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Therapeutic Category
- CARDIOVASCULAR DRUGS
- ANTITHROMBOTIC DRUGS
- Pharmaceutical Form : Film coated tablets
- Composition : Prasugel Hcl 5 mg
- Active Substance : Prasugel Hcl
INDICATIONS:
Acute Coronary Syndrome
-MEDI-GREL 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.
-MEDI-GREL 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 MEDI-GREL, MEDI-GREL 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 MEDI-GREL, the risk of significant bleeding was substantial. 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 MEDI-GREL must then be balanced against the increased rate of bleeding in patients who do need to undergo urgent CABG
MEDI-GREL contains the medicine prasugrel. MEDI-GREL belongs to the group of medicine called antiplatelet medicines.
Antiplatelet agents reduce the ability of blood to clot. By preventing blood cells from clumping, antiplatelet medicines reduce the chances of blood clots forming (a process called thrombosis).
You may have been prescribed MEDI-GREL to prevent blood clots from forming and to reduce the risk of stroke, heart attack, chest pain or death because:
* You have suffered an acute coronary syndrome (either a severe type of chest pain called unstable angina or a heart attack) and have been treated with PCI (a procedure where a balloon-tipped tube is used to open a blocked artery). In this case you may have also been prescribed aspirin.
CONTRAINDICATIONS
Active Bleeding
MEDI-GREL is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage
Prior Transient Ischemic Attack or Stroke
MEDI-GREL 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 MEDI-GREL (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 MEDI-GREL and clopidogrel, respectively. 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 MEDI-GREL generally should have therapy discontinued.
ADVERSE REACTIONS
Clinical Trials Experience
- Bleeding
- Thrombotic thrombocytopenic purpura
-Safety in patients with ACS undergoing PCI was evaluated in a clopidogrel-controlled study, TRITON-TIMI 38, in which 6741 patients were treated with MEDI-GREL (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 MEDI-GREL 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.
Drug Discontinuation
The rate of study drug discontinuation because of adverse reactions was 7.2% for MEDI-GREL and 6.3% for clopidogrel. Bleeding was the most common adverse reaction leading to study drug discontinuation for both drugs (2.5% for MEDI-GREL and 1.4% for clopidogrel).
Bleeding
Bleeding Unrelated to CABG Surgery—In TRITON-TIMI 38, overall rates of TIMI Major or Minor bleeding adverse reactions unrelated to coronary artery bypass graft surgery (CABG) were significantly higher on MEDI-GREL than on clopidogrel
Other Adverse Events
-In TRITON-TIMI 38, common and other important non-hemorrhagic adverse events were, for MEDI-GREL 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 173 patients
WARNINGS AND PRECAUTION
- General Risk of Bleeding
Thienopyridines, including MEDI-GREL, 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 MEDI-GREL than on clopidogrel The bleeding risk is highest initially, as shown in Figure 1 (events through 450 days; inset shows events through 7 days).
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 MEDI-GREL in patients with active bleeding, prior TIA or stroke
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 MEDI-GREL 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 CABG or other surgical procedure
- Body weight <60 kg. Consider a lower (5 mg) maintenance dose
- Propensity to bleed (e.g., recent trauma, recent surgery, recent or recurrent gastrointestinal (GI) bleeding, active peptic ulcer disease, or severe hepatic impairment)
- 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
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.
2- Coronary Artery Bypass Graft Surgery-Related Bleeding
– The risk of bleeding is increased in patients receiving MEDI-GREL who undergo CABG. If possible, MEDI-GREL 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 MEDI-GREL group and 4.5% in the clopidogrel group. The higher risk for bleeding events in patients treated with MEDI-GREL 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 MEDI-GREL 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 MEDI-GREL 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 MEDI-GREL
Discontinue thienopyridines, including MEDI-GREL, 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.
- 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.
DRUG INTERACTIONS
1-Warfarin
Co-administration of MEDI-GREL and warfarin increases the risk of bleeding
2-Non-Steroidal Anti-Inflammatory Drugs
Coadministration of MEDI-GREL and NSAIDs (used chronically) may increase the risk of bleeding.
3-Other Concomitant Medications
MEDI-GREL can be administered with drugs that are inducers or inhibitors of cytochrome P450 enzymes.
MEDI-GREL 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.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category B—There are no adequate and well-controlled studies of MEDI-GREL 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. MEDI-GREL 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 Nursing Mothers
It is not known whether MEDI-GREL is excreted in human milk; however, metabolites of MEDI-GREL 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.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established
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 (MEDI-GREL compared with clopidogrel) was similar across age groups.
Patients ≥75 years of age who received MEDI-GREL 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 MEDI-GREL 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 MEDI-GREL 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
Low Body Weight
In TRITON-TIMI 38, 4.6% of patients treated with MEDI-GREL 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 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.
Renal Impairment
No dosage adjustment is necessary for patients with renal impairment. There is limited experience in patients with end-stage renal disease
Hepatic Impairment
No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. 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
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.
DOSAGE AND ADMINISTRATION
-Initiate MEDI-GREL treatment as a single 60 mg oral loading dose and then continue at 10 mg orally once daily.
-Patients taking MEDI-GREL should also take aspirin (75 mg to 325 mg) daily .
-MEDI-GREL 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.
OVERDOSAGE
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.
Recommendations about Specific Treatment
Platelet transfusion may restore clotting ability. The prasugrel active metabolite is not likely to be removed by dialysis.
STORAGE CONDITIONS:
Store at temperature between15° to 30°C
Protect MEDI-GREL tablets from moisture and air.
PACKING:
Box of 10 coated tablets
Box of 30 coated tablets