PERGUS

Prasugrel tablets

USP contain prasugrel, a thienopyridine class inhibitor of platelet activation and aggregation mediated by the P2Y 12 ADP receptor.

Prasugrel is formulated as the hydrochloride salt, a racemate, which is chemically designated as 5-[(1RS)-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate hydrochloride.

Prasugrel hydrochloride USP has the molecular formula C 20 H 20 FNO 3 S•HCl representing a molecular weight of 409.90.

The chemical structure of prasugrel hydrochloride USP is: Prasugrel hydrochloride USP is a white to practically white powder.

It is freely soluble in methanol, practically insoluble in water.

USP are available for oral administration as 5 mg or 10 mg elongated hexagonal, film-coated, non-scored tablets, debossed on each side.

Each yellow 5 mg tablet is manufactured with 5.49 mg prasugrel hydrochloride USP, equivalent to 5 mg prasugrel and each beige 10 mg tablet with 10.98 mg prasugrel hydrochloride USP, equivalent to 10 mg of prasugrel.

Other ingredients include glyceryl dibehenate, hypromellose, lactose monohydrate, low substituted hydroxypropyl cellulose, mannitol, microcrystalline cellulose, sucrose stearate, titanium dioxide, triacetin, and yellow iron oxide.

In addition, the 10 mg tablets contain red iron oxide.

Prasugrel tablets are a

P2Y 12 platelet inhibitor indicated for the reduction of thrombotic cardiovascular events (including stent thrombosis) in patients with acute coronary syndrome who are to be managed with percutaneous coronary intervention (PCI) as follows: Patients with unstable angina or non-ST-elevation myocardial infarction (NSTEMI) .

Patients with

ST-elevation myocardial infarction (STEMI) when managed with either primary or delayed PCI. 1.1 Acute Coronary Syndrome Prasugrel tablets are indicated to reduce the rate of thrombotic 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).

ST-elevation myocardial infarction (STEMI) when managed with primary or delayed PCI.

Prasugrel tablets have 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.

Gastrointestinal haemorrhage, recent history (d) Recidivating gastrointestinal haemorrhage Myocardial infarction without ST segment over-decadal Moderate hepatic impairment Renal impairment Surgical intervention Subject at risk of bleeding Subject under 18 Subject less than 60 kg Subject over 75 years Trauma, recent history (de).

Prasugrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y 12 class of ADP receptors on platelets. 12.2 Pharmacodynamics Prasugrel produces inhibition of platelet aggregation to 20 μM or 5 μM ADP, as measured by light transmission aggregometry.

Following a 60 mg loading dose of prasugrel, approximately 90% of patients had at least 50% inhibition of platelet aggregation by 1 hour.

Maximum platelet inhibition was about 80% .

Mean steady-state inhibition of platelet aggregation was about 70% following to 5 days of dosing at 10 mg daily after a 60 mg loading dose of prasugrel.

Figure 2: Inhibition (Mean ± SD) of 20 μM ADP-induced Platelet Aggregation (IPA) Measured by Light Transmission Aggregometry after Prasugrel 60 mg Platelet aggregation gradually returns to baseline values over to 9 days after discontinuation of prasugrel, this time course being a reflection of new platelet production rather than pharmacokinetics of prasugrel.

Discontinuing clopidogrel 75 mg and initiating a prasugrel 10 mg maintenance dose with or without a prasugrel 60 mg loading dose results in a decrease of 14 percentage points in maximum platelet aggregation (MPA) by Day 7.

This decrease in

MPA is not greater than that typically produced by a 10 mg maintenance dose of prasugrel alone.

The relationship between inhibition of platelet aggregation and clinical activity has not been established. 5 mg in Low Body Weight Patients In patients with stable coronary artery disease, mean platelet inhibition in subjects <60 kg taking 5 mg prasugrel was similar to that of subjects ≥60 kg taking 10 mg prasugrel.

The relationship between inhibition of platelet aggregation and clinical activity has not been established.

Figure 2: Inhibition (Mean±SD) of 20 μM ADP-induced Platelet Aggregation (IPA) Measured by Light Transmission Aggregometry after Prasugrel 60 mg. 12.3 Pharmacokinetics Prasugrel is a prodrug and is rapidly metabolized to a pharmacologically active metabolite and inactive metabolites.

The active metabolite has an elimination half-life of about 7 hours (range to 15 hours).

Healthy subjects, patients with stable atherosclerosis, and patients undergoing PCI show similar pharmacokinetics.

Following oral administration, ≥79% of the dose is absorbed.

The absorption and metabolism are rapid, with peak plasma concentrations (C max ) of the active metabolite occurring approximately 30 minutes after dosing.

The active metabolite’s exposure (AUC) increases slightly more than proportionally over the dose range of to 60 mg. Repeated daily doses of 10 mg do not lead to accumulation of the active metabolite.

In a study of healthy subjects given a single 15 mg dose, the AUC of the active metabolite was unaffected by a high-fat, high-calorie meal, but C max was decreased by 49% and T max was increased from 0.5 to 1.5 hours.

Prasugrel can be administered without regard to food.

The active metabolite is bound about 98% to human serum albumin.

Prasugrel is not detected in plasma following oral administration.

It is rapidly hydrolyzed in the intestine to a thiolactone, which is then converted to the active metabolite by a single step, primarily by CYP3A4 and CYP2B6 and to a lesser extent by CYP2C9 and CYP2C19.

The estimates of apparent volume of distribution of prasugrel’s active metabolite ranged from to 68 L and the estimates of apparent clearance ranged from to 166 L/hr in healthy subjects and patients with stable atherosclerosis.

The active metabolite is metabolized to two inactive compounds by S-methylation or conjugation with cysteine.

The major inactive metabolites are highly bound to human plasma proteins.

Approximately 68% of the prasugrel dose is excreted in the urine and 27% in the feces as inactive metabolites.

In a study of 32 healthy subjects between the ages of and 80 years, age had no significant effect on pharmacokinetics of prasugrel’s active metabolite or its inhibition of platelet aggregation.

In TRITON-TIMI 38, the mean exposure (AUC) of the active metabolite was 19% higher in patients ≥75 years of age than in patients <75 years of age.

In a study in subjects with stable atherosclerosis, the mean exposure (AUC) to the active metabolite of prasugrel in subjects ≥75 years old taking a 5 mg maintenance dose was approximately half that seen in subjects to 64 years old taking a 10 mg maintenance dose.

The mean exposure (AUC) to the active metabolite is approximately to 40% higher in subjects with a body weight of <60 kg than in those weighing ≥60 kg. In a study in subjects with stable atherosclerosis, the AUC of the active metabolite on average was 38% lower in subjects <60 kg taking 5 mg (N=34) than in subjects ≥60 kg taking 10 mg (N=38) .

Pharmacokinetics of prasugrel’s active metabolite is similar in men and women.

Racial or Ethnic Groups Exposure in subjects of African and Hispanic descent is similar to that in Caucasians.

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 than in Caucasian subjects.

Pharmacokinetics of prasugrel’s active metabolite is similar in smokers and nonsmokers.

Pharmacokinetics of prasugrel’s active metabolite and its inhibition of platelet aggregation is similar in patients with moderate renal impairment (CrCL=30 to 50 mL/min) and healthy subjects.

In patients with end-stage renal disease, exposure to the active metabolite (both C max and AUC (0-t last )) was about half that in healthy controls and patients with moderate renal impairment.

Pharmacokinetics of prasugrel’s active metabolite and inhibition of platelet aggregation was similar in patients with mild to moderate hepatic impairment compared to healthy subjects.

The pharmacokinetics and pharmacodynamics of prasugrel’s active metabolite in patients with severe hepatic disease have not been studied.

Drug Interaction Studies 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 inhibition of platelet aggregation or the active metabolite’s AUC and T max, but decreased the C max by 34% to 46%.

Therefore, CYP3A inhibitors such as verapamil, diltiazem, indinavir, ciprofloxacin, clarithromycin, and grapefruit juice are not expected to have a significant effect on the pharmacokinetics of the active metabolite of prasugrel.

• 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’s active metabolite or its inhibition of platelet aggregation.

Therefore, known CYP3A inducers such as rifampicin, carbamazepine, and other inducers of cytochromes P450 are not expected to have significant effect on the pharmacokinetics of the active metabolite of prasugrel.

Drugs that Elevate

Gastric pH.

• Daily coadministration of ranitidine (an H 2 blocker) or lansoprazole (a proton pump inhibitor) decreased the C max of the prasugrel active metabolite by 14% and 29%, respectively, but did not change the active metabolite’s AUC and T max.

In TRITON-TIMI 38, prasugrel was administered without regard to coadministration of a proton pump inhibitor or H 2 blocker.

• Atorvastatin (80 mg daily), a drug metabolized by CYP450 3A4, did not alter the pharmacokinetics of prasugrel’s active metabolite or its inhibition of platelet aggregation.

• A single intravenous dose of unfractionated heparin (100 units/kg) did not significantly alter coagulation or the prasugrel-mediated inhibition of platelet aggregation; however, bleeding time was increased compared with either drug alone.

• Aspirin 150 mg daily did not alter prasugrel-mediated inhibition of platelet aggregation; however, bleeding time was increased compared with either drug alone.

• A significant prolongation of the bleeding time was observed when prasugrel was coadministered with 15 mg of warfarin.

Potential for Prasugrel to Affect Other Drugs In vitro metabolism studies demonstrate that prasugrel’s main circulating metabolites are not likely to cause clinically significant inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A, or induction of CYP1A2 or CYP3A.

Drugs Metabolized by

• Prasugrel is a weak inhibitor of CYP2B6.

In healthy subjects, prasugrel decreased exposure to hydroxybupropion, a CYP2B6-mediated metabolite of bupropion, by 23%, an amount not considered clinically significant.

Prasugrel is not anticipated to have significant effect on the pharmacokinetics of drugs that are primarily metabolized by CYP2B6, such as halothane, cyclophosphamide, propofol, and nevirapine.

Effect on

• The potential role of prasugrel as a Pgp substrate was not evaluated.

Prasugrel is not an inhibitor of

Pgp, as digoxin clearance was not affected by prasugrel coadministration.

• Coadministration of 5 mg intravenous morphine with 60 mg loading dose of prasugrel in healthy adults decreased the C max of prasugrel’s active metabolite by 31% with no change in AUC, T max, or inhibition of ADP-induced platelet aggregation.

ADP-induced platelet aggregation was higher up to 2 hours following 60 mg loading dose of prasugrel in stable patients more than 1 year after an ACS who were coadministered morphine.

In the patients with a 2-hour delay in the onset of platelet aggregation (5 of 11), T max was delayed and prasugrel active metabolite levels were significantly lower at 30 min (5 vs 120 ng/mL) following coadministration with morphine. 12.5 Pharmacogenomics There is 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.

Mechanism of action

Prasugrel is an inhibitor of platelet activation and aggregation via irreversible binding of its active metabolite to P2Y12 ADP receptors on platelets.

Since platelets are involved in the onset and/or evolution of thrombotic complications of atherosclerotic disease, inhibition of platelet function may reduce the rate of cardiovascular events such as death, myocardial infarction or stroke.

• Rash (Common)
• Subcutaneous haematoma (Rare)
• Contusion (Common)
• Echymosis (Common)
• Anemia (Common)
• Post-intervention haemorrhage (Uncommon)
• Hematoma (Common)
• Hematoma at the puncture site (Common)
• Thrombocytopenia (Rare)
• Thrombotic thrombocytopenic purpura Hypersensitivity (Uncommon)
• Angioedema Hemorrhage at the puncture site (Common)
• Eye haemorrhage (Uncommon)
• Gingivorrhagic (Uncommon)
• Epistaxis (Common)
• Rectorragie (Uncommon)
• Gastrointestinal haemorrhage (Common)
• Retroperitoneal haemorrhage (Uncommon)
• Hematochesis (Uncommon)
• Intracranial haemorrhage Hemoptysis (Uncommon)
• Haematuria (Common).

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. 10.2 Recommendations about Specific Treatment Platelet transfusion may restore clotting ability.

The prasugrel active metabolite is not likely to be removed by dialysis.

Active pathological bleeding Prior transient ischemic attack or stroke Hypersensitivity to prasugrel or any component of the product 4.1 Active Bleeding Prasugrel tablets are contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage (ICH) . 4.2 Prior Transient Ischemic Attack or Stroke Prasugrel tablets are contraindicated in patients with a history of prior transient ischemic attack (TIA) or stroke.

In TRITON-TIMI 38 ( TR ial to Assess I mprovement in T herapeutic Outcomes by O ptimizing Platelet Inhibitio N with Prasugrel), patients with a history of TIA or ischemic stroke (>3 months prior to enrollment) had a higher rate of stroke on prasugrel tablets (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 prasugrel tablets and clopidogrel, respectively.

Patients with a history of ischemic stroke within 3 months of screening and 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 prasugrel tablets generally should have therapy discontinued. 4.3 Hypersensitivity Prasugrel tablets are contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to prasugrel or any component of the product.

Initiate prasugrel tablets treatment as a single 60 mg oral loading dose and then continue at 10 mg orally once daily.

Patients taking prasugrel tablets should also take aspirin (75 mg to 325 mg) daily.

Prasugrel tablets may be administered with or without food.

In the clinical trial that established the efficacy and safety of prasugrel tablets, the loading dose of prasugrel tablets was not administered until coronary anatomy was established in UA/NSTEMI patients and in STEMI patients presenting more than 12 hours after symptom onset.

In STEMI patients presenting within 12 hours of symptom onset, the loading dose of prasugrel tablets was administered at the time of diagnosis, although most received prasugrel tablets at the time of PCI.

For the small fraction of patients that required urgent CABG after treatment with prasugrel tablets, the risk of significant bleeding was substantial.

Although 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 a trial of 4033 NSTEMI patients, no clear benefit was observed when prasugrel tablets loading dose was administered prior to diagnostic coronary angiography compared to at the time of PCI; however, risk of bleeding was increased with early administration in patients undergoing PCI or early CABG.

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.

Initiate treatment with a single 60 mg oral loading dose.

Continue at 10 mg once daily with or without food.

Consider 5 mg once daily for patients <60 kg.

Patients should also take aspirin (75 mg to 325 mg) daily.

USP, 10 mg are beige, elongated hexagonal, film-coated, non-scored tablets debossed with ‘I’ on one side and ‘24’ on the other side.

Unit dose packages of 30 (3 x 10) NDC 60687-883-21 16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F) .

Keep and dispense only in original container.

Do not break the tablet.

Do not use if blister is torn or broken.

There are no data with prasugrel use in pregnant women to inform a drug-associated risk.

No structural malformations were observed in animal reproductive and developmental toxicology studies when rats and rabbits were administered prasugrel during organogenesis at doses of up to 30 times the recommended therapeutic exposures in humans.

Due to the mechanism of action of prasugrel, and the associated identified risk of bleeding, consider the benefits and risks of prasugrel and possible risks to the fetus when prescribing prasugrel to a pregnant woman.

The background risk of major birth defects and miscarriage for the indicated population is unknown.

The background risk in the

U.S. general population of major birth defects is to 4% and of miscarriage is to 20% of clinically recognized pregnancies.

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 fetal 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.

There is no information regarding the presence of prasugrel in human milk, the effects on the breastfed infant, or the effects on milk production.

Metabolites of prasugrel were found in rat milk.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for prasugrel and any potential adverse effects on the breastfed child from prasugrel or from the underlying maternal condition.

Following a 5 mg/kg oral dose of [ 14 C]-prasugrel to lactating rats, metabolites of prasugrel were detected in the maternal milk and blood.

Safety and effectiveness in pediatric patients have not been established.

In a randomized, placebo-controlled trial, the primary objective of reducing the rate of vaso-occlusive crisis (painful crisis or acute chest syndrome) in pediatric patients, aged to less than 18 years, with sickle cell anemia was not met.

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 (prasugrel compared with clopidogrel) was similar across age groups.

Patients ≥75 years of age who received prasugrel 10 mg had an increased risk of fatal bleeding events (1.0%) compared to patients who received clopidogrel (0.1%).

In patients ≥75 years of age, symptomatic intracranial hemorrhage occurred in 7 patients (0.8%) who received prasugrel 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 prasugrel 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.