TABLE OF CONTENTS
Prasugrel is a thienopyridine class inhibitor of platelet activation and aggregation mediated by the P2Y12 ADP receptor. Prasugrel 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.
Prasugrel 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. During manufacture and storage, partial conversion from prasugrel hydrochloride to prasugrel free base may occur. Other ingredients include mannitol, hypromellose, croscarmellose sodium, microcrystalline cellulose, and vegetable magnesium stearate. The color coatings contain lactose, hypromellose, titanium dioxide, triacetin, iron oxide yellow, and iron oxide red (only in prasugrel 10 mg tablet).
|2. INDICATIONS AND USAGE|
Acute Coronary Syndrome
Prasugrel is indicated to reduce the rate of thrombotic cardiovascular (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.
Prasugrel 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.
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 the clinical trial that established the efficacy of prasugrel, prasugrel and the control drug were not administered to UA/NSTEMI patients until coronary anatomy was established. For the small fraction of patients that required urgent CABG after treatment with prasugrel, the risk of significant bleeding was substantial [see Warnings and Precautions]. Because the large majority of patients are managed without CABG, however, treatment can be considered before determining coronary anatomy if need for CABG is considered unlikely. The advantages of earlier treatment with prasugrel must then be balanced against the increased rate of bleeding in patients who do need to undergo urgent CABG.
|3. DOSAGE AND ADMINISTRATION|
Initiate prasugrel treatment as a single 60 mg oral loading dose and then continue at 10 mg orally once daily. Patients taking prasugrel should also take aspirin (75 mg to 325 mg) daily [see Drug Interactions]. Prasugrel may be administered with or without food.
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.
4.1 Active Bleeding
Prasugrel is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage [see Warnings and Precautions and Adverse Reactions].
4.2 Prior Transient Ischemic Attack or Stroke
Prasugrel 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 prasugrel (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 prasugrel 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 prasugrel generally should have therapy discontinued [see Adverse Reactions].
Prasugrel is contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to prasugrel or any component of the product [see Adverse Reactions].
|5. 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.
|6. USE IN SPECIFIC POPULATIONS|
6.1 Usage in Pregnancy
Pregnancy Category B
There are no adequate and well-controlled studies of prasugrel use in pregnant women. Reproductive and developmental toxicology studies in rats and rabbits at doses of up to 30 times the recommended therapeutic exposures in humans (based on plasma exposures to the major circulating human metabolite) revealed no evidence of fetal harm; however, animal studies are not always predictive of a human response. Prasugrel should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
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 pup 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.
6.2 Nursing Mothers
It is not known whether prasugrel is excreted in human milk; however, metabolites of prasugrel were found in rat milk. Because many drugs are excreted in human milk, prasugrel should be used during nursing only if the potential benefit to the mother justifies the potential risk to the nursing infant.
6.3 Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
6.4 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 (prasugrel compared with clopidogrel) was similar across age groups.
Patients ≥ 75 years of age who received prasugrel 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 prasugrel 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, use of prasugrel 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].
6.5 Low Body Weight
In TRITON-TIMI 38, 4.6% of patients treated with prasugrel 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, Warnings and Precautions]. 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.
6.6 Renal Impairment
No dosage adjustment is necessary for patients with renal impairment. There is limited experience in patients with end-stage renal disease.
6.7 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].
6.8 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.
|7. WARNINGS AND PRECAUTIONS|
7.1 General Risk of Bleeding
Thienopyridines, including prasugrel, 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 prasugrel than on clopidogrel [see Adverse Reactions]. 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 prasugrel in patients with active bleeding, prior TIA or stroke [see Contraindications].
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 prasugrel 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, Use in Specific Populations].
• CABG or other surgical procedure [see Warnings and Precautions].
• Body weight < 60 kg. Consider a lower (5 mg) maintenance dose [see Dosage and Administration, Adverse Reactions, Use in Specific Populations].
• 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 and Use in Specific Populations].
• 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 [see Drug Interactions].
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.
7.2 Coronary Artery Bypass Graft Surgery-Related Bleeding
The risk of bleeding is increased in patients receiving prasugrel who undergo CABG. If possible, prasugrel 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 prasugrel group and 4.5% in the clopidogrel group [see Adverse Reactions]. The higher risk for bleeding events in patients treated with prasugrel 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 prasugrel 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 prasugrel 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.
7.3 Discontinuation of Prasugrel
Discontinue thienopyridines, including prasugrel, 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 and Warnings and Precautions].
7.4 Thrombotic Thrombocytopenic Purpura
Thrombotic thrombocytopenic purpura (TTP) has been reported with the use of other thienopyridines, sometimes 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.
7.5 Hypersensitivity Including Angioedema
Hypersensitivity including angioedema has been reported in patients receiving prasugrel, including patients with a history of hypersensitivity reaction to other thienopyridines [see Contraindications, Adverse Reactions].
|8. ADVERSE REACTIONS|
8.1 Clinical Trials Experience
The following serious adverse reactions are also discussed elsewhere in the labeling:
• Bleeding [see Boxed Warning and Warnings and Precautions].
• Thrombotic thrombocytopenic purpura [see Warnings and Precautions].
Safety in patients with ACS undergoing PCI was evaluated in a clopidogrel-controlled study, TRITON-TIMI 38, in which 6741 patients were treated with prasugrel (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 prasugrel 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 cannot be directly compared with the rates observed in other clinical trials of another drug and may not reflect the rates observed in practice.
The rate of study drug discontinuation because of adverse reactions was 7.2% for prasugrel and 6.3% for clopidogrel. Bleeding was the most common adverse reaction leading to study drug discontinuation for both drugs (2.5% for prasugrel and 1.4% for clopidogrel).
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 prasugrel than on clopidogrel, as shown in Table 1.
Table 1: Non-CABG-Related Bleedinga (TRITON-TIMI 38)
a Patients may be counted in more than one row.
b See WARNINGS AND PRECAUTIONS for definition.
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].
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 prasugrel group and 4.5% in the clopidogrel group (Table 3). The higher risk for bleeding adverse reactions in patients treated with prasugrel persisted up to 7 days from the most recent dose of study drug.
Table 3: CABG-Related Bleedinga (TRITON-TIMI 38)
a Patients may be counted in more than one row.
Bleeding Reported as Adverse Reactions - Hemorrhagic events reported as adverse reactions in TRITON-TIMI 38 were, for prasugrel 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%), and retinal hemorrhage (0.0%, 0.1%).
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. It is unclear if these observations are causally-related or are random occurrences.
Other Adverse Events
In TRITON-TIMI 38, common and other important non-hemorrhagic adverse events were, for prasugrel 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
9.1 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.
9.2 Recommendations about Specific Treatment
Platelet transfusion may restore clotting ability. The prasugrel active metabolite is not likely to be removed by dialysis.
|10. DRUG INTERACTIONS|
Coadministration of prasugrel and warfarin increases the risk of bleeding [see Warnings and Precautions].
10.2 Non-Steroidal Anti-Inflammatory Drugs
Coadministration of prasugrel and NSAIDs (used chronically) may increase the risk of bleeding [see Warnings and Precautions].
10.3 Other Concomitant Medications
Prasugrel can be administered with drugs that are inducers or inhibitors of cytochrome P450 enzymes.
Prasugrel 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.
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.
Absorption and Binding - Following oral administration, ≥ 79% of the dose is absorbed. The absorption and metabolism are rapid, with peak plasma concentrations (Cmax) of the active metabolite occurring approximately 30 minutes after dosing. The active metabolite's exposure (AUC) increases slightly more than proportionally over the dose range of 5 to 60 mg. Repeated daily doses of 10 mg do not lead to accumulation of the active metabolite. In a study of healthy subjects given a single 15 mg dose, the AUC of the active metabolite was unaffected by a high fat, high calorie meal, but Cmax was decreased by 49% and Tmax was increased from 0.5 to 1.5 hours. Prasugrel can be administered without regard to food. The active metabolite is bound about 98% to human serum albumin.
Metabolism and Elimination - Prasugrel is not detected in plasma following oral administration. It is rapidly hydrolyzed in the intestine to a thiolactone, which is then converted to the active metabolite by a single step, primarily by CYP3A4 and CYP2B6 and to a lesser extent by CYP2C9 and CYP2C19. The estimates of apparent volume of distribution of prasugrel's active metabolite ranged from 44 to 68 L and the estimates of apparent clearance ranged from 112 to 166 L/hr in healthy subjects and patients with stable atherosclerosis. The active metabolite is metabolized to two inactive compounds by S-methylation or conjugation with cysteine. The major inactive metabolites are highly bound to human plasma proteins. Approximately 68% of the prasugrel dose is excreted in the urine and 27% in the feces as inactive metabolites.
Pediatric - Pharmacokinetics and pharmacodynamics of prasugrel have not been evaluated in a pediatric population [see Use in Specific Populations].
Geriatric - In a study of 32 healthy subjects between the ages of 20 and 80 years, age had no significant effect on pharmacokinetics of prasugrel's active metabolite or its inhibition of platelet aggregation. In TRITON-TIMI 38, the mean exposure (AUC) of the active metabolite was 19% higher in patients ≥ 75 years of age than in patients < 75 years of age [see Warnings and Precautions, Adverse Reactions, and Use in Specific Populations].
Body Weight - The mean exposure (AUC) to the active metabolite is approximately 30 to 40% higher in subjects with a body weight of < 60 kg than in those weighing ≥ 60 kg [see Dosage and Administration, Warnings and Precautions, Adverse Reactions, and Use in Specific Populations].
Gender - Pharmacokinetics of prasugrel's active metabolite are similar in men and women.
Ethnicity - Exposure in subjects of African and Hispanic descent is similar to that in Caucasians. In clinical pharmacology studies, after adjusting for body weight, the AUC of the active metabolite was approximately 19% higher in Chinese, Japanese, and Korean subjects than in Caucasian subjects.
Smoking - Pharmacokinetics of prasugrel's active metabolite are similar in smokers and nonsmokers.
Renal Impairment - Pharmacokinetics of prasugrel's active metabolite and its inhibition of platelet aggregation are similar in patients with moderate renal impairment (CrCL=30 to 50 mL/min) and healthy subjects. In patients with end stage renal disease, exposure to the active metabolite (both Cmax and AUC(0-tlast)) was about half that in healthy controls and patients with moderate renal impairment [see Use in Specific Populations].
Hepatic Impairment - Pharmacokinetics of prasugrel's active metabolite and inhibition of platelet aggregation were similar in patients with mild to moderate hepatic impairment compared to healthy subjects. The pharmacokinetics and pharmacodynamics of prasugrel's active metabolite in patients with severe hepatic disease have not been studied [see Warnings and Precautions and Use in Specific Populations].
|12. HOW SUPPLIED/STORAGE AND HANDLING|
1) How Available:
a) Brand name: EFFIENT, by ELI LILLY AND CO.
b) Generic drugs: NONE.
2) How Supplied:
Effient (prasugrel) 5 mg is supplied as a yellow, elongated hexagonal, film-coated, non-scored tablet debossed with “5” on one side and with “5121” on the other side.
5 mg tablets are supplied as follows:
Bottles of 30 - NDC 0002-5121-30
Blisters ID*24 - NDC 0002-5121-52
Effient (prasugrel) 10 mg is supplied as a beige, elongated hexagonal, film-coated, non-scored tablet debossed with “10” on one side and “5123” on the other side.
10 mg tablets are supplied as follows:
Bottles of 30 – NDC 0002-5123-30
Blisters ID 90* NDC 0002-5123-77
(* Identi Dose®, unit dose medication, Lilly)
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).
Dispense and keep product in original container. Keep container closed and do not remove desiccant from bottle. Do not break the tablet.