"The U.S. Food and Drug Administration today expanded the approved use of the CoreValve System to treat certain patients who have previously had a tissue aortic valve replacement and are in need of a second one.
This first-of-its-kind use is"...
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]. 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
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, Use In Specific Populations, CLINICAL PHARMACOLOGY, and Clinical Trials].
- CABG or other surgical procedure [see Coronary Artery Bypass Graft Surgery-Related Bleeding].
- Body weight < 60 kg. Consider a lower (5-mg) maintenance dose [see DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS, and 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 TRITONTIMI 38 [see DRUG INTERACTIONS, and Clinical Studies].
Thienopyridines inhibit platelet aggregation for the lifetime of the platelet (7-10 days), so withholding a dose will not be useful in managing a bleeding event or the risk of bleeding associated with an invasive procedure. Because the half-life of prasugrel's active metabolite is short relative to the lifetime of the platelet, it may be possible to restore hemostasis by administering exogenous platelets; however, platelet transfusions within 6 hours of the loading dose or 4 hours of the maintenance dose may be less effective.
Coronary Artery Bypass Graft Surgery-Related Bleeding
The risk of bleeding is increased in patients receiving Effient who undergo CABG. If possible, Effient should be discontinued at least 7 days prior to CABG.
Of the 437 patients who underwent CABG during TRITON-TIMI 38, the rates of CABG-related TIMI Major or Minor bleeding were 14.1% in the Effient group and 4.5% in the clopidogrel group [see ADVERSE REACTIONS]. The higher risk for bleeding events in patients treated with Effient persisted up to 7 days from the most recent dose of study drug. For patients receiving a thienopyridine within 3 days prior to CABG, the frequencies of TIMI Major or Minor bleeding were 26.7% (12 of 45 patients) in the Effient group, compared with 5.0% (3 of 60 patients) in the clopidogrel group. For patients who received their last dose of thienopyridine within 4 to 7 days prior to CABG, the frequencies decreased to 11.3% (9 of 80 patients) in the prasugrel group and 3.4% (3 of 89 patients) in the clopidogrel group.
Do not start Effient in patients likely to undergo urgent CABG. CABG-related bleeding may be treated with transfusion of blood products, including packed red blood cells and platelets; however, platelet transfusions within 6 hours of the loading dose or 4 hours of the maintenance dose may be less effective.
Discontinuation Of Effient
Discontinue thienopyridines, including Effient, for active bleeding, elective surgery, stroke, or TIA. The optimal duration of thienopyridine therapy is unknown. In patients who are managed with PCI and stent placement, premature discontinuation of any antiplatelet medication, including thienopyridines, conveys an increased risk of stent thrombosis, myocardial infarction, and death. Patients who require premature discontinuation of a thienopyridine will be at increased risk for cardiac events. Lapses in therapy should be avoided, and if thienopyridines must be temporarily discontinued because of an adverse event(s), they should be restarted as soon as possible [see CONTRAINDICATIONS and General Risk of Bleeding].
Thrombotic Thrombocytopenic Purpura
Thrombotic thrombocytopenic purpura (TTP) has been reported with the use of Effient. TTP can occur after a brief exposure ( < 2 weeks). TTP is a serious condition that can be fatal and requires urgent treatment, including plasmapheresis (plasma exchange). TTP is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes [fragment red blood cells] seen on peripheral smear), neurological findings, renal dysfunction, and fever [see ADVERSE REACTIONS].
Hypersensitivity Including Angioedema
Hypersensitivity including angioedema has been reported in patients receiving Effient, including patients with a history of hypersensitivity reaction to other thienopyridines [see CONTRAINDICATIONS and ADVERSE REACTIONS].
Patient Counseling Information
See FDA-approved patient labeling (Medication Guide)
Benefits and Risks
- Summarize the effectiveness features and potential side effects of Effient.
- Tell patients to take Effient exactly as prescribed.
- Remind patients not to discontinue Effient without first discussing it with the physician who prescribed Effient.
- Recommend that patients read the Medication Guide.
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.
Other Signs and Symptoms Requiring Medical Attention
- 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 any of the following symptoms that cannot otherwise be explained: fever, weakness, extreme skin paleness, purple skin patches, yellowing of the skin or eyes, or neurological changes.
- Inform patients that they may have hypersensitivity reactions including rash, angioedema, anaphylaxis, or other manifestations. Patients who have had hypersensitivity reactions to other thienopyridines may have hypersensitivity reactions to Effient.
Instruct patients to:
- inform physicians and dentists that they are taking Effient before any invasive procedure is scheduled.
- tell the doctor performing the invasive procedure to talk to the prescribing health care professional before stopping Effient.
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).
Carcinogenesis, Mutagenesis, Impairment Of Fertility
No compound-related tumors were observed in a 2-year rat study with prasugrel at oral doses up to 100 mg/kg/day ( > 100 times the recommended therapeutic exposures in humans (based on plasma exposures to the major circulating human metabolite). There was an increased incidence of tumors (hepatocellular adenomas) in mice exposed for 2 years to high doses ( > 250 times the human metabolite exposure).
Prasugrel was not genotoxic in two in vitro tests (Ames bacterial gene mutation test, clastogenicity assay in Chinese hamster fibroblasts) and in one in vivo test (micronucleus test by intraperitoneal route in mice).
Impairment of Fertility
Prasugrel had no effect on fertility of male and female rats at oral doses up to 300 mg/kg/day (80 times the human major metabolite exposure at daily dose of 10-mg prasugrel).
Use In Specific Populations
Pregnancy Category B
There are no adequate and well-controlled studies of Effient 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. Effient 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 [see Nonclinical Toxicology].
It is not known whether Effient is excreted in human milk; however, metabolites of Effient 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.
Safety and effectiveness in pediatric patients have not been established [see CLINICAL PHARMACOLOGY].
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], 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, CLINICAL PHARMACOLOGY, and Clinical Studies].
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, WARNINGS AND PRECAUTIONS, and CLINICAL PHARMACOLOGY]. 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 and CLINICAL PHARMACOLOGY].
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 and CLINICAL PHARMACOLOGY].
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 and CLINICAL PHARMACOLOGY].
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.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 7/29/2015
Additional Effient Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Get the latest treatment options.