Active ingredients: Prasugrel
Efient 10 mg film-coated tablets
Efient 5 mg film-coated tablets
Why is Efient used? What is it for?
Efient, which contains the active substance prasugrel, belongs to a group of medicines called antiplatelet agents. Platelets are very small cells that circulate in the blood. When a blood vessel is damaged, for example if it is cut, the platelets clump together to contribute to the formation of a blood clot (thrombus). Therefore, platelets are essential to help stop bleeding. If clots form inside a hardened blood vessel, such as an artery, they can be very dangerous as they can block the passage of blood, causing a heart attack ( myocardial infarction), stroke or death Clots in the arteries that carry blood to the heart can also reduce the flow of blood to the heart, causing unstable angina (severe pain in the chest).
Efient inhibits platelet aggregation and therefore reduces the chance of blood clots forming.
Efient was prescribed for you because you have previously had a heart attack or unstable angina and were treated with a procedure to open blocked heart arteries. You may also have had one or more stents placed in the blocked or narrowed artery to restore blood flow. Efient reduces the chances of you having another heart attack or stroke or dying from one of these atherothrombotic events. Your doctor will also prescribe acetylsalicylic acid (i.e. aspirin), another antiplatelet drug.
Contraindications When Efient should not be used
Do not take Efient
- If you are allergic (hypersensitive) to prasugrel or any of the other ingredients of Efient. An allergic reaction can be recognized because it causes a rash, itching, swelling of the face, swelling of the lips or wheezing. If any of these occur, tell your doctor immediately.
- If you have a medical condition that is causing you to be bleeding, such as bleeding in your stomach or intestines.
- If you have previously had a stroke or transient ischemic attack (TIA).
- If you have severe liver disease.
Precautions for use What you need to know before taking Efient
If any of the situations mentioned below occur, tell your doctor before taking Efient:
- If you have an increased risk of bleeding, such as:
- 75 years of age or older. Your doctor will prescribe a daily dose of 5 mg as there is an increased risk of bleeding in patients over 75 years of age.
- a recent severe trauma
- recent surgery (including some dental procedures)
- recent or recurrent bleeding in the stomach or intestines (for example a stomach ulcer or colon polyp)
- a body weight of less than 60 kg. Your doctor will prescribe a daily dose of 5 mg of Efient if your weight is less than 60 kg - moderate liver or kidney disease
- if you are taking certain medicines (see "Taking Efient with other medicines")
- if you are due to have a scheduled surgery (including some dental procedures) within the next seven days. Your doctor may advise you to temporarily stop taking Efient due to an increased risk of bleeding
- If you have ever had allergic (hypersensitivity) reactions to clopidogrel or any other antiplatelet drug, please tell your doctor before starting treatment with Efient. If you then take Efient and experience allergic reactions which may be recognized as a "rash, itching, swelling of the face, swollen lips or shortness of breath, you should tell your doctor immediately.
While taking Efient:
Tell your doctor right away if you develop a medical condition called Thrombotic Thrombocytopenic Purpura (PTT), which includes fever and bruising under the skin which may appear as tiny red dots, with or without unexplained profound tiredness, confusion, discoloration. yellow skin or eyes (jaundice) (see section 4 "Possible side effects").
Children and adolescents
Efient is not for use in children and adolescents under 18 years of age.
Interactions Which drugs or foods can change the effect of Efient
Tell your doctor if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription, dietary supplements and herbal remedies. It is especially important that you tell your doctor if you are being treated with clopidogrel (an antiplatelet medicine), warfarin (an anticoagulant), or with "non-steroidal anti-inflammatory drugs" to relieve pain and reduce fever (such as ibuprofen, naproxen, etoricoxib ). When given in combination with Efient these medicines may increase the risk of bleeding.
Only take other medicines while on Efient if your doctor says you can.
Warnings It is important to know that:
Pregnancy and breastfeeding
Tell your doctor if you are pregnant or planning to become pregnant while you are taking Efient. You should only use Efient after discussing the potential benefits and any potential risks to your unborn child with your doctor.
If you are breastfeeding, ask your doctor or pharmacist for advice before taking any medicine
Driving and using machines
Efient is unlikely to affect your ability to drive or use machines.
Efient contains lactose.
If you have been told by your doctor that you have an "intolerance to some sugars, consult your doctor before taking this medicine.
Dose, Method and Time of Administration How to use Efient: Posology
Always take Efient exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
The usual dose of Efient is 10 mg per day. Treatment will start with a single dose of 60 mg. If your body weight is less than 60 kg or if you are over 75 years of age, the dose is 5 mg of Efient per day.
Your doctor will also tell you to take acetylsalicylic acid - he will tell you the exact dose to take (usually between 75 mg and 325 mg per day).
You can take Efient with or without food. Take Efient at about the same time each day. Do not crush or break the tablet.
It is important that you tell your doctor, pharmacist and dentist that you are taking Efient.
Overdose What to do if you have taken too much Efient
If you take more Efient than you should
Contact your doctor or the nearest hospital straight away, because of the risk of excessive bleeding. Show your doctor your pack of Efient.
If you forget to take Efient
If you forget to take a dose, take one tablet as soon as you notice it. If you forget to take your dose all day, just take your normal dose of Efient the following day. Do not take two doses on the same day. For packs of 14, 28, 56, 84 and 98 tablets, you can check the day you took your last Efient tablet by checking the calendar printed on the blister.
If you stop taking Efient
Do not stop taking Efient without talking to your doctor If you stop taking Efient too soon, the risk of a myocardial infarction may be higher.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Efient
Like all medicines, Efient can cause side effects, although not everybody gets them.
You should contact your doctor immediately if you notice any of the following side effects:
- Sudden sleepiness or weakness in an arm, leg or face, especially if limited to one side of the body
- Sudden confusion, difficulty speaking or understanding what others are saying
- Sudden difficulty walking or loss of balance or coordination
- Sudden dizziness or sudden severe headache with no known cause.
All of the above can be signs of a stroke. Stroke is an uncommon side effect of Efient in patients who have never had a stroke or transient ischemic attack (TIA).
Also contact your doctor immediately if you notice any of the following side effects:
- fever and bruising under the skin which may appear as very small red dots, with or without unexplained profound tiredness, confusion, yellowing of the skin or eyes (jaundice) (see section 2 "BEFORE YOU TAKE EFIENT")
- a "skin rash, itching, or swelling of the face, swelling of the lips / tongue or wheezing. All these may be signs of a serious allergic reaction (see section 2" What you need to know before you take Efient ")
You should contact your doctor promptly if you notice any of the following side effects:
- Blood in the urine
- Bleeding from the rectum, blood in the stool or black colored stool
- Uncontrollable bleeding, for example from a cut
All of the above may be signs of bleeding, the most common side effect with Efient. While uncommon, severe bleeding can be life-threatening.
Common side effects (may affect up to 1 in 10 people)
- Bleeding in the stomach or intestines
- Bleeding from the site of a needle prick
- Nosebleeds
- Rash on the skin
- Small red bruises on the skin (bruising)
- Blood in the urine
- Hematoma (bleeding under the skin at the site of an injection, or into a muscle, causing swelling)
- Low hemoglobin or low red blood cell count (anemia)
- Bruises
Uncommon side effects (may affect up to 1 in 100 people)
- Allergic reaction (rash, itching, swelling of the lips / tongue or wheezing)
- Spontaneous bleeding from the eye, rectum, gums or abdomen around internal organs
- Bleeding after surgery
- Coughing up blood
- Blood in the stool
Rare side effects (may affect up to 1 in 1,000 people)
- Low number of platelets in the blood
- Subcutaneous hematoma (bleeding under the skin causing swelling)
Reporting of side effects
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep Efient out of the sight and reach of children.
Do not use Efient after the expiry date which is stated on the blister and carton after EXP. The expiry date refers to the last day of the month.
Store in the original package to protect from air and moisture.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What Efient contains
- The active ingredient is prasugrel.
Efient 10 mg: Each tablet contains 10 mg of prasugrel (as hydrochloride).
Efient 5 mg: Each tablet contains 5 mg of prasugrel (as hydrochloride).
- The other ingredients are microcrystalline cellulose, mannitol (E421), croscarmellose sodium, hypromellose (E464), magnesium stearate, lactose monohydrate, titanium dioxide (E171), triacetin (E1518), red iron oxide (only for 10 mg tablets) ( E172), yellow iron oxide (E172) and talc.
What Efient looks like and contents of the pack
Efient 10 mg: The tablets are beige in color and shaped like a double arrow, debossed with "10 MG" on one side and "4759" on the other side.
Efient 5 mg: The tablets are yellow and double arrow shaped, debossed with "5 MG" on one side and "4760" on the other side.
Efient is available in packs of 14, 28, 30, 56, 84, 90 and 98 tablets.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
EFIENT 10 MG TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 10 mg of prasugrel (as hydrochloride).
Excipients with known effects: each tablet contains 2.1 mg of lactose.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablet (tablet).
Beige colored, double arrow shaped tablets, debossed with "10 MG" on one side and "4759" on the other.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Efient, given in combination with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic events in adult patients with acute coronary syndrome (ACS) (i.e. unstable angina, myocardial infarction without ST segment elevation [UA / NSTEMI] or ST-segment elevation myocardial infarction [STEMI]) undergoing primary or delayed percutaneous coronary intervention (PCI).
For further information see section 5.1.
04.2 Posology and method of administration
Dosage
Adults
Efient should be started with a single 60 mg loading dose and then continued at 10 mg once daily. Patients taking Efient should also take acetylsalicylic acid (ASA) 75 mg - 325 mg per day.
In patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention, early discontinuation of any antiplatelet drug, including Efient, could lead to an increased risk of thrombosis, myocardial infarction or death due to the patient's underlying medical condition. Treatment of up to 12 months duration is recommended unless discontinuation of Efient is clinically indicated (see sections 4.4 and 5.1).
Age patients ≥ 75 years old
The use of Efient in patients ≥ 75 years of age is generally not recommended. If, after careful consideration of the individual benefit / risk ratio by the prescribing physician (see section 4.4), treatment with Efient is deemed necessary in patients in the age group ≥ 75 years, then a reduced maintenance dose of 5 mg should be prescribed after the 60 mg loading dose. Patients aged ≥ 75 years have increased bleeding sensitivity and increased exposure to the metabolite active ingredient of prasugrel (see sections 4.4, 4.8, 5.1 and 5.2).
Patients with body weight
Efient should be administered as a single 60 mg loading dose followed by a 5 mg once daily dose. A maintenance dose of 10 mg 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 weight
Renal impairment
No dose adjustment is required for patients with renal insufficiency, including patients with end stage renal disease (see section 5.2). There is limited therapeutic experience in patients with renal insufficiency (see section 4.4).
Hepatic impairment
No dose adjustment is required 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 impairment (see section 4.4). Efient is contraindicated in patients with severe hepatic impairment (Child Pugh class C).
Pediatric population
The safety and efficacy of Efient in children below 18 years of age have not yet been established. There are no data available.
Method of administration
For oral use. Efient can be given without regard for food. Administration of the 60 mg loading dose of prasugrel in the fasted state may result in a more rapid onset of action of the medicinal product (see section 5.2). Do not crush or break the tablet.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Pathological bleeding in progress.
History of stroke or transient ischemic attack (TIA).
Severe hepatic dysfunction (Child-Pugh class C).
04.4 Special warnings and appropriate precautions for use
Risk of bleeding
In the Phase 3 clinical trial, the key exclusion criteria included an increased risk of bleeding; anemia; thrombocytopenia; a history of findings indicative of intracranial pathology.
Patients with acute coronary syndromes undergoing percutaneous coronary intervention 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 with an increased risk of bleeding should only be considered when the benefits in terms of prevention of ischemic events are considered to outweigh the risk of serious bleeding. This precaution applies especially to patients:
• aged ≥75 years (see below).
• with a propensity to bleed (eg due to recent trauma, recent surgery, recent or recurrent gastrointestinal bleeding, or ongoing peptic ulcer disease)
• with body weight
• in concomitant treatment with medicines that may increase the risk of bleeding, including oral anticoagulants, clopidogrel, non-steroidal anti-inflammatory drugs (NSAIDs), and fibrinolytics.
For patients with ongoing bleeding who need to reverse the pharmacological effects of Efient, platelet transfusion may be appropriate.
Administration of Efient to patients ≥75 years of age is generally not recommended and should only be done with caution after a "careful individual benefit / risk assessment by the prescribing physician indicates that the prevention benefits of ischemic events are greater than the risk of serious bleeding. In the phase 3 clinical trial these patients were at an increased risk of bleeding, including fatal bleeding, compared to patients of age
Therapeutic experience with prasugrel is limited in patients with renal dysfunction (including patients with end stage renal disease (ESRD)) and in patients with moderate hepatic dysfunction. These patients may have an increased risk of bleeding.
Therefore, prasugrel should be used with caution in these patients.
Patients should be advised that when taking prasugrel (in combination with ASA) it may take longer than usual to stop bleeding and should inform their doctor of any unusual bleeding (by location or duration).
Surgical intervention
Before undergoing any surgery and before taking a new medicine, patients should tell their doctors and dentists that they are taking prasugrel. If a patient is to undergo elective surgery and an antiplatelet effect is not considered appropriate, Efient should be stopped at least 7 days prior to surgery. An increased (3-fold) frequency and severity of bleeding may occur in patients. undergoing CABG surgery within 7 days of stopping prasugrel (see section 4.8). The benefits and risks of prasugrel should be carefully considered in those patients whose coronary anatomy has not been defined and urgent CABG surgery is possible.
Hypersensitivity including angioedema
Hypersensitivity reactions including angioedema have been reported in patients receiving prasugrel, including patients with a history of hypersensitivity reactions to clopidogrel. Monitoring for signs of hypersensitivity is advised in patients with a known history of allergy to thienopyridines (see section 4.8).
Thrombotic Thrombocytopenic Purpura (PTT)
PTT has been reported with the use of prasugrel. PTT is a serious condition that requires immediate treatment.
Lactose
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Efient..
04.5 Interactions with other medicinal products and other forms of interaction
Warfarin: Co-administration of Efient and coumarin derivatives other than warfarin has not been studied. Due to the possibility of an increased risk of bleeding, caution should be exercised in co-administration of warfarin (or other coumarin derivatives) and prasugrel (see section 4.4).
Non-steroidal anti-inflammatory drugs (NSAIDs):
Co-administration of chronic NSAIDs has not been studied. Due to the possibility of an increased risk of bleeding, co-administration of chronic NSAIDs (including COX-2 inhibitors) and Efient should be done with caution (see section 4.4).
Efient can be administered in combination 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 given in combination with ASA, heparin, digoxin, and drugs that raise gastric pH, including proton pump inhibitors and H2 blockers.
Although not the subject of specific interaction studies, Efient was administered in the phase 3 clinical study in combination with low molecular weight heparin, bivalirudin, and GP IIb / IIIa inhibitors (no information is available regarding the type of inhibitor of the GP IIb / IIIa used) with no evidence of clinically significant adverse interactions.
Effects of other medicinal products on Efient:
Acetylsalicylic acid: Efient must be administered in combination with ASA. Although a pharmacodynamic interaction with ASA with a consequent increased risk of bleeding is possible, evidence of the efficacy and safety of prasugrel comes from patients treated in combination 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 coagulation parameters.
Therefore, both medicines can be administered in combination. An increased risk of bleeding is possible when Efient is given in combination with heparin.
Statins: Atorvastatin (80 mg daily) did not alter the pharmacodynamic activity of prasugrel or its inhibition of platelet aggregation. Therefore, CYP3A substrate statins are not expected to have an effect on the pharmacokinetics of prasugrel or its inhibition of platelet aggregation. platelet aggregation.
Medicines that raise gastric pH: Co-administration of ranitidine (an H2 blocker) or lansoprazole (a proton pump inhibitor) daily did not change the AUC and Tmax of the active metabolite of prasugrel, but decreased Cmax by 14% and 29%, In the Phase 3 clinical trial, Efient was administered independently of concomitant administration of a proton pump inhibitor or H2 blocker. Administration of the 60 mg loading dose of prasugrel without concomitant use of proton pump inhibitors. it may result in a faster onset of the medicine's action.
CYP3A inhibitors: Ketoconazole (400 mg daily), a potent and selective inhibitor of CYP3A4 and CYP3A5, did not change the inhibition of prasugrel-mediated platelet aggregation or the AUC and T of the active metabolite of prasugrel, but decreased the Cmax 34% to 46%. Therefore, CYP3A inhibitors such as azole antifungals, HIV protease inhibitors, clarithromycin, telithromycin, verapamil, diltiazem, indinavir, ciprofloxacin, and grapefruit juice are not expected to have a significant effect on the pharmacokinetics of the metabolite. active.
Inducers of cytochrome P450: Rifampicin (600 mg daily), a potent inducer of CYP3A and CYP2B6, as well as inducer of CYP2C9, CYP2C19, and CYP2C8, did not significantly alter the pharmacokinetics of prasugrel. Therefore, known inducers of CYP3A such as rifampicin, carbamazepine, and other inducers of cytochromes P450 are not expected to have a significant effect on the pharmacokinetics of the active metabolite.
Effects of Efient on other medicinal products:
Digoxin: Prasugrel has no clinically significant effect on digoxin pharmacokinetics.
Medicinal products metabolised by CYP2C9: Prasugrel did not inhibit CYP2C9, as it did not affect the pharmacokinetics of warfarin-S. Due to a potential increased risk of bleeding, caution should be exercised when administering warfarin and Efient in combination (see section 4.4).
Medicinal products metabolised by CYP2B6: Prasugrel is a weak CYP2B6 inhibitor. In healthy subjects, prasugrel reduced exposure to hydroxybupropion, a CYP2B6-mediated metabolite of bupropion, by 23%. This effect is likely to be of clinical concern only when prasugrel is administered in combination with medicinal products for which CYP2B6 is the only metabolic pathway and which have a limited therapeutic window (eg cyclophosphamide, efavirenz).
04.6 Pregnancy and lactation
No clinical studies have been performed in pregnant or breastfeeding women.
Pregnancy
Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal / fetal development, parturition or postnatal development (see section 5.3). Since reproductive activity studies in animals are not always predictive of effects in humans, Efient should only be used in pregnancy if the potential benefit justifies the potential risk to the fetus.
Feeding time
It is not known whether prasugrel is excreted in human milk. Studies in animals have shown the elimination of prasugrel in breast milk. The use of prasugrel during breastfeeding is not recommended.
Fertility
Prasugrel had no effect on male and female fertility in rats exposed to oral doses up to 240 times the recommended human maintenance daily dose (assessed in mg / m2).
04.7 Effects on ability to drive and use machines
Prasugrel is not expected to affect or negligibly affect the ability to drive or use machines.
04.8 Undesirable effects
Summary of the safety profile
Safety in patients with acute coronary syndrome undergoing percutaneous coronary intervention was evaluated in a clopidogrel controlled clinical trial (TRITON) in which 6,741 patients were treated with prasugrel (with a loading dose of 60 mg and a maintenance dose of 10 mg per day) for a median of 14.5 months (5,802 patients were treated for more than 6 months, 4,136 patients were treated for more than 1 year). The rate of study drug discontinuation due to adverse events was 7.2% for prasugrel and 6.3% for clopidogrel. Of these, 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
Bleeding not related to coronary artery bypass grafting (CABG)
In the TRITON study, the frequency of patients who experienced a bleeding episode not related to coronary artery bypass grafting (CABG) is shown in Table 1.The incidence of major bleeding (according to TIMI definitions) not related to coronary artery bypass grafting (CABG), including those at risk of death and fatal ones, as well as that of minor bleeding (according to TIMI definitions), was statistically significantly higher in subjects treated with prasugrel compared to subjects treated with clopidogrel in both the UA / NSTEMI population and the whole ACS population. No significant differences were observed in the STEMI population. The most common site of spontaneous bleeding was the gastrointestinal tract (1.7% with prasugrel and 1.3% with clopidogrel); the most common site of induced bleeding was the arterial access site (1.3% with prasugrel and 1.2% with clopidogrel).
Table 1: Incidence of Bleeding Not Related to Coronary Artery Bypass Surgery (CABG) a (% of Patients)
a Events defined by the criteria of the Study Group Thrombolysis in Myocardial Infarction (TIMI) undergoing evaluation centralized.
b Other standard therapies were administered as appropriate.
c Any intracranial haemorrhage or any clinically evident bleeding associated with a decrease of hemoglobin ≥5 g / dl.
d Bleeding at risk of death is a subgroup of major bleeding (according to TIMI definitions) e includes the types listed below. Patients can be counted in more than one row.
and ICH = intracranial haemorrhage.
f Clinically evident bleeding associated with a decrease in hemoglobin ≥3 g / dl but
Age patients ≥ 75 years old
Rates of major or minor bleeding (TIMI) not related to coronary artery bypass grafting (CABG):
* TRITON study in patients with ACS undergoing PCI
** TRILOGY-ACS study in patients not undergoing PCI (see section 5.1):
to prasugrel 10 mg; prasugrel 5 mg if
Patients with body weight
Rates of major or minor bleeding (TIMI) not related to coronary artery bypass grafting (CABG):
* TRITON study in patients with ACS undergoing PCI
** TRILOGY-ACS study in patients not undergoing PCI (see section 5.1):
to prasugrel 10 mg; prasugrel 5 mg if ≥75 years of age
Patients weighing ≥60 kg and age
In patients weighing ≥60 kg and age
Bleeding Related to Coronary Artery Bypass Surgery (CABG)
In the Phase 3 clinical trial, 437 patients underwent coronary artery bypass grafting (CABG). Of these patients, the rate of major or minor bleeding (TIMI) related to coronary artery bypass grafting (CABG) was 14.1% for the prasugrel group and 4.5% for the clopidogrel group. The highest risk for bleeding episodes in subjects treated with prasugrel persisted for up to 7 days after the most recent dose of the study drug. For patients who received their thienopyridine within 3 days before coronary artery bypass grafting (CABG), the rates of major or minor bleeding (TIMI) 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 coronary artery bypass grafting (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. More than 7 days after stopping the drug, the observed rates of bleeding related to coronary artery bypass grafting (CABG) were similar between the 2 treatment groups (see section 4.4).
Summary table of adverse reactions
Table 2 summarizes the haemorrhagic and non-haemorrhagic adverse reactions in the TRITON study, or from spontaneous reports, classified by frequency and by systems and organs. Their frequency is defined using the following conventions: Very common (≥ 1/10); common (≥ 1/100,
Table 2: Haemorrhagic and Non-haemorrhagic adverse reactions
In patients with or without a history of transient ischemic attack (TIA) or stroke, the incidence of stroke in the phase 3 study was as follows (see section 4.4):
* ICH = intracranial hemorrhage.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. in "Annex V.
04.9 Overdose
Overdose of Efient can lead to prolonged bleeding time and consequent bleeding complications. There is no information on the "cancellation of" the pharmacological activity of prasugrel; however, when rapid correction of prolonged bleeding time is required, transfusion of platelets or other blood products may be considered.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antiplatelet agents, excluding heparin.
ATC code: B01AC22.
Pharmacodynamic effects
Prasugrel is an inhibitor of platelet activation and aggregation which acts through the irreversible binding of its active metabolite to the P2Y12 class ADP platelet receptors. Platelet function can lead to a reduction in the frequency of cardiovascular events such as death, myocardial infarction, or stroke.
After a loading dose of 60 mg prasugrel, ADP-induced inhibition of platelet aggregation occurs at 15 minutes with 5 mcM of ADP and at 30 minutes with 20 mcM of ADP. Maximum inhibition of platelet aggregation. induced by ADP obtained with prasugrel is 83% with 5 mcM of ADP and 79% with 20 mcM of ADP, in both cases with 89% of healthy subjects and patients with stable atherosclerosis reaching at least 50% of inhibition of platelet aggregation within 1 hour. The inhibition of platelet aggregation achieved with Prasugrel shows reduced inter- (9%) and intra-individual (12%) variability with both 5 mcM and 20 mcM of ADP. The mean inhibition of platelet aggregation at equilibrium was 74% and 69%, with 5 mcM of ADP and 20 mcM of ADP, respectively, and was achieved after a period of 3 to 5 days of administration of a single dose. maintenance dose of 10 mg prasugrel preceded by a 60 mg loading dose. Over 98% of subjects had ≥ 20% inhibition of platelet aggregation during the maintenance dose.
After treatment, platelet aggregation gradually returned to baseline over a period of 7 to 9 days after administration of a single 60 mg loading dose of prasugrel and 5 days after discontinuation of balance maintenance dosing. .
Data on switching from clopidogrel to prasugrel: After administration of clopidogrel 75 mg once daily for 10 days, 40 healthy subjects were switched to prasugrel 10 mg once daily, with or without a 60 mg loading dose. Similar or higher inhibition of platelet aggregation was observed with prasugrel. Switching directly to a loading dose of 60 mg of prasugrel resulted in a more rapid onset of greater platelet inhibition. After administration of a loading dose of 900 mg of clopidogrel (in combination with ASA), 56 subjects with ACS were treated for 14 days with prasugrel 10 mg once daily or clopidogrel 150 mg once daily, then underwent a treatment change to clopidogrel 150 mg or 10 mg prasugrel for an additional 14 days ("switch"), respectively. The greatest inhibition of platelet aggregation was observed in patients switched to 10 mg prasugrel compared to those treated with 150 mg clopidogrel. In a study of 276 ACS patients undergoing PCI, switching from an "initial loading dose of 600 mg of clopidogrel or placebo, given on admission to hospital, prior to coronary angiography, to a loading dose of 60 mg of prasugrel given at the time of PCI resulted in a similar increase in inhibition of platelet aggregation over the 72-hour study duration.
Efficacy and safety in acute coronary syndrome
In the phase 3 TRITON trial, Efient (prasugrel) was compared with clopidogrel, both given in combination with ASA and other standard therapies. TRITON is an international, randomized, double-blind, parallel group, multicenter study involving 13,608 patients. Patients had ACS with moderate to high risk UA and NSTEMI or STEMI and were managed with PCI.
Patients with UA / NSTEMI within 72 hours of symptom onset or with STEMI within 12 hours to 14 days of symptom onset were randomized after knowledge of the anatomy of the coronary circulation. Patients with STEMI within 12 hours of symptom onset and Scheduled for primary PCI could be randomized without knowledge of the coronary picture. In all patients, the loading dose could be administered at any time from randomization up to 1 hour after the patient left the laboratory where the cardiac catheterization.
Patients randomized to prasugrel (a 60 mg loading dose followed by 10 mg once daily) or clopidogrel (a 300 mg loading dose followed by 75 mg once daily) were treated for a median of 14.5 months (for a maximum of 15 months with a minimum of 6 months follow-up). Patients also received ASA (75 mg to 325 mg once daily).
The use of any thienopyridine in the 5 days prior to enrollment was an exclusion criterion. Other therapies, such as heparin and GPIIb / IIIa inhibitors, were administered at the physician's discretion. Approximately 40% of patients (in each treatment group) had received GPIIb / IIIa inhibitors to support PCI ( no information is available on the type of GP IIb / IIIa inhibitor used.) Approximately 98% of patients (in each treatment group) had directly received antithrombins (heparin, low molecular weight heparin, bivalirudin, or other medicine) as support. to the PCI.
The primary measure of the study outcome was the time to first event of cardiovascular (CV) death, non-fatal myocardial infarction (MI), or non-fatal stroke. The composite target analysis in the whole ACS population (including the UA / NSTEMI and STEMI groups) was conditional on the demonstration of statistical superiority of prasugrel over clopidogrel in the UA / NSTEMI group (p
Overall population of ACS: Efient demonstrated superior efficacy over clopidogrel in reducing the primary composite endpoint as well as pre-specified secondary endpoints, including stent thrombosis (see Table 3). The benefit of prasugrel was evident within the first 3 days and continued until the end of the study. Superior efficacy was accompanied by an increase in major bleeding (see sections 4.4 and 4.8). The patient population was 92% Caucasian, with 26% female and 39% ≥ 65 years of age. The benefits associated with prasugrel were independent of the use of other acute and long-term cardiovascular therapies, including low molecular weight heparin / heparin, bivalirudin, intravenous GPIIb / IIIa inhibitors, lipid-lowering drugs, beta - blockers and angiotensin converting enzyme inhibitors. The efficacy of prasugrel was independent of the dose of ASA (75-325 mg once daily). The use of oral anticoagulants, antiplatelet medicinal products other than those under study and chronic NSAIDs was not permitted in the TRITON study. In the overall ACS population, prasugrel was associated with a lower incidence of CV death. of non-fatal AMI, and of non-fatal stroke compared to clopidogrel, regardless of baseline characteristics such as age, gender, body weight, geographic region, use of GPIIb / IIIa inhibitors, and type of stent. The benefit was mainly due to a significant reduction in non-fatal AMI cases (see Table 3) Diabetics presented significant reductions in primary and all secondary composite endpoints.
The benefit of prasugrel observed in patients ≥ 75 years of age was less than that observed in patients with diabetes, STEMI, increased risk of stent thrombosis or recurrent events.
Patients with a history of TIA or with a history of ischemic attack dating back to more than 3 months prior to prasugrel therapy did not have a reduction in the primary composite goal.
Table 3: Patients with clinical outcomes in the primary analysis of the TRITON study
In the overall ACS population, analysis of each of the secondary endpoints demonstrated significant benefit (p
Prasugrel was associated with a 50% reduction in stent thrombosis during the 15-month follow-up period. Reduction in stent thrombosis with Efient was observed both early and beyond 30 days for both metal and medicated stents.
In an analysis of patients who survived an ischemic event, prasugrel was associated with a reduction in the incidence of subsequent primary endpoint events (7.8% with prasugrel vs. 11.9% with clopidogrel).
Although bleeding was increased with prasugrel, a composite "goal analysis" consisting of death from all causes, non-fatal myocardial infarction, non-fatal stroke, and TIMI non-CABG-related major bleeding was favorable for Efient compared to clopidogrel (HR 0.87; 95% CI, 0.79 to 0.95; p = 0.004). In the TRITON study, for every 1,000 patients treated with Efient, there were 22 fewer patients with myocardial infarction, and 5 more with TIMI non-CABG-related major bleeding, compared to patients treated with clopidogrel.
Results from a pharmacodynamic / pharmacogenomics study in 720 Asian ACS patients undergoing PCI demonstrated that higher levels of platelet inhibition are achieved with prasugrel than with clopidogrel, and that prasugrel 60 mg loading / 10 mg maintenance dose is an appropriate dosing regimen in Asian subjects who weigh at least 60 kg and are less than 75 years of age (see section 4.2).
In a 30-month study (TRILOGY-ACS), conducted in 9326 medically treated ACS UA / NSTEMI patients without revascularization (unregistered indication), prasugrel did not significantly reduce the frequency of the composite CV death target of MI , or stroke compared to clopidogrel.Major bleeding rates (TIMI) (including at-risk of death, fatal and intracranial haemorrhage) were similar in prasugrel-treated and clopidogrel-treated patients. Patients ≥ 75 years of age or weighing less than 60 kg (N = 3022) were randomized to 5 mg prasugrel. As in aged patients
05.2 Pharmacokinetic properties
Prasugrel is a prodrug and is rapidly metabolised in vivo to an active metabolite and inactive metabolites. Active metabolite exposure (AUC) has moderate to low inter-subject (27%) and within-subject (19%) variability. The pharmacokinetics of prasugrel are similar in healthy subjects, patients with stable atherosclerosis, and patients undergoing percutaneous coronary intervention.
Absorption
Absorption and metabolism of prasugrel are rapid, with peak plasma concentrations (Cmax) of the active metabolite reached in approximately 30 minutes. Exposure to the active metabolite (AUC) increases proportionally over the therapeutic dose. In one study in healthy subjects, the AUC of the active metabolite was not altered by a high-fat and high-calorie meal, but Cmax was reduced by 49% and the time to reach Cmax (Tmax) increased from 0, 5 to 1.5 hours. In the TRITON study, Efient was administered without regard to food intake. Therefore Efient can be administered without regard to food intake; however, administration of the loading dose of prasugrel in the fasted state may result in a more rapid onset of action (see section 4.2).
Distribution
The active metabolite binding to human serum albumin (4% buffer solution) was 98%.
Metabolism
Prasugrel does not appear in plasma following oral administration. It is rapidly hydrolyzed in the intestine to thiolactone, which is then converted to the active metabolite in a single metabolic step by cytochrome P450, mainly CYP3A4 and CYP2B6 and to a lesser extent by CYP2C9 and CYP2C19. The active metabolite is subsequently metabolised to two compounds. inactive by S-methylation or conjugation with cysteine.
In healthy subjects, patients with stable atherosclerosis and patients with ACS who received Efient, there was no relevant effect of the genetic variation of CYP3A5, CYP2B6, CYP2C9, or CYP2C19 on the pharmacokinetics of prasugrel or its inhibition of aggregation. platelet.
Elimination
Approximately 68% of the prasugrel dose is eliminated in the urine and 27% in the faeces as inactive metabolites. The active metabolite has an elimination half-life of approximately 7.4 hours (2 to 15 hours).
Particular populations:
Senior citizens: In a study in healthy subjects between the ages of 20 and 80, age had no significant effect on the pharmacokinetics of prasugrel or the inhibition of platelet aggregation it produces. In the large phase 3 clinical trial, exposure to the active metabolite (AUC) was 19% higher in very elderly patients (age ≥ 75 years) compared to subjects aged
Prasugrel should be used with caution in patients ≥ 75 years of age due to the potential for bleeding risk in this population (see sections 4.2 and 4.4). In a study in subjects with stable atherosclerosis, the mean exposure (AUC) to the active metabolite in patients ≥75 years of age taking 5 mg prasugrel was approximately half that in patients aged ≥75 years.
Hepatic insufficiency: No dose adjustment is required for patients with mild to moderate hepatic impairment (Child-Pugh class A or B). The pharmacokinetics of prasugrel and its inhibition of platelet aggregation were similar in subjects with mild to moderate hepatic impairment compared to healthy subjects. The pharmacokinetics and pharmacodynamics of prasugrel in patients with severe hepatic impairment have not been studied. it must not be used in patients with severe hepatic impairment (see section 4. 3).
Kidney failure: No dose adjustment is required for patients with renal insufficiency, including patients with end stage renal disease (ESRD). The pharmacokinetics of prasugrel and its inhibition of platelet aggregation are similar in patients with moderate renal impairment (glomerular filtration rate (GFR) 30-2) and healthy subjects. The inhibition of prasugrel-mediated platelet aggregation was similar. also in ESRD patients requiring hemodialysis compared to healthy subjects, although the Cmax and AUC of the active metabolite decreased by 51% and 42%, respectively, in ESRD patients.
Body weight: The active metabolite exposure (AUC) of prasugrel is approximately 30 to 40% higher in healthy subjects and patients with a body weight
Ethnicity: In clinical pharmacology studies, after adjustment for body weight, the AUC of the active metabolite was approximately 19% higher in Chinese, Japanese, and Korean subjects compared to that of Caucasians, mainly in relation to the higher exposure in Asian subjects with body weight
Sex: In healthy subjects and patients, the pharmacokinetics of prasugrel in women and men are similar.
Pediatric population: The pharmacokinetics and pharmacodynamics of prasugrel have not been evaluated in the pediatric population (see section 4.2).
05.3 Preclinical safety data
Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, or toxicity for reproduction. Effects in non-clinical studies were observed. only at exposures considered sufficiently in excess of the maximum human exposure indicating low relevance for clinical use.
Toxicological studies on embryo-fetal development in rats and rabbits showed no evidence of malformations caused by prasugrel. At a very high dose (> 240 times the recommended human maintenance daily dose in mg / m2) that caused effects on maternal body weight and / or food consumption, there was a slight decrease in body weight in the offspring (compared to controls) In pre- and postnatal studies in rats, maternal treatment had no effect on the behavioral or reproductive development of the offspring at doses up to 240 times the recommended human maintenance daily dose (expressed in mg / m2).
No compound-related tumors were observed in a 2-year rat study with prasugrel exposures ranging from greater than 75 times the recommended human therapeutic exposures (based on human plasma exposures to the active metabolite and human metabolites). main ones in circulation). In mice exposed for 2 years to high doses (> 75 times the human exposure) there was an "increased incidence of tumors (hepatocellular adenomas), but this was considered secondary to prasugrel-induced enzyme induction. L "Rodent-specific association of liver tumors and drug-induced enzyme induction is well documented in the literature. The increase in liver tumors with the administration of prasugrel in mice is not considered a relevant risk for humans.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Core of the tablet:
Microcrystalline cellulose
Mannitol (E421)
Croscarmellose sodium
Hypromellose (E464)
Magnesium stearate
Coating:
Lactose monohydrate
Hypromellose (E464)
Titanium dioxide (E171)
Triacetin (E1518)
Red iron oxide (E172)
Yellow iron oxide (E172)
Talc
6.2 Incompatibility
Not applicable.
06.2 Incompatibility
2 years.
06.3 Period of validity
2 years.
06.4 Special precautions for storage
This medicinal product does not require any special storage temperatures. Store in the original package to protect from air and moisture.
06.5 Nature of the immediate packaging and contents of the package
Aluminum blisters in cartons of 14, 28, 30, 30 (x1), 56, 84, 90 (x1) and 98 tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
Eli Lilly Nederland BV, Grootslag 1-5, NL-3991 RA Houten, The Netherlands.
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/08/503/008
039055088
EU / 1/08/503/009
039055090
EU / 1/08/503/010
039055102
EU / 1/08/503/011
039055114
EU / 1/08/503/012
039055126
EU / 1/08/503/013
039055138
EU / 1/08/503/014
039055140
EU / 1/08/503/016
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 25 February 2009
Latest renewal date:
10.0 DATE OF REVISION OF THE TEXT
11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY
12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL
AGREED WITH THE EUROPEAN MEDICINAL AGENCY (EMA) AND THE ITALIAN DRUG AGENCY (AIFA)
December 2013
Increased risk of severe bleeding in patients with unstable angina / non-ST-segment elevation myocardial infarction (UA) / NSTEMI when EFIENT (prasugrel) is administered prior to diagnostic coronary angiography.
Dear Doctor, Dear Doctor,
the "European Medicines Agency and the Italian Medicines Agency - AIFA, in agreement with Daiichi-Sankyo and Eli Lilly Italia, wish to inform you about the following recommendation regarding the use of EFIENT (prasugrel), an antiplatelet drug indicated for the treatment of acute coronary syndrome (ACS) in patients undergoing percutaneous coronary intervention (PCI):
In patients with unstable angina / non-ST segment elevation myocardial infarction (UA) / NSTEMI, when coronary angiography is performed within 48 hours of hospitalization, the loading dose of EFIENT should only be given at the time of PCI in order to minimize the risk of bleeding.
This recommendation is based on the results of a recently completed clinical study in NSTEMI patients scheduled to undergo coronary angiography 2 to 48 hours after randomization. The study compared the effects of administering an initial loading dose of prasugrel of 30 mg before coronary angiography (4 hours on average), followed by an "additional 30 mg dose at the time of PCI, with the effect produced. from the administration of a full loading dose of 60 mg at the time of PCI. The results showed a greater risk of bleeding associated with the use of an initial loading dose before coronary angiography, followed by an additional dose at the time of PCI compared to a single loading dose of prasugrel at the time of PCI. No difference in efficacy was observed between the two dosing regimens.
The "ACCOAST" study entitled: A Comparison of Prasugrel at the Time of Percutaneous Coronary Intervention Or as Pre-treatment at the Time of Diagnosis in Patients with Non-ST-Elevation Myocardial Infarction.
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ACCOAST was a 30-day study conducted in 4,033 patients with NSTEMI and elevated troponin who were scheduled to undergo coronary angiography followed by PCI 2 to 48 hours after randomization. Subjects who received a prasugrel loading dose of 30 mg on average 4 hours before coronary angiography, followed by a loading dose of 30 mg at the time of PCI (n = 2037), had an increased risk of peri-procedural bleeding. non-CABG (unrelated to coronary artery bypass surgery) and no additional benefit over patients receiving a loading dose of 60 mg at the time of PCI (n = 1996). Specifically, the frequency of the composite goal of cardiovascular death, myocardial infarction, stroke, urgent revascularization, or use of a glycoprotein (GP) IIb / IIIa inhibitor "in bail-out therapy" within 7 days of randomization was not significantly reduced in subjects receiving prasugrel prior to coronary angiography compared to patients receiving the full loading dose of prasugrel at the time of PCI. In addition, the frequency of the main safety objective, represented by all major bleeding according to TIMI (CABG and non-CABG events) within 7 days of randomization in all treated subjects, was significantly higher in the subjects who received prasugrel in two divided doses (4 hours before coronary angiography and at the time of PCI), compared to patients receiving the full loading dose of prasugrel in single administration at the time of PCI.
Reporting of Suspected Adverse Reactions
Doctors and other healthcare professionals are required to report any suspected adverse reactions associated with medicines containing prasugrel.
Doctors and other health professionals must, by law, send reports of suspected adverse reactions, using the special paper form (available on the website http://www.agenziafarmaco.gov.it/sites/default/files/tipo_filecb84.pdf) or by filling in the electronic form online (http://www.agenziafarmaco.gov.it/sites/default/files/scheda_aifa_oper_sanitario16.07.2 012.doc) promptly, to the Pharmacovigilance Manager of the healthcare facility to which they belong or, if operating in private health facilities, through the Health Department, to the pharmacovigilance manager of the ASL competent for the area.
Further information
For questions and / or further information, please contact Eli Lilly's "Medical Information" office by calling the following toll-free number: 800117678, or by writing to the following address: [email protected]
Reports of Suspected Adverse Reaction from Drugs must be sent to the Head of Pharmacovigilance of the Structure to which the Operator belongs.
This Information Note is also published on the AIFA website (www.agenziafarmaco.it) whose regular consultation is recommended for the best professional and service information to the citizen.
