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Prasugrel

(pra' soo grel)

Molecule Info

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WARNING

BLEEDING RISK

Prasugrel can cause significant, sometimes fatal, bleeding. Do not use Prasugrel in patients with active pathological bleeding or a history of transient ischemic attack or stroke.

In patients ≥75 years of age, Prasugrel is generally not recommended, because of the increased risk of fatal and intracranial bleeding and uncertain benefit, except in high-risk situations (patients with diabetes or a history of prior MI) where its effect appears to be greater and its use may be considered.

Do not start Prasugrel in patients likely to undergo urgent coronary artery bypass graft surgery (CABG). When possible, discontinue Prasugrel at least 7 days prior to any surgery.

Additional risk factors for bleeding include: body weight <60 kg; propensity to bleed; concomitant use of medications that increase the risk of bleeding (e.g., warfarin, heparin, fibrinolytic therapy, chronic use of non-steroidal anti-inflammatory drugs [NSAIDs]). Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (PCI), CABG, or other surgical procedures in the setting of Prasugrel.

If possible, manage bleeding without discontinuing Prasugrel. Discontinuing Prasugrel, particularly in the first few weeks after acute coronary syndrome, increases the risk of subsequent cardiovascular events.

Content & Description

Prasugrel HCl.

Each 5- or 10-mg tablet contains prasugrel HCl 5.49 or 10.98 mg, equivalent to prasugrel 5 or 10 mg, respectively.
Prasugrel, an adenosine diphosphate (ADP) receptor antagonist of the thienopyridine class, is a potent inhibitor of platelet activation and aggregation mediated by the P2Y12 ADP receptor.
Prasugrel HCl is (±)-2-[2-acetyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]-1-cyclopropyl-2-(2-fluorophenyl)ethanone HCl. It has an empirical formula of C20H20FNO3S·HCl which corresponds to a molecular weight of 409.9. It is a white to light brown solid. Prasugrel HCl is soluble at pH 2, slightly soluble at pH 3-4 and practically insoluble at pH 6-7.5. It also dissolves freely in methanol and is slightly soluble in 1- and 2-propanol and acetone. It is practically insoluble in diethyl ether and ethyl acetate.
It also contains the following excipients: Mannitol, hypromellose, croscarmellose sodium, cellulose (microcrystalline) and vegetable magnesium stearate. The colour coatings contain: Lactose, hypromellose, titanium dioxide, glycerol triacetate, yellow iron oxide CI77492 and red iron oxide CI77491.
 

Indications In combination with aspirin, for the prevention of atherothrombotic events (myocardial infarction, stroke and cardiovascular death) in patients with acute coronary syndromes [moderate to high risk unstable angina (UA), non ST-segment elevation myocardial infarction (NSTEMI) or ST-segment elevation myocardial infarction (STEMI)] who are to undergo percutaneous coronary intervention (PCI).
Dosage & Administration Adults (≥18 years) Starting dose: Single 60-mg loading dose (LD) then continued at a 10-mg once daily dose maintenance dose (MD). Patients taking prasugrel should also take aspirin (75-325 mg) daily.
May be taken with or without food (see Pharmacology under Actions).
Elderly (≥75 years): Generally not recommended in patients ≥75 years due to the risk of bleeding (including fatal bleeding) (see Precautions).
Patients Weighing <60 kg: A single 60-mg LD and then continued at a 5-mg once daily MD. The 10-mg MD is not recommended. The evidence for the 5-mg dose is based on pharmacodynamic/pharmacokinetic analyses only and no clinical data currently exist on the safety and efficacy of this dose (see Precautions).
Children and Adolescents: The safety and efficacy of prasugrel has not been established in paediatric patients (see Precautions).
Renal Impairment: No dosage adjustment is necessary for patients with renal impairment; including patients with end-stage renal disease (ESRD). As ESRD significantly impacts both the AUC and Cmax of the active metabolite of prasugrel, the use of prasugrel needs to be closely monitored in this class of patient (see Pharmacokinetics: Special Populations under Actions).
Hepatic Impairment: No dosage adjustment is necessary in patients with mild to moderate hepatic impairment (Child-Pugh class A and B). The pharmacokinetics and pharmacodynamics of prasugrel in patients with severe hepatic disease (Child-Pugh class C) have not been studied (see Contraindications, Precautions and Pharmacokinetics: Special Populations under Actions).
Asian Populations: No dosage adjustment is necessary based on ethnicity alone. In clinical pharmacology studies, the AUC of the active metabolite of prasugrel was higher in Chinese, Japanese and Korean subjects compared to Caucasian subjects. Therapeutic experience with prasugrel is limited in Asian patients therefore; the use of prasugrel needs to be closely monitored in these patients (see Pharmacokinetics: Special Populations under Actions).
Overdose Overdose following prasugrel administration may lead to prolonged bleeding time and subsequent bleeding complications. In rats, lethality was observed only after administration of the very high dose 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. Consistent with known pharmacologic activity, platelet aggregation was inhibited in dogs.
No data are available on the reversal of the pharmacological effect of prasugrel; however, if prompt correction of prolonged bleeding time is required, platelet transfusion and/or other blood products may be considered at the discretion of the treating physician.
Contraindications Known hypersensitivity to prasugrel HCl or to any of the excipients of Prasugrel.
Active pathological bleeding; known history of transient ischaemic attack (TIA) or stroke; severe hepatic impairment (Child-Pugh class C).
Lactose: Patient with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Prasugrel.  
Special Precautions Prior TIA or Stroke: In the phase 3 clinical trial, prasugrel-treated patients with a history of TIA or a history of ischaemic stroke >3 months prior to drug therapy had a higher rate of the primary composite endpoint, including ischaemic or haemorrhagic stroke compared to clopidogrel. The rate of TIMI major or minor bleeding was also increased in these patients compared to patients without a history of TIA or stroke. Patients with a history of ischaemic stroke within 3 months of drug therapy or haemorrhagic stroke were excluded from the phase 3 clinical trial (see Adverse Reactions and Clinical Trials under Actions).
Prasugrel has not been studied without aspirin in patients with prior history of TIA or stroke.
Bleeding Risk: In the phase 3 clinical trial, 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 prasugrel showed an increased risk of major and minor bleeding according to the TIMI classification system. Therefore, use of prasugrel 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 bleeding. In particular, caution is necessary in patients: ≥75 years [In the phase 3 clinical trial, patients ≥75 years taking prasugrel were at a greater risk of bleeding, including fatal bleeding, compared to patients <75 years. In these patients, prasugrel is generally not recommended; with a propensity to bleed [eg, due to recent trauma or surgery; recent or recurrent gastrointestinal bleeding, active peptic ulcer disease, severe hepatic impairment or moderate to severe renal impairment]; with body weight <60 kg. In these patients, a 5-mg MD is recommended (see Body Weight, Adverse Reactions and Dosage & Administration); with concomitant administration of medications that may increase the risk of bleeding, including oral anticoagulants, nonsteroidal anti-inflammatory drugs (NSAIDs) and fibrinolytics.
Patients should be told that it may take longer than usual for bleeding to stop when they take prasugrel and that they should report any unusual bleeding (site or duration) to their physician.
For patients with active bleeding for whom reversal of the pharmacological effects of prasugrel is required, platelet transfusion may be appropriate.
Body Weight: Of the total number of prasugrel patients in the TRITON study, 4.6% had body weight <60 kg. Individuals with body weight <60 kg had an increased risk of TIMI major or minor bleeding and an increased exposure to the active metabolite of prasugrel. Prasugrel should be used with caution after a careful individual benefit/risk evaluation by the prescribing physician indicates that benefits in terms of prevention of ischaemic events outweigh the risk of bleeding. For patients <60 kg, a 5-mg once daily MD should be used, the 10-mg MD is not recommended for these patients (see Bleeding Risk, Dosage & Administration, Adverse Reactions and Pharmacology under Actions).
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, prasugrel 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. 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.
Discontinuation of Prasugrel: In patients with ACS who are managed with PCI, premature discontinuation of any antiplatelet medication, including prasugrel, could result in an increased risk of thrombosis, MI or death. Patients who require premature discontinuation of prasugrel (eg, secondary to active bleeding) should be monitored for cardiac events. Once the patient is stabilised at the discretion of the patient's treating physician, restarting antiplatelet treatment may be considered.
Neoplasms: In TRITON, the incidence of newly diagnosed neoplasms was higher for prasugrel-treated patients compared to clopidogrel-treated patients [1.4% (94/6741) to 1.2% (80/6716) respectively, p=0.3]. The higher incidence appeared to be related to a higher incidence of colorectal neoplasms (19 prasugrel versus 10 clopidogrel). This imbalance may have resulted from the more potent antiplatelet effect of prasugrel bringing more events to medical attention. The nonclinical studies were negative for carcinogenicity and tumour stimulation (see Carcinogenicity in the following text). Bleeding in patients taking antiplatelet therapy warrants diagnostic investigation since it may unmask a previously unsuspected lesion (eg, tumour, ulcer).
Thrombotic Thrombocytopenic Purpura (TTP): TTP has been reported with the use of Prasugrel. TTP is a serious condition and requires prompt treatment.
Hypersensitivity Including Angioedema: Hypersensitivity including angioedema has been reported in patients receiving Prasugrel, including in patients with a history of hypersensitivity reaction to other thienopyridines.
Renal Impairment: No dosage adjustment is necessary for patients with renal impairment; including patients with end-stage renal disease (see Bleeding Risk, Dosage & Administration and Pharmacology under Actions).
Hepatic Impairment: No dosage adjustment is necessary in patients with mild to moderate hepatic impairment (Child-Pugh class A and B). The pharmacokinetics and pharmacodynamics of prasugrel in patients with severe hepatic disease have not been studied. Prasugrel should not be used in patients with severe hepatic disease due to the potential risk of bleeding in this population (see Precautions and Pharmacology under Actions).
Effects on the Ability to Drive or Operate Machinery: No studies on effects on ability to drive and use machines have been performed. Prasugrel is expected to have no or negligible influence on the ability to drive and use machines.
Carcinogenicity: No compound-related tumours were observed in a 2-year rat study with prasugrel exposures ranging to >75 times the recommended therapeutic exposures in humans (based on plasma exposures to the active and major circulating human metabolites). There was an increased incidence of tumours (hepatocellular adenomas) in mice exposed for 2 years to high doses (>75 times human exposure) but this was considered secondary to prasugrel-induced enzyme-induction. The rodent-specific association of liver tumours and drug-induced enzyme induction is well documented in the literature. Therefore, the increase in liver tumours with prasugrel administration in mice is not considered a relevant human risk.
Genotoxicity: Assays for gene mutations (Ames test) and chromosomal damage (Chinese Hamster Ovary cells in vitro, mouse micronucleus in vivotest) did not provide any evidence of a genotoxic potential for prasugrel.
Effects on Fertility: Animal studies did not indicate direct harmful effects with respect to fertility. Prasugrel had no effect on fertility of male or female rats at oral doses up to 300 mg/kg/day, corresponding to an active metabolite exposure (based on AUC) of approximately 1500 times that anticipated at the recommended human MD.
Use in pregnancy: Pregnancy Category B1: There are no adequate and well-controlled studies in pregnant women.
Because animal reproduction studies are not always predictive of a human response, prasugrel should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the foetus.
Embryo foetal developmental toxicology studies in rats and rabbits showed no evidence of malformations at doses corresponding to >100 times the active metabolite exposure anticipated in humans at the MD of 10 mg daily (based on AUC) of prasugrel. Only minor decreases in maternal body weight gain (3%) and offspring body weight (3-5%) were observed relative to controls. In prenatal and postnatal rat studies, a similar dose exposure had no effect on the behavioural or reproductive development of offspring.
Use in lactation: There are no clinical studies in lactating women.
A study in rats has shown that prasugrel metabolites are excreted in the animals' milk. It is not known whether prasugrel is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the benefit of the drug to the nursing woman.
Use in children: Safety and effectiveness in paediatric patients has not been established (see Pharmacology under Actions).
Use in the elderly: Of the total number of prasugrel-treated patients in TRITON, 38.5% were ≥65 years and 13.2% were ≥75 years. The event rate of the primary composite endpoint with prasugrel compared to clopidogrel for patients ≥75 years was 15.98% versus 16.96%; (HR=0.94; 95% CI 0.749, 1.181; p=0.596). Individuals ≥75 years had an increased risk of TIMI major or minor bleeding (including life-threatening and fatal bleeding) due to greater sensitivity to bleeding and higher exposure to the active metabolite of prasugrel in patients ≥75 years compared to patients <75 years. There was also an increase in the incidence of stroke in patients ≥75 years compared to those <75 years. The use of prasugrel in patients ≥75 years is generally not recommended due to the risk of bleeding (including fatal bleeding) (see Bleeding Risk, Dosage & Administration, Adverse Reactions and Pharmacology under Actions).
Adverse Drug Reactions

Safety in patients with ACS undergoing PCI was evaluated in a clopidogrel-controlled study, TRITON, in which 6741 patients were treated with Prasugrel (60-mg LD and 10 mg once daily MD) for a median of 14.5 months (5802 patients were treated for over 6 months; 4136 patients were treated for >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 for both drugs leading to study drug discontinuation (2.5% for Prasugrel and 1.4% for clopidogrel).
Non-CABG-Related Bleeding: In TRITON, the frequency of patients experiencing a non-CABG-related bleeding event is shown in Table 5. The incidence of non-CABG-related TIMI major bleeding, including life-threatening and fatal, as well as TIMI minor bleeding, was statistically significantly higher in subjects treated with Prasugrel compared to clopidogrel in the UA/NSTEMI and "All ACS" populations. No significant difference was seen in the STEMI population. The most common site of spontaneous bleeding was the gastrointestinal tract (1.7% rate with Prasugrel and 1.3% rate with clopidogrel); the most frequent site of provoked bleeding was the arterial puncture site (1.3% rate with Prasugrel and 1.2% with clopidogrel). (See Table 5.)        

EffientT5_SG_2c.png   

Patients <60 kg: In TRITON, non-CABG-related TIMI Major or Minor bleeding rates for patients in 2 weight groups were as follows: See Table 6.
EffientT6_SG_2c.png

Patients (≥75 years): In TRITON, non-CABG-related TIMI Major or Minor bleeding rates for patients in 2 age groups were as follows: See Table 7.

EffientT7_SG_2c.png
In patients ≥60 kg and age <75 years, non-CABG-related TIMI major or minor bleeding rates were 3.6% for Prasugrel and 2.8% for clopidogrel; rates for fatal bleeding were 0.2% for Prasugrel and 0.1% for clopidogrel.
Prior TIA or Stroke: In TRITON, non-CABG-related TIMI Major or Minor bleeding for patients with and without a history of TIA or stroke were as follows: See Table 8.

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In TRITON, in patients with or without a history of TIA or stroke, the incidence of stroke was as follows: See Table 9.

EffientT9_SG_2c.png

CABG-Related Bleeding: In TRITON, 437 patients underwent CABG during the course of the study. Of those patients, the rate of CABG-related TIMI Major or Minor bleeding was 14.1% for the Prasugrel group and 4.5% in the clopidogrel group. The higher risk for bleeding events in patients treated with Prasugrel persisted up to 7 days from the most recent dose of study drug. For patients who received their thienopyridine within 3 days prior to CABG, the frequencies of TIMI major or minor bleeding were 26.7% (12 of 45 patients) in the Prasugrel group, compared with 5% (3 of 60 patients) in the clopidogrel group. For patients who received their last dose of thienopyridine within 4-7 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. Beyond 7 days after drug discontinuation, the observed rates of CABG-related bleeding were similar between treatment groups (see Precautions).
Table 10 summarises haemorrhagic and non-haemorrhagic adverse reactions in TRITON, or that were spontaneously reported, classified by frequency and system organ class. Frequencies are defined as follows: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); not known (cannot be estimated from the available data). 

Drug Interactions Prasugrel can be concomitantly administered with medicinal products metabolised by cytochrome P-450 enzymes (including statins) or medicinal products that are inducers or inhibitors of cytochrome P-450 enzymes. Prasugrel 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, prasugrel was co-administered in the phase 3 clinical trial with low molecular weight heparin, bivalirudin and GPIIb/IIIa inhibitors (no information is available regarding the type of GPIIb/IIIa inhibitor used) without evidence of clinically significant adverse interactions.
Potential for Other Drugs to Affect Prasugrel: Inhibitors of CYP3A:Ketoconazole (400 mg daily), a selective and potent inhibitor of CYP3A4 and CYP3A5, did not affect prasugrel-mediated IPA or the active metabolite's AUC and Tmax, but decreased the Cmax by 34%-46%. Therefore, CYP3A inhibitors eg, verapamil, diltiazem, indinavir, ciprofloxacin, clarithromycin and grapefruit juice are not anticipated to have a significant effect on the pharmacokinetics of the active metabolite.
Inducers of Cytochrome P-450: 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 and its IPA. Therefore, known CYP3A inducers eg, rifampicin, carbamazepine and other inducers of cytochrome P-450 are not anticipated to have significant effect on the pharmacokinetics of the active metabolite.
Drugs that Elevate Gastric pH: Daily co-administration of ranitidine (an H2receptor blocker) or lansoprazole (a proton pump inhibitor) did not change the metabolite's AUC and Tmax, but decreased the Cmax by 14% and 29%, respectively. In the pivotal phase 3 trial, prasugrel was administered without regard to co-administration of a proton pump inhibitor (PPI) or H2 receptor blocker and the reduction in the primary endpoint from 0-3 days was consistent for patients taking prasugrel with and without concomitant use of a PPI or H2 receptor blocker.
Statins: Atorvastatin (80 mg daily) did not alter the pharmacokinetics of prasugrel or its IPA. Therefore, statins that are substrates of CYP3A are not anticipated to have an effect on the pharmacokinetics of prasugrel or its IPA.
Heparin: A single IV dose of unfractionated heparin (100 units/kg) did not significantly alter the prasugrel-mediated IPA. Likewise, prasugrel did not significantly alter the effect of heparin on measures of coagulation. An increased risk of bleeding is possible when prasugrel is co-administered with heparin.
Aspirin: Aspirin (150 mg daily with an additional single 900 mg) did not alter prasugrel-mediated IPA. Although a pharmacodynamic interaction with aspirin leading to an increased risk of bleeding is possible, the demonstration of the efficacy and safety of prasugrel comes from patients concomitantly treated with aspirin.
NSAIDs: Concomitant administration with chronic NSAIDs has not been studied. Because of the potential for increased risk of bleeding, chronic NSAIDs and prasugrel should be co-administered with caution.
Clopidogrel: Following administration of clopidogrel 75 mg daily for 10 days, healthy subjects were switched to prasugrel 10 mg once daily, with or without a 60-mg LD. Throughout the study, all subjects were concurrently taking 81 mg of aspirin once daily. Higher IPA was observed with prasugrel compared to clopidogrel.
Potential for Prasugrel to Affect Other Drugs: Drugs Metabolised by CYP2C9 and 2C19: Prasugrel did not inhibit CYP2C9 or CYP2C19, as it did not affect the pharmacokinetics of S-warfarin or R-warfarin. Because of the potential for increased risk of bleeding, warfarin and prasugrel should be co-administered with caution.
Drugs Metabolised by CYP2B6: Prasugrel is a weak inhibitor of CYP2B6. In healthy subjects, prasugrel decreased exposure to hydroxybupropion, a CYP2B6-mediated metabolite of bupropion, by 23%, which is not considered to be clinically significant. This effect is likely to be of clinical concern only when prasugrel is co-administered with medicinal products for which CYP2B6 is the only metabolic pathway and have a narrow therapeutic window (eg, cyclophosphamide, efavirenz).
Effect on Digoxin: Prasugrel has no clinically significant effect on the pharmacokinetics of digoxin. When prasugrel was co-administered with digoxin, a substrate of P-glycoprotein transporter, the AUC of digoxin was not altered, while Cmax decreased by 17%.    
Pregnancy Category (US FDA) Category B: Either animal-reproduction studies have not demonstrated a foetal risk but there are no controlled studies in pregnant women or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the 1sttrimester (and there is no evidence of a risk in later trimesters).
Caution For Usage Do not crush or break the tablet.
Storage Store below 30°C. Store in the original package.
Pharmacology

Pharmacotherapeutic Group: Platelet aggregation inhibitors excluding heparin. ATC Code: B01AC22.

Pharmacodynamics: Inhibition of platelet aggregation (IPA) induced by 5 or 20 micromol ADP (termed "platelet inhibition" in the remainder of this document) measured by light transmission aggregometry has been assessed in clinical pharmacology studies in healthy subjects and patients with stable atherosclerosis for both prasugrel and clopidogrel with or without aspirin. Following a 60-mg loading dose (LD) of prasugrel, IPA occurs at 15 min for 5 micromol ADP and 30 min for 20 micromol ADP (see Figure 1). This rapid onset of action is a result of the rapid biotransformation of prasugrel to its active metabolite which is responsible for the IPA. 

The mean maximum IPA after a 60-mg LD of prasugrel was 79% and 83%, respectively for 20 micromol and 5 micromol ADP, with at least 89% of all healthy subjects and patients with stable atherosclerosis achieving at least 50% IPA by 1 hr for both ADP concentrations. Prasugrel-mediated IPA exhibits low between-subject (9%) and within-subject (12%) variability with both 5 micromol and 20 micromol ADP.
Mean steady-state IPA was 69% and 74%, respectively for 20 micromol and 5 micromol ADP, and was achieved following 3-5 days of 10-mg maintenance dosing with a preceding LD of prasugrel. Greater than 98% of subjects had ≥20% IPA during maintenance dosing. The extent of IPA is dependent on the dose of prasugrel and exposure to the active metabolite.
Platelet aggregation gradually returned to baseline values after treatment in 7-9 days following a single 60-mg LD of prasugrel and in 5 days following discontinuation of maintenance dosing at steady state.
Mechanism of Action:
 Prasugrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y12 class of ADP receptors on platelets. A variety of drugs that inhibit platelet function have been shown to decrease morbid events in people with established atherosclerotic disease. Since platelets participate in the initiation and/or evolution of thrombotic complications of atherosclerotic disease, inhibition of platelet function can result in the reduction of the rate of death and the rate of ischaemic cardiovascular events eg, myocardial infarction or stroke.

Pharmacokinetics: Prasugrel is a prodrug and is rapidly metabolised to a pharmacologically active metabolite and inactive metabolites. The active metabolite's exposure (AUC) has moderate to low between-subject (27%) and within-subject (19%) variability. Prasugrel's pharmacokinetics are similar in healthy subjects, patients with stable atherosclerosis and patients undergoing percutaneous coronary intervention (PCI).
Absorption: Following oral administration, ≥79% of the dose is absorbed. The absorption and metabolism are rapid, with peak plasma concentrations (Cmax) of the active metabolite occurring approximately 30 min after dosing. The active metabolite's exposure (AUC) increases proportionally over the therapeutic dose range. In a study of healthy subjects, AUC of the active metabolite was unaffected by a high fat, high calorie meal, but Cmax was decreased by 49% and the time to reach Cmax (Tmax) was increased from 0.5-1.5 hrs. Prasugrel was administered without regard to food in the large phase 3 clinical trial. Therefore, Prasugrel can be administered without regard to food.
Distribution: In a sodium phosphate buffer (pH 7.4), active metabolite binding to 4% human serum albumin was 98%. Prasugrel metabolites have limited penetration into red blood cells.
Metabolism: Prasugrel is not detected in plasma following oral administration. It is rapidly hydrolysed in the intestine to a thiolactone, which is then converted to the active metabolite by a single step of cytochrome P-450 metabolism, primarily by CYP3A4 and CYP2B6 and to a lesser extent by CYP2C9 and CYP2C19. The active metabolite is further metabolised to 2 inactive compounds by S-methylation or conjugation with cysteine.
In healthy subjects, patients with stable atherosclerosis and patients with Acute Coronary Syndromes (ACS) receiving Prasugrel, there was no relevant effect of genetic variation in CYP3A, CYP2B6, CYP2C9 or CYP2C19 on the pharmacokinetics of prasugrel of its IPA.
Elimination: Approximately 68% of the prasugrel dose is excreted in the urine and 27% in the faeces, as inactive metabolites. The active metabolite has an elimination t½ of about 7.4 hrs (range 2-15 hrs).
In healthy subjects, patients with stable atherosclerosis and patients with ACS receiving prasugrel, there was no relevant effect of genetic variation in CYP3A5, CYP2B6, CYP2C9 or CYP2C19 on the pharmacokinetics of prasugrel or its IPA.
Special Populations: Elderly: In a study of 32 healthy subjects between the ages of 20-80 years, age had no significant effect on pharmacokinetics of prasugrel or its IPA. In the large phase 3 clinical trial, the mean estimated exposure (AUC) of the active metabolite was 19% higher in very elderly patients (≥75 years) compared to patients <75 years (see Dosage & Administration, Precautions and Adverse Reactions).
Paediatric: Pharmacokinetics and pharmacodynamics of prasugrel have not been evaluated in a paediatric population (see Dosage & Administration).
Gender and Ethnicity: In healthy subjects and patients, the pharmacokinetics of prasugrel are similar in men and women.
In clinical pharmacology studies, after adjusting for body weight, the AUC of the active metabolite was approximately 19% higher in Chinese, Japanese and Korean subjects compared to Caucasian subjects. There is no difference in exposure among Chinese, Japanese and Korean subjects. Exposure in subjects of African and Hispanic descent is comparable to that of Caucasians. No dose adjustment is recommended based on ethnicity alone.
Body Weight: The mean exposure (AUC) of the active metabolite is approximately 30-40% higher in healthy subjects with a body weight of <60 kg and patients with a body weight of <60 kg compared to those weighing ≥60 kg (see Dosage & Administration, Precautions and Adverse Reactions).
Smoking: Pharmacokinetics of prasugrel are similar in smokers and non-smokers.
Renal Impairment: No dosage adjustment is necessary for patients with renal impairment, including patients with end-stage renal disease (ESRD). Pharmacokinetics of prasugrel and its IPA are similar in patients with moderate renal impairment (creatinine clearance 30-50 mL/min) and healthy subjects. Prasugrel-mediated IPA was also similar in patients with ESRD who required haemodialysis compared to healthy subjects, although Cmax and AUC of the active metabolite decreased 51% and 42%, respectively, in ESRD patients.
Hepatic Impairment: Pharmacokinetics of prasugrel and its IPA were similar in patients with mild to moderate hepatic impairment (Child-Pugh class A and B) compared to healthy subjects. No dose adjustment is thus necessary for these patients.
Pharmacokinetics and pharmacodynamics of prasugrel in patients with severe hepatic disease have not been studied. Prasugrel should not be used in patients with severe hepatic disease due to the potential risk of bleeding in this population (see Contraindications and Precautions).
Clinical Trials: The clinical evidence for the efficacy of prasugrel is derived from a large phase 3 clinical trial (the TRITON study), comparing prasugrel to clopidogrel, with both given in combination with aspirin and other standard therapy.
The TRITON study was a 13,608-patient, multicenter, international, randomised, double-blind, double dummy and parallel-group study. The patients randomised had Acute Coronary Syndrome (ACS) with moderate to high risk unstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI) or ST-segment elevation myocardial infarction (STEMI) and were managed with PCI.
Patients with UA/NSTEMI within 72 hrs of symptoms or STEMI between 12 hrs to 14 days of symptoms were randomised after coronary angiography. Patients with STEMI within 12 hrs of symptoms and planned for primary PCI could be randomised prior to coronary angiography. For all patients, the LD could be administered anytime between randomisation and 1 hr after the patient left the catheterisation lab. If patients with STEMI were treated with thrombolytic therapy, randomisation could not occur until after 24 hrs for fibrin-specific lytic therapy or 48 hrs for nonfibrin-specific lytic therapy.
Patients were randomised to receive prasugrel (60-mg LD followed by 10 mg once daily) or clopidogrel (300-mg LD followed by 75 mg once daily) and were to be followed for a maximum of 15 months and a minimum of 6 months (actual median 14.5 months). Patients also received aspirin (75-325 mg once daily). At the discretion of the physician, approximately 40% of patients (in each of the treatment groups) received GPIIb/IIIa inhibitors in support of PCI (no information available regarding the type of GP IIb/IIIa inhibitor used) and approximately 98% of patients (in each of the treatment groups) received antithrombins (heparin, low molecular weight heparin, bivalirudin or other agent) directly in support of PCI. 
The trial's primary outcome was the composite of cardiovascular (CV) death, nonfatal MI or nonfatal stroke. Analysis of the composite endpoint in the "All ACS" population (combined UA/NSTEMI and STEMI cohorts) was contingent upon showing statistical superiority of prasugrel versus clopidogrel in the UA/NSTEMI cohort (p<0.05).
Analysis of the "All ACS" Population: In TRITON, prasugrel showed superior efficacy compared to clopidogrel in reducing the primary composite outcome events and the pre-specified secondary outcome events, including stent thrombosis (see Table 1). The superior efficacy was accompanied by an increase in major bleeding (see Precautions and Adverse Reactions).
The patient population was 92% Caucasian, 26% female and 39% ≥65 years. The benefits associated with prasugrel were independent of the use of other acute and long-term cardiovascular therapies, including heparin/low molecular weight heparin, bivalirudin, IV GPIIb/IIIa inhibitors, lipid-lowering drugs, β-blockers and angiotensin-converting enzyme inhibitors. The efficacy of prasugrel was independent of aspirin dose (75-325 mg once daily). The use of oral anticoagulants, non-study antiplatelet drugs and chronic NSAIDs was not allowed in TRITON. 
  

The Kaplan-Meier curve shows the primary composite endpoint of CV death, nonfatal MI or nonfatal stroke over time in the "All ACS" population (see Figure 2). The "All ACS" event curves separated as early as 3 days and continued to diverge over the 15-month follow-up period. Prasugrel demonstrated a relative risk reduction of 18% and an absolute risk reduction of 0.9% in the primary composite endpoint from 0-3 days (4.7% in the prasugrel group and 5.6% in the clopidogrel group; HR 0.825; 95% CI, 0.711, 0.957; p=0.011). Prasugrel demonstrated a relative risk reduction of 20% and an absolute risk reduction of 1.2% in the primary composite endpoint from 3 days to the end of the study (5.2% in the prasugrel group and 6.4% in the clopidogrel group; HR 0.805; 95% CI, 0.698, 0.927; p=0.003). Primary individual outcome events showed an absolute risk reduction of 2.1% and relative risk reduction of 24.3% in nonfatal MI with prasugrel compared to clopidogrel. A 0.2% absolute risk reduction and 11.4% relative risk reduction in CV death was seen in the prasugrel group compared to clopidogrel while for nonfatal stroke, there was no difference between the prasugrel-treated groups and clopidogrel-treated groups (see Table 1).
The incidence of non-CABG-related major bleeding, including life-threatening and fatal, as well as TIMI minor bleeding was higher in prasugrel-treated patients compared to clopidogrel-treated patients (4.5% for prasugrel and 3.4% for clopidogrel; HR 1.314; 95% CI, 1.107, 1.559; p=0.002). In the prasugrel group, the incidence of fatal bleeding was 0.3% compared to 0.1% in clopidogrel-treated patients (HR 4.664; 95% CI, 1.341, 16.23; p=0.008). Study drug discontinuation due to bleeding events was 2.5% in the prasugrel arm and 1.4% for clopidogrel (OR 1.872; 95% CI, 1.448, 2.421; p<0.001) (see Adverse Reactions).
Prasugrel demonstrated a relative risk reduction of 50.2% and an absolute risk reduction of 0.9% in stent thrombosis through the 15-month follow-up period (see Table 2). The reduction in stent thrombosis with prasugrel was observed both early and beyond 30 days for both bare metal and drug eluting stents. 

For patients who survived an on-study stroke or myocardial infarction, prasugrel-treated patients demonstrated a relative risk reduction of 33% and an absolute risk reduction of 4.1% in the incidence of subsequent primary endpoint events compared to clopidogrel-treated patients (7.8% for prasugrel and 11.9% for clopidogrel, HR 0.67; 95% CI, 0.45, 0.98, p=0.037).
An analysis of the composite endpoint of death from any cause, nonfatal MI, nonfatal stroke or non-Coronary Artery Bypass Graft (CABG)-related TIMI major haemorrhage favoured prasugrel compared to clopidogrel (11.5% in the prasugrel group and 13.1% in the clopidogrel group; HR, 0.87; 95% CI, 0.79-0.95; p=0.004). In TRITON, for every 1000 patients treated with prasugrel, there were 22 fewer patients with MI and 5 more with non–CABG-related TIMI major haemorrhages, compared with patients treated with clopidogrel.

Analyses were performed to assess the effect of demographics, baseline characteristics and medical history on the incidence of the primary endpoint of CV death, nonfatal MI or nonfatal stroke by patients randomised to prasugrel or clopidogrel. The treatment benefit associated with prasugrel was preserved across the major pre-specified subgroups in all 3 populations (UA/NSTEMI, STEMI and All ACS).
Analysis of Patients with Diabetes: Patients with diabetes treated with prasugrel had a greater treatment benefit with respect to the primary composite efficacy endpoint when compared to those with diabetes treated with clopidogrel. In the "All ACS" population, the relative risk reduction with prasugrel compared to clopidogrel in 3146 patients with diabetes was 11.42% versus 15.8%; (HR=0.705; 95% CI 0.582, 0.854; p<0.001) while for patients without diabetes (N=10,462), it was 8.84% versus 10.2%; (HR=0.861; 95% CI 0.761, 0.976; p=0.019). A similar pattern was seen for the UA/NSTEMI and STEMI populations. There were also reductions in Urgent Target Vessel Revascularistion (UTVR) and stent thrombosis in patients with diabetes treated with prasugrel.
The incidence of TIMI major or minor bleeding was similar in patients with and without diabetes. TIMI major or minor bleeding in patients with diabetes treated with prasugrel was 4.9% compared to 3.8% with clopidogrel (HR 1.297; 95% CI, 0.923, 1.822; p=0.133) and for patients without diabetes, TIMI major or minor bleeding was 4.4% for prasugrel and 3.3% with clopidogrel (HR 1.32; 95% CI, 1.083, 1.609; p=0.006).
Analysis of Patients According to Age: In the "All ACS" population, the event rate with prasugrel compared to clopidogrel for patients <75 years was 8.44% versus 10.65%; (HR=0.784; 95% CI 0.687, 0.881; p<0.001) while for patients ≥75 years, it was 15.98% versus 16.96%; (HR=0.94; 95% CI 0.749, 1.181; p=0.596). Similar results were seen in the UA/NSTEMI and STEMI populations.
In the elderly (≥75 years), there was an increased risk of non-CABG-related bleeding compared to patients <75 years, including an increased risk of both life-threatening and fatal bleeding. Life-threatening bleeding in patients <75 years treated with prasugrel was 1.06% (0.2% fatal) compared to 0.72% (0.1% fatal) with clopidogrel (HR=1.475; 95% CI 0.997, 2.182; p=0.051) and for patients ≥75 years, it was 2.58% (1% fatal) with prasugrel versus 1.57% (0.1% fatal) with clopidogrel (HR=1.694; 95% CI 0.87, 3.298; p=0.117) (see Precautions and Adverse Reactions). Patients ≥75 years also had a higher rate of stroke with prasugrel compared to clopidogrel (2.89% versus 1.43%; HR 2.117; 95% CI 1.087, 4.125; p=0.024) while for patients <75 years, the rate of stroke was 0.83% with prasugrel and 0.99% with clopidogrel (HR 0.841; 95% CI 0.575, 1.23; p=0.371).
In subgroup analyses, data suggest that prasugrel reduces ischemic events in elderly patients (≥75 years) with diabetes mellitus or prior MI. These observations are based on subgroup analyses and must be interpreted with caution. See Table 3.

EffientT3_SG_2c.png

Analysis of Patients by Body Weight: In the "All ACS" population, the event rate with prasugrel compared to clopidogrel for patients with body weight ≥60 kg was 8.6% versus 10.7%; (HR=0.8; 95% CI 0.71, 0.9; p<0.001) while for patients with body weight <60 kg, it was 14.4% versus 16.4%; (HR=0.86; 95% CI 0.66, 1.121; p=0.255). In patients with low body weight (<60 kg), there was an increased risk of non-CABG-related bleeding compared to patients ≥60 kg (see Precautions and Adverse Reactions).
Analysis of Patients with Prior TIA/Stroke: In the "All ACS" population, there was an increase in the incidence of the primary composite endpoint with prasugrel compared to clopidogrel in patients with prior TIA or stroke (17.94% versus 13.67%; HR=1.375; p=0.153). This was primarily due to an increase in all stroke in patients with prior TIA or stroke randomised to prasugrel compared to clopidogrel (6.49% versus 1.17%; HR=5.643; p=0.002). There was also an increased risk of non-CABG-related bleeding in patients with a history of prior TIA or stroke compared to those not in this population (see Contraindications and Adverse Reactions).
Analysis of the UA/NSTEMI and STEMI Populations: Prasugrel reduced the occurrence of the primary composite endpoint compared to clopidogrel in both the UA/NSTEMI and STEMI populations.

The secondary endpoint data for the UA/NSTEMI and STEMI populations are similar to those for the "All ACS" population.
The Kaplan-Meier curves show the primary composite endpoint of CV death, nonfatal MI, or nonfatal stroke over time in the UA/NSTEMI population and the STEMI population. The UA/NSTEMI event curve separated as early as 3 days and continued to diverge over the 15-month follow-up period. The STEMI event curve separated as early as 3 days and remained separate over the 15-month follow-up period.

ATC Classification B01AC22 - prasugrel, in the class of platelet aggregation inhibitors (excluding heparin), used in the treatment of thrombosis.

Brand/Product Info


Total Products : 10          
Brand Name Manufacturer/Marketer Composition Dosage Form Pack Size & Price
APAGREL 10 Healthcare Pharmacuticals Ltd. Prasugrel Hydrochloride INN which is equivalent to Prasugrel 10mg Tablet 30's MRP 600 Tk
APAGREL 5 Healthcare Pharmacuticals Ltd. Prasugrel Hydrochloride INN which is equivalent to Prasugrel 5mg Tablet 30's MRP 360 Tk
EFIGREL 10 Square Pharmaceuticals Ltd. Prasugrel Hydrochloride 10mg Tablet 2x10's: 401.20 MRP
EFIREL Opsonin Pharma Limited Prasugrel hydrochloride INN 5mg & 10mg Tablet 5mg x20's, 10mg x10's: 240.00 & 200.00 MRP
HEMAGREL ACI Ltd. Prasugrel hydrochloride INN 5mg & 10mg Tablet 5mg x30's, 10mg x20's: 360.00 & 400.00 MRP
PRASULET Beacon Pharmaceuticals Limited Prasugrel hydrochloride INN 5mg & 10mg Tablet 5mg x30's, 10mg x30's: 359.00 & 599.00 MRP
Prasurel 10 Incepta Pharmaceuticals Limited Prasugrel Hydrochloride INN which is eq. to prasugrel 10mg Tablet 10x2's:MRP 400 Tk
Prasurel 5 Incepta Pharmaceuticals Limited Prasugrel Hydrochloride INN which is eq. to prasugrel 5 mg Tablet 10x3's:MRP 360 Tk
PRASUVA 10 Beximco Pharmaceuticals Ltd Prasugrel Hydrochloride INN which is eq. to Prasugrel 10mg Tablet 20's: 400.00 MRP
PRASUVA 5 Beximco Pharmaceuticals Ltd Prasugrel Hydrochloride INN which is eq. to Prasugrel 5mg Tablet 30's: 360.00 MRP

Gen. MedInfo

IMPORTANT WARNING:

Prasugrel may cause serious or life-threatening bleeding. inform your doctor if you currently have or have had a condition that causes you to bleed more easily than normal, if you have recently had surgery or been injured in any way, or if you have or have ever had a stomach ulcer; bleeding in your stomach, intestines, or head; a stroke or mini-stroke; a condition that may cause bleeding in your intestines such as polyps (abnormal growths in the lining of the large intestine) or diverticulitis (inflamed bulges in the lining of the large intestine); or liver disease. inform your doctor if you are taking medications that may cause bleeding including anticoagulants (blood thinners) such as warfarin (Coumadin); heparin; other medications to treat or prevent blood clots; or regular use of a non-steroidal anti-inflammatory medications such as ibuprofen (Advil, Motrin) and naproxen (Aleve). Your doctor may not prescribe prasugrel for you if you have any of these conditions, you are taking any of these medications, you weigh less than 132 lb (60 kg), or you are older than 75 years of age. Your doctor also will probably not prescribe prasugrel if you are likely to need heart bypass surgery (a certain type of open heart surgery) right away. While you are taking prasugrel, you will probably bruise and bleed more easily than usual, bleed for longer than usual, and have nosebleeds. However, if you experience any of the following symptoms, call your doctor immediately: bleeding that is unexplained, severe, long-lasting, or uncontrollable; pink or brown urine; red or black, tarry stools; vomit that is bloody or that looks like coffee grounds; coughing up blood or blood clots; or bruises that are unexplained or that get larger.

If you are having surgery, including dental surgery, or any type of medical procedure, inform your doctor or dentist that you are taking prasugrel. Your doctor will probably inform you to stop taking prasugrel at least 7 days before your surgery is scheduled.

Your doctor will give you the manufacturer's patient information sheet (Medication Guide) when you begin treatment with prasugrel and each time you refill your prescription. Read the information carefully and ask your doctor if you have any questions. You can also visit the Food and Drug Administration (FDA) website (http://www.fda.gov/Drugs/DrugSafety/ucm085729.htm) to obtain the Medication Guide.

Talk to your doctor about the risk of taking prasugrel.

 

Why is Prasugrel prescribed?

Prasugrel is used along with aspirin to prevent serious or life-threatening problems with the heart and blood vessels in people who have had a heart attack or severe chest pain and have been treated with angioplasty (procedure to open the blood vessels that supply blood to the heart). Prasugrel is in a class of medications called anti-platelet medications. It works by preventing platelets (a type of blood cell) from collecting and forming clots that may cause a heart attack or stroke.

How should Prasugrel be used?

Prasugrel comes as a tablet to take by mouth. It is usually taken once a day with or without food. Take prasugrel at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor to explain any part you do not understand. Take prasugrel exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Swallow the tablet whole; do not split, chew, or crush it.

Prasugrel will help prevent serious problems with your heart and blood vessels only as long as you take the medication. Do not stop taking prasugrel without talking to your doctor. If you stop taking prasugrel, there is a higher risk that you may have a heart attack, develop a blood clot, or die.

Other uses for Prasugrel

Prasugrel may be prescribed for other uses; ask your doctor for more information.

What special precautions to follow?   

Before taking prasugrel,

  • inform your doctor if you are allergic to prasugrel, any other medications, or any of the ingredients in prasugrel tablets. Ask your pharmacist for a list of the ingredients.
  • inform your doctor what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention the medications listed in the IMPORTANT WARNING section.
  • inform your doctor if you have or have ever had kidney disease.
  • inform your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking prasugrel, call your doctor.

What special dietary instructions to follow? 

Unless your doctor informs you otherwise, continue your normal diet.

What to do if I forget a dose? 

Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

What side effects can Prasugrel cause?

 

Prasugrel may cause side effects. inform your doctor if any of these symptoms are severe or do not go away:

  • dizziness

  • excessive tiredness

  • pain in the back, arms, or legs

  • cough

Some side effects can be serious. If you experience any of these symptoms or those listed in the IMPORTANT WARNING section, call your doctor immediately:  

  • fever

  • weakness

  • paleness

  • purple patches on the skin

  • yellowing of the skin or eyes

  • shortness of breath

  • slow, fast, or irregular heartbeat

  • headache

  • confusion

  • seizures

  • slow or difficult speech

  • sudden weakness of an arm or leg

  • stomach pain

  • nausea

  • vomiting

  • diarrhea

  • decreased urination

  • rash

  • swelling of the eyes, face, mouth, lips, tongue, throat, arms, hands, feet, ankles, or lower legs

  • rash

Prasugrel may cause other side effects. Call your doctor if you have any unusual problems while taking Prasugrel.

What to know about storage and disposal of Prasugrel? 

Keep Prasugrel in the container it came in, tightly closed, and out of reach of children. The medication will come with a gray cylinder that helps keep the tablets dry; leave this cylinder in the container with the medication. Store it at room temperature and away from excess heat and moisture (not in the bathroom). Throw away any medication that is outdated or no longer needed. Talk to your pharmacist about the proper disposal of your medication.

In case of emergency/overdose

In case of overdose, consult your doctor. If the victim has collapsed or is not breathing, consult local medical emergency services.

What other information to know?

Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests to check your response to Prasugrel.

Do not let anyone else use your medication. If you still have symptoms and need further treatment, consult your doctor.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

Ref:  U.S. National Library of Medicine.


This information is provided for reference only and not a replacement for and should only be used in conjunction with full consultation with a registered medical practitioner. It may not contain all the available information you require and cannot substitute professional medical care, nor does it take into account all individual circumstances. Although great effort has been made to ensure content accuracy, mph-bd shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise.

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*Trademark name & prescribing information are the property of their respective Manufacturers.

 

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