4 × 109 WBC*/L) | 2.8 | 3.5 |
| Rash | 2.8 | 2.4 |
| Pyrexia | 2.7 | 2.2 |
| Peripheral edema | 2.7 | 3.0 |
| Pain in extremity | 2.6 | 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) [see Warnings and Precautions (5.4) and Patient Counseling Information (17)]
Immune system disorders — hypersensitivity reactions including anaphylaxis [see Contraindications (4.3)]
7. Drug Interactions
7.1 Warfarin
Coadministration of Effient and warfarin increases the risk of bleeding [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
7.2 Nonsteroidal Anti-Inflammatory Drugs
Coadministration of Effient and NSAIDs (used chronically) may increase the risk of bleeding [see Warnings and Precautions (5.1)].
7.3 Opioids
As with other oral P2Y12 inhibitors, coadministration of opioid agonists delay and reduce the absorption of prasugrel's active metabolite presumably because of slowed gastric emptying [see Clinical Pharmacology (12.3)]. Consider the use of a parenteral anti-platelet agent in acute coronary syndrome patients requiring coadministration of morphine or other opioid agonists.
7.4 Other Concomitant Medications
Effient can be administered with drugs that are inducers or inhibitors of cytochrome P450 enzymes [see Clinical Pharmacology (12.3)].
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 [see Clinical Pharmacology (12.3)].
8. Use In Specific Populations
8.4 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.
8.5 Geriatric Use
In TRITON-TIMI 38, 38.5% of patients were ≥65 years of age and 13.2% were ≥75 years of age. The risk of bleeding increased with advancing age in both treatment groups, although the relative risk of bleeding (Effient compared with clopidogrel) was similar across age groups.
Patients ≥75 years of age who received Effient 10 mg had an increased risk of fatal bleeding events (1.0%) compared to patients who received clopidogrel (0.1%). In patients ≥75 years of age, symptomatic intracranial hemorrhage occurred in 7 patients (0.8%) who received Effient and in 3 patients (0.3%) who received clopidogrel. Because of the risk of bleeding, and because effectiveness is uncertain in patients ≥75 years of age [see Clinical Studies (14)], use of Effient is generally not recommended in these patients, except in high-risk situations (diabetes and past history of myocardial infarction) where its effect appears to be greater and its use may be considered [see Warnings and Precautions (5.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].
8.6 Low Body Weight
In TRITON-TIMI 38, 4.6% of patients treated with Effient had body weight <60 kg. Individuals with body weight <60 kg had an increased risk of bleeding and an increased exposure to the active metabolite of prasugrel [see Dosage and Administration (2), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)]. 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 [see Dosage and Administration (2) and Clinical Pharmacology (12.3)].
8.7 Renal Impairment
No dosage adjustment is necessary for patients with renal impairment. There is limited experience in patients with end-stage renal disease, but such patients are generally at higher risk of bleeding [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
8.8 Hepatic Impairment
No dosage adjustment is necessary in patients with mild to moderate hepatic impairment (Child-Pugh Class A and B). The pharmacokinetics and pharmacodynamics of prasugrel in patients with severe hepatic disease have not been studied, but such patients are generally at higher risk of bleeding [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
8.9 Metabolic Status
In healthy subjects, patients with stable atherosclerosis, and patients with ACS receiving prasugrel, there was no relevant effect of genetic variation in CYP2B6, CYP2C9, CYP2C19, or CYP3A5 on the pharmacokinetics of prasugrel's active metabolite or its inhibition of platelet aggregation.
10. Overdosage
10.1 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.
11. Effient Description
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).
12. Effient - Clinical Pharmacology
12.1 Mechanism of Action
Prasugrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y12 class of ADP receptors on platelets.
12.2 Pharmacodynamics
Prasugrel produces inhibition of platelet aggregation to 20 µM or 5 µM ADP, as measured by light transmission aggregometry. Following a 60 mg loading dose of Effient, approximately 90% of patients had at least 50% inhibition of platelet aggregation by 1 hour. Maximum platelet inhibition was about 80% (see Figure 2). Mean steady-state inhibition of platelet aggregation was about 70% following 3 to 5 days of dosing at 10 mg daily after a 60 mg loading dose of Effient.
Platelet aggregation gradually returns to baseline values over 5-9 days after discontinuation of prasugrel, this time course being a reflection of new platelet production rather than pharmacokinetics of prasugrel. Discontinuing clopidogrel 75 mg and initiating a prasugrel 10 mg maintenance dose with or without a prasugrel 60 mg loading dose results in a decrease of 14 percentage points in maximum platelet aggregation (MPA) by Day 7. This decrease in MPA is not greater than that typically produced by a 10 mg maintenance dose of prasugrel alone. The relationship between inhibition of platelet aggregation and clinical activity has not been established.
12.3 Pharmacokinetics
Prasugrel is a prodrug and is rapidly metabolized to a pharmacologically active metabolite and inactive metabolites. The active metabolite has an elimination half-life of about 7 hours (range 2-15 hours). Healthy subjects, patients with stable atherosclerosis, and patients undergoing PCI show similar pharmacokinetics.
Drug Interaction Studies
14. Clinical Studies
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 Figure 3 and Table 5). 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.
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.
| Patients with events | From Kaplan-Meier analysis | |||
|---|---|---|---|---|
| Effient (%) | Clopidogrel (%) | Relative Risk Reduction (%)*
(95% CI) | p-value | |
|
||||
| UA/NSTEMI | N=5044 | N=5030 | ||
| CV death, nonfatal MI, or nonfatal stroke | 9.3 | 11.2 | 18.0 (7.3, 27.4) | 0.002 |
| CV death | 1.8 | 1.8 | 2.1 (-30.9, 26.8) | 0.885 |
| Nonfatal MI | 7.1 | 9.2 | 23.9 (12.7, 33.7) | <0.001 |
| Nonfatal Stroke | 0.8 | 0.8 | 2.1 (-51.3, 36.7) | 0.922 |
| STEMI | N=1769 | N=1765 | ||
| CV death, nonfatal MI, or nonfatal stroke | 9.8 | 12.2 | 20.7 (3.2, 35.1) | 0.019 |
| CV death | 2.4 | 3.3 | 26.2 (-9.4, 50.3) | 0.129 |
| Nonfatal MI | 6.7 | 8.8 | 25.4 (5.2, 41.2) | 0.016 |
| Nonfatal Stroke | 1.2 | 1.1 | -9.7 (-104.0, 41.0) | 0.77 |
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.
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.
| Effient | Clopidogrel | Hazard Ratio (95% CI) |
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|---|---|---|---|---|---|
| N | % with events | N | % with events | ||
| Age ≥75 | |||||
| Diabetes – yes | 249 | 14.9 | 234 | 21.8 | 0.64 (0.42, 0.97) |
| Diabetes – no | 652 | 16.4 | 674 | 15.3 | 1.1 (0.83, 1.43) |
| Age <75 | |||||
| Diabetes – yes | 1327 | 10.8 | 1336 | 14.8 | 0.72 (0.58, 0.89) |
| Diabetes – no | 4585 | 7.8 | 4551 | 9.5 | 0.82 (0.71, 0.94) |
| Age ≥75 | |||||
| Prior MI – yes | 220 | 17.3 | 212 | 22.6 | 0.72 (0.47, 1.09) |
| Prior MI – no | 681 | 15.6 | 696 | 15.2 | 1.05 (0.80, 1.37) |
| Age <75 | |||||
| Prior MI – yes | 1006 | 12.2 | 996 | 15.4 | 0.78 (0.62, 0.99) |
| Prior MI – no | 4906 | 7.7 | 4891 | 9.7 | 0.78 (0.68, 0.90) |
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 prodrugs that must be metabolized to their active moieties. Whereas the pharmacokinetics of prasugrel's active metabolite is not known to be affected by genetic variations in CYP2B6, CYP2C9, CYP2C19, or CYP3A5, the pharmacokinetics of clopidogrel's active metabolite is 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.
16. How is Effient supplied
16.1 How Supplied
Effient (prasugrel) is available as elongated hexagonal, film-coated, non-scored tablets in the following strengths, colors, debossing, and presentations:
| Features | Strengths | |
|---|---|---|
| 5 mg | 10 mg | |
| Tablet color | yellow | beige |
| Tablet debossing | 5 | 10 |
| Tablet debossing | 5121 | 5123 |
| Presentations and NDC Codes | ||
| Bottles of 30 | 65597-601-30 | 65597-602-30 |
17. Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
| This Medication Guide has been approved by the U.S. Food and Drug Administration. | Revised: 12/2020 |
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| Medication Guide EFFIENT® (Ef´-fee-ent) (prasugrel) tablets |
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| 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. |
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| What is Effient?
Effient is a prescription medicine used to treat people who:
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. |
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Who should not take Effient?
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| What should I tell my doctor before taking Effient? Before you take Effient, tell your doctor about all of your medical conditions, including if you:
Tell your doctor about all the medicines you take, including prescription and nonprescription 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. |
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How should I take Effient?
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| What are the possible side effects of Effient?
Effient can cause serious side effects, including:
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. |
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How should I store Effient?
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| General information about the safe and effective use of 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. |
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| 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). Manufactured by Daiichi Sankyo, Inc., Basking Ridge, NJ 07920 Effient® is a registered trademark of Daiichi Sankyo Company, Ltd. Copyright © 2009, 2020 Daiichi Sankyo, Inc. All rights reserved. USMG-EFF-1220-r100 For more information, call 1-877-437-7763 or go to www.effient.com. |
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| EFFIENT
prasugrel hydrochloride tablet, coated |
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| EFFIENT
prasugrel hydrochloride tablet, coated |
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| Labeler - Daiichi Sankyo, Inc. (068605067) |
| Establishment | |||
| Name | Address | ID/FEI | Business Operations |
|---|---|---|---|
| Daiichi Sankyo Europe GmBH | 551338593 | ANALYSIS(65597-601, 65597-602) , MANUFACTURE(65597-601, 65597-602) | |
