Efient 5mg & 10mg film-coated tablets (Eli Lilly and Company Ltd Daiichi Sankyo UK Limited) Daiichi Sankyo UK Limited
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Active ingredient
prasugrel hydrochloride
Legal Category
POM: Prescription only medicine
Efient 10 mg film-coated tablets.
Efient 5 mg film-coated tablets.
Efient 10 mg:
Each tablet contains 10 mg prasugrel (as hydrochloride).
Excipient(s) with known effect
Each tablet contains 2.1 mg lactose.
Efient 5 mg:
Each tablet contains 5 mg prasugrel (as hydrochloride).
Excipient(s) with known effect
Each tablet contains 2.7 mg lactose.
For the full list of excipients, see section 6.1.
Film-coated tablet (tablet).
Efient 10 mg:
Beige and double-arrow shaped tablets, debossed with “10 MG” on one side and “4759” on the other.
Efient 5 mg:
Yellow and double-arrow shaped tablets, debossed with “5 MG” on one side and “4760” on the other.
Efient, co-administered with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic events in adult patients with acute coronary syndrome (i.e. unstable angina, non-ST segment elevation myocardial infarction [UA/NSTEMI] or ST segment elevation myocardial infarction [STEMI]) undergoing primary or delayed percutaneous coronary intervention (PCI).
For further information please refer to section 5.1.
Posology
Adults
Efient should be initiated with a single 60 mg loading dose and then continued at 10 mg once a day. In UA/NSTEMI patients, where coronary angiography is performed within 48 hours after admission, the loading dose should only be given at the time of PCI (see sections 4.4, 4.8 and 5.1). Patients taking Efient should also take ASA daily (75 mg to 325 mg).
In patients with acute coronary syndrome (ACS) who are managed with PCI, premature discontinuation of any antiplatelet agent, including Efient, could result in an increased risk of thrombosis, myocardial infarction or death due to the patient's underlying disease. A treatment of up to 12 months is recommended unless the discontinuation of Efient is clinically indicated (see sections 4.4 and 5.1).
Patients ≥ 75 years old
The use of Efient in patients ≥ 75 years of age is generally not recommended. If, after a careful individual benefit/risk eva luation by the prescribing physician (see section 4.4), treatment is deemed necessary in the patients age group ≥ 75 years, then following a 60 mg loading dose a reduced maintenance dose of 5 mg should be prescribed. Patients ≥ 75 years of age have greater sensitivity to bleeding and higher exposure to the active metabolite of prasugrel (see sections 4.4, 4.8, 5.1 and 5.2).
Patients weighing < 60 kg
Efient should be given as a single 60 mg loading dose and then continued at a 5 mg once daily dose. The 10 mg maintenance dose is not recommended. This is due to an increase in exposure to the active metabolite of prasugrel, and an increased risk of bleeding in patients with body weight < 60 kg when given a 10 mg once daily dose compared with patients ≥ 60 kg (see sections 4.4, 4.8 and 5.2).
Renal impairment
No dose adjustment is necessary for patients with renal impairment, including patients with end stage renal disease (see section 5.2). There is limited therapeutic experience in patients with renal impairment (see section 4.4).
Hepatic impairment
No dose adjustment is necessary in subjects with mild to moderate hepatic impairment (Child Pugh class A and B) (see section 5.2). There is limited therapeutic experience in patients with mild and moderate hepatic dysfunction (see section 4.4). Efient is contraindicated in patients with severe hepatic impairment (Child Pugh class C).
Paediatric population
The safety and efficacy of Efient in children below age 18 has not been established. Limited data are available in children with sickle cell anaemia (see section 5.1).
Method of administration
For oral use. Efient may be administered with or without food. Administration of the 60 mg prasugrel loading dose in the fasted state may provide most rapid onset of action (see section 5.2). Do not crush or break the tablet.
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Active pathological bleeding.
History of stroke or transient ischaemic attack (TIA).
Severe hepatic impairment (Child Pugh class C).
Bleeding risk
In the phase 3 clinical trial (TRITON) key exclusion criteria included an increased risk of bleeding; anaemia; thrombocytopaenia; a history of pathological intracranial findings. Patients with acute coronary syndromes undergoing PCI treated with Efient and ASA showed an increased risk of major and minor bleeding according to the TIMI classification system. Therefore, the use of Efient in patients at increased risk of bleeding should only be considered when the benefits in terms of prevention of ischaemic events are deemed to outweigh the risk of serious bleedings. This concern applies especially to patients:
• ≥ 75 years of age (see below).
• with a propensity to bleed (e.g. due to recent trauma, recent surgery, recent or recurrent gastrointestinal bleeding, or active peptic ulcer disease)
• with body weight < 60 kg (see sections 4.2 and 4.8). In these patients the 10 mg maintenance dose is not recommended. A 5 mg maintenance dose should be used.
• with concomitant administration of medicinal products that may increase the risk of bleeding, including oral anticoagulants, clopidogrel, non-steroidal anti-inflammatory drugs (NSAIDs), and fibrinolytics.
For patients with active bleeding for whom reversal of the pharmacological effects of Efient is required, platelet transfusion may be appropriate.
The use of Efient in patients ≥75 years of age is generally not recommended and should only be undertaken with caution after a careful individual benefit/risk eva luation by the prescribing physician indicates that benefits in terms of prevention of ischaemic events outweigh the risk of serious bleedings. In the phase 3 clinical trial these patients were at greater risk of bleeding, including fatal bleeding, compared to patients <75 years of age. If prescribed, a lower maintenance dose of 5 mg should be used; the 10 mg maintenance dose is not recommended (see sections 4.2 and 4.8).
Therapeutic experience with prasugrel is limited in patients with renal impairment (including ESRD) and in patients with moderate hepatic impairment. These patients may have an increased bleeding risk. Therefore, prasugrel should be used with caution in these patients.
Patients should be told that it might take longer than usual to stop bleeding when they take prasugrel (in combination with ASA), and that they should report any unusual bleeding (site or duration) to their physician.
Bleeding Risk Associated with Timing of Loading Dose in NSTEMI
In a clinical trial of NSTEMI patients (the ACCOAST study), where patients were scheduled to undergo coronary angiography within 2 to 48 hours after randomization, a prasugrel loading dose given on average 4 hours prior to coronary angiography increased the risk of major and minor peri-procedural bleeding compared with a prasugrel loading dose at the time of PCI. Therefore, in UA/NSTEMI patients, where coronary angiography is performed within 48 hours after admission, the loading dose should be given at the time of PCI. (see sections 4.2, 4.8 and 5.1).
Surgery
Patients should be advised to inform physicians and dentists that they are taking prasugrel before any surgery is scheduled and before any new medicinal product is taken. If a patient is to undergo elective surgery, and an antiplatelet effect is not desired, Efient should be discontinued at least 7 days prior to surgery. Increased frequency (3-fold) and severity of bleeding may occur in patients undergoing CABG surgery within 7 days of discontinuation of prasugrel (see section 4.8). The benefits and risks of prasugrel should be carefully considered in patients in whom the coronary anatomy has not been defined and urgent CABG is a possibility.
Hypersensitivity including angioedema
Hypersensitivity reactions including angioedema have been reported in patients receiving prasugrel, including in patients with a history of hypersensitivity reaction to clopidogrel. Monitoring for signs of hypersensitivity in patients with a known allergy to thienopyridines is advised (see section 4.8).
Thrombotic Thrombocytopaenic Purpura (TTP)
TTP has been reported with the use of prasugrel. TTP is a serious condition and requires prompt treatment.
Lactose
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Efient.
Warfarin:
Concomitant administration of Efient with coumarin derivatives other than warfarin has not been studied. Because of the potential for increased risk of bleeding, warfarin (or other coumarin derivatives) and prasugrel should be co-administered with caution (see section 4.4).
Non-steroidal anti-inflammatory drugs (NSAIDs):
Concomitant administration with chronic NSAIDs has not been studied. Because of the potential for increased risk of bleeding, chronic NSAIDs (including COX-2 inhibitors) and Efient should be co-administered with caution (see section 4.4).
Efient can be concomitantly administered with medicinal products metabolised by cytochrome P450 enzymes (including statins), or medicinal products that are inducers or inhibitors of cytochrome P450 enzymes. Efient can also be concomitantly administered with ASA, heparin, digoxin, and medicinal products that elevate gastric pH, including proton pump inhibitors and H2 blockers. Although not studied in specific interaction studies, Efient has been co-administered in the phase 3 clinical trial with low molecular weight heparin, bivalirudin, and GP IIb/IIIa inhibitors (no information available regarding the type of GP IIb/IIIa inhibitor used) without evidence of clinically significant adverse interactions.
Effects of other medicinal products on Efient
Acetylsalicylic acid:
Efient is to be administered concomitantly with acetylsalicylic acid (ASA). Although a pharmacodynamic interaction with ASA leading to an increased risk of bleeding is possible, the demonstration of the efficacy and safety of prasugrel comes from patients concomitantly treated with ASA.
Heparin:
A single intravenous bolus dose of unfractionated heparin (100 U/kg) did not significantly alter the prasugrel-mediated inhibition of platelet aggregation. Likewise, prasugrel did not significantly alter the effect of heparin on measures of coagulation. Therefore, both medicinal products can be administered concomitantly. An increased risk of bleeding is possible when Efient is co-administered with heparin.
Statins:
Atorvastatin (80 mg daily) did not alter the pharmacokinetics of prasugrel and its inhibition of platelet aggregation. Therefore, statins that are substrates of CYP3A are not anticipated to have an effect on the pharmacokinetics of prasugrel or its inhibition of platelet aggregation.
Medicinal products that elevate gastric pH:
Daily co-administration of ranitidine (an H2 blocker) or lansoprazole (a proton pump inhibitor) did not change the prasugrel active metabolite's AUC and Tmax, but decreased the Cmax by 14% and 29%, respectively. In the phase 3 clinical trial, Efient was administered without regard to co-administration of a proton pump inhibitor or H2 blocker. Administration of the 60 mg prasugrel loading dose without concomitant use of proton pump inhibitors may provide most rapid onset of action.
Inhibitors of CYP3A:
Ketoconazole (400 mg daily), a selective and potent inhibitor of CYP3A4 and CYP3A5, did not affect prasugrel-mediated inhibition of platelet aggregation or the prasugrel active metabolite's AUC and Tmax, but decreased the Cmax by 34% to 46%. Therefore, CYP3A inhibitors such as azol antifungals, HIV protease inhibitors, clarithromycin, telithromycin, verapamil, diltiazem, indinavir, ciprofloxacin, and grapefruit juice are not anticipated to have a significant effect on the pharmacokinetics of the active metabolite.
Inducers of cytochromes P450:
Rifampicin (600 mg daily), a potent inducer of CYP3A and CYP2B6, and an inducer of CYP2C9, CYP2C19, and CYP2C8, did not significantly change the pharmacokinetics of prasugrel. Therefore, known CYP3A inducers such as rifampicin, carbamazepine, and other inducers of cytochromes P450 are not anticipated to have significant effect on th
