Cordipraz

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Cordipras (Cordipras)

Composition:

Active substance: prasugrel;

One film-coated tablet contains 5 mg or 10 mg of prasugrel as prasugrel hydrobromide;

Excipients: core: microcrystalline cellulose, mannitol (E 421), hypromellose, low-substituted hydroxypropylcellulose, glycerol dibehenate, sucrose stearate;

Film coating for 5 mg tablets: polyvinyl alcohol partially hydrolyzed, titanium dioxide (E 171), polyethylene glycol 3350, talc, yellow iron oxide (E 172), red iron oxide (E 172), black iron oxide (E 172);

Film coating for 10 mg tablets: polyvinyl alcohol partially hydrolyzed, titanium dioxide (E 171), polyethylene glycol 3350, talc, yellow iron oxide (E 172), red iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

5 mg film-coated tablets: yellow, oval, film-coated tablets, embossed with “P5” on one side and smooth on the other;

10 mg film-coated tablets: beige, oval, film-coated tablets, embossed with “P10” on one side and a break line on the other.

Pharmacotherapeutic group. Platelet aggregation inhibitors, excluding heparin. ATC code B01AC22.

Pharmacological Properties

Pharmacodynamics

Mechanism of action. Prasugrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the adenosine diphosphate (ADP) P2Y12 receptors on platelets. Since platelets play a role in the development and/or progression of thrombotic complications in atherosclerosis, inhibition of platelet function may reduce the incidence of cardiovascular events such as death, myocardial infarction, or stroke. After administration of a 60 mg loading dose of prasugrel, inhibition of ADP-induced platelet aggregation occurs within 15 minutes (with 5 µM ADP) and 30 minutes (with 20 µM AD0). Maximum inhibition of ADP-induced platelet aggregation by prasugrel is 83% (with 5 µM ADP) and 79% (with 20 µM ADP). In both cases, at least 50% inhibition of platelet aggregation is achieved within 1 hour in 89% of healthy individuals and patients with stable atherosclerosis. Prasugrel-mediated inhibition of platelet aggregation demonstrates low inter-individual (9%) and intra-individual variability (12%) (both at 5 µM and 20 µM ADP). Mean inhibition of platelet aggregation at steady state was 74% and 69% for 5 µM and 20 µM ADP, respectively, achieved after 3–5 days of 10 mg maintenance dose following a 60 mg loading dose. Over 98% of individuals achieved ≥20% inhibition of platelet aggregation with maintenance dosing. Platelet aggregation gradually returned to baseline values within 7–9 days after a single 60 mg loading dose and within 5 days after discontinuation of the maintenance dose at steady state.

Data on switching from another agent. After administration of 75 mg clopidogrel once daily for 10 days, 40 healthy subjects were switched to 10 mg prasugrel once daily with or without a 60 mg loading dose. Prasugrel treatment resulted in similar or higher inhibition of platelet aggregation. Immediate switch with a 60 mg loading dose of prasugrel led to the fastest onset of higher platelet inhibition. After administration of a 900 mg loading dose of clopidogrel (with acetylsalicylic acid [ASA]), 56 patients with acute coronary syndrome (ACS) were treated for 14 days either with 10 mg prasugrel once daily or 150 mg clopidogrel once daily, then crossed over to either clopidogrel 150 mg once daily or prasugrel 10 mg once daily for another 14 days. Higher inhibition of platelet aggregation was observed in patients switched to 10 mg prasugrel compared to those receiving 150 mg clopidogrel. In a study involving 276 ACS patients undergoing percutaneous coronary intervention (PCI), switching from an initial 600 mg loading dose of clopidogrel or placebo administered after hospitalization and prior to coronary angiography to a 60 mg loading dose of prasugrel given during PCI resulted in similar enhanced inhibition of platelet aggregation over the 72-hour study period.

Pharmacokinetics

Prasugrel is a prodrug rapidly metabolized in vivo to an active metabolite and inactive metabolites. Exposure to the active metabolite (AUC) shows moderate or low inter-individual variability (27%) and intra-individual variability (19%). The pharmacokinetics of prasugrel are similar in healthy individuals, patients with stable atherosclerosis, and patients undergoing PCI.

Absorption. Prasugrel is rapidly absorbed and metabolized; peak plasma concentration (Cmax) of the active metabolite is reached approximately within 30 minutes. Exposure to the active metabolite (AUC) increases proportionally within the therapeutic dose range. In a study involving healthy subjects, administration of a high-fat, high-calorie meal did not affect the AUC of the active metabolite, but reduced Cmax by 49% and increased the time to reach Cmax (Tmax) from 0.5 to 1.5 hours. In the TRITON study, prasugrel was administered regardless of food intake. Therefore, prasugrel can be taken independently of food; however, administration of the loading dose on an empty stomach may provide the fastest onset of action.

Distribution. Binding of the active metabolite to human serum albumin is 98%.

Biological transformation. After oral administration, prasugrel is not detectable in plasma. It is rapidly hydrolyzed in the intestine to a thiolactone, which is then converted to the active metabolite by cytochrome P450 isoenzymes, primarily CYP3A4 and CYP2B6, and to a lesser extent CYP2C9 and CYP2C19. The active metabolite is further metabolized to two inactive compounds via S-methylation or cysteine conjugation. In healthy individuals, patients with stable atherosclerosis, and ACS patients receiving prasugrel, no relevant impact of genetic variations in CYP3A5, CYP2B6, CYP2C9, or CYP2C19 on prasugrel pharmacokinetics or inhibition of platelet aggregation has been observed.

Elimination. Approximately 68% of the prasugrel dose is excreted in urine and 27% in feces as inactive metabolites. The elimination half-life of the active metabolite is approximately 7.4 hours (ranging from 2 to 15 hours).

Pharmacokinetics in special populations

Elderly patients. In a study involving healthy individuals aged 20 to 80 years, age did not significantly affect the pharmacokinetics of prasugrel or its inhibition of platelet aggregation. In a large phase 3 clinical trial, mean estimated exposure (AUC) of the active metabolite was 19% higher in patients aged ≥75 years compared to those <75 years. Prasugrel should be used with caution in patients aged ≥75 years due to the potential risk of bleeding. In a study involving patients with stable atherosclerosis, the mean AUC of the active metabolite in patients aged ≥75 years receiving 5 mg prasugrel was approximately half that in patients <65 years receiving 10 mg prasugrel; however, the antiplatelet effect of 5 mg was reduced but not inferior compared to 10 mg.

Hepatic impairment. Dose adjustment is not required for patients with mild or moderate hepatic impairment (Child–Pugh class A and B). The pharmacokinetics of prasugrel and its inhibitory effect on platelet aggregation are similar in individuals with mild or moderate hepatic impairment compared to healthy individuals. Pharmacokinetics and pharmacodynamics of prasugrel have not been studied in patients with severe hepatic impairment. Prasugrel is contraindicated in patients with severe hepatic impairment.

Renal impairment. Dose adjustment is not required for patients with renal impairment, including those with end-stage renal disease (ESRD). The pharmacokinetics of prasugrel and its inhibitory effect on platelet aggregation are similar in patients with moderate renal impairment (glomerular filtration rate 30–<50 mL/min/1.73 m²) and healthy individuals. Prasugrel-mediated inhibition of platelet aggregation was also similar in patients with ESRD requiring hemodialysis and healthy individuals, although in ESRD patients, Cmax and AUC of the active metabolite were reduced by 51% and 42%, respectively.

Body weight. Mean exposure (AUC) of the active metabolite of prasugrel is approximately 30–40% higher in healthy individuals and patients with body weight <60 kg compared to those with body weight ≥60 kg. Prasugrel should be used with caution in patients with body weight <60 kg due to the potential risk of bleeding. In a study involving patients with stable atherosclerosis, the mean AUC of the active metabolite in patients <60 kg receiving 5 mg prasugrel was 38% lower than in patients ≥60 kg receiving 10 mg prasugrel, while the antiplatelet effect of 5 mg was comparable to that of 10 mg.

Ethnicity. In clinical studies, AUC of the active metabolite, adjusted for body weight, was approximately 19% higher in individuals of Chinese, Japanese, and Korean ethnicity compared to those of Caucasian ethnicity, primarily due to higher exposure in individuals of Mongoloid race with body weight <60 kg. No differences in exposure were observed among individuals of Chinese, Japanese, and Korean ethnicity. Exposure in individuals of African descent and those of Latin American origin is comparable to that in Caucasians. Dose adjustment based solely on ethnicity is not recommended.

Gender. Pharmacokinetics of prasugrel are similar in men and women.

Pediatric population. The pharmacokinetics and pharmacodynamics of prasugrel have not been studied in children.

Clinical characteristics.

Indications.

Cordipraz in combination with acetylsalicylic acid is indicated for the prevention of atherothrombotic events in adult patients with acute coronary syndrome, i.e.:

• unstable angina (UA),
• myocardial infarction without ST-segment elevation (NSTEMI), or
• myocardial infarction with ST-segment elevation (STEMI),

who are undergoing primary or delayed percutaneous coronary intervention.

See also section "Pharmacological properties".

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Active pathological bleeding.

History of stroke or transient ischemic attack (TIA).

Severe hepatic impairment (Child–Pugh class C).

Interaction with other medicinal products and other forms of interaction.

Warfarin. Concomitant use of prasugrel with coumarin derivatives other than warfarin has not been studied. Due to the potential increased risk of bleeding, caution should be exercised when using warfarin (or other coumarin derivatives) concomitantly with prasugrel (see section "Special precautions for use").

Nonsteroidal anti-inflammatory drugs (NSAIDs). Concomitant use with NSAIDs (long-term use) has not been studied. Due to the potential increased risk of bleeding, caution should be exercised during long-term concomitant use of NSAIDs (including COX-2 inhibitors) and prasugrel (see section "Special precautions for use").

Prasugrel may be used concomitantly with medicinal products metabolized by cytochrome P450 enzymes (including statins), or with medicinal products that are inducers or inhibitors of cytochrome P450 enzymes. Prasugrel may also be used concomitantly with ASA, heparin, digoxin, and medicinal products that increase gastric pH, including proton pump inhibitors and H2-blockers.

Although specific interaction studies have not been conducted, in clinical trials prasugrel was used concomitantly with low-molecular-weight heparin, bivalirudin, and glycoprotein IIb/IIIa inhibitors (no information on the type of glycoprotein IIb/IIIa inhibitor used), without evidence of clinically significant adverse interactions.

Effect of other medicinal products on prasugrel

Acetylsalicylic acid. Prasugrel should be used in combination with ASA. Although pharmacodynamic interaction with ASA may increase the risk of bleeding, the efficacy and safety of prasugrel have been demonstrated in patients receiving prasugrel concomitantly with ASA.

Heparin. A single intravenous bolus dose of unfractionated heparin (100 IU/kg) does not significantly alter prasugrel-mediated inhibition of platelet aggregation. Similarly, prasugrel does not significantly affect the impact of heparin on coagulation parameters. Therefore, both medicinal products may be used concomitantly. Concomitant use of prasugrel with heparan may increase the risk of bleeding.

Statins. Atorvastatin (80 mg daily) did not alter the pharmacokinetics of prasugrel or its inhibition of platelet aggregation. Therefore, statins that are substrates of CYP3A are not expected to affect the pharmacokinetics of prasugrel or its inhibition of platelet aggregation.

Medicinal products that increase gastric pH. Daily concomitant use of ranitidine (H2-blocker) or lansoprazole (proton pump inhibitor) did not alter the AUC and Tmax of the active metabolite of prasugrel, but reduced Cmax by 14% and 29%, respectively. In clinical trials, prasugrel was administered regardless of concomitant use of proton pump inhibitors or H2-blockers. Administration of a 60 mg loading dose of prasugrel without concomitant use of proton pump inhibitors may ensure the fastest onset of action.

Inhibitors of CYP3A4. Ketoconazole (400 mg daily), a selective and potent inhibitor of CYP3A4 and CYP3A5, did not affect prasugrel-mediated inhibition of platelet aggregation or the AUC and Tmax of the active metabolite of prasugrel, but reduced Cmax by 34–46%. Therefore, inhibitors of CYP3A4 such as azole antifungal agents, 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 active metabolite.

Inducers of cytochrome P450. Rifampicin (600 mg daily), a potent inducer of CYP3A and CYP2B6 and an 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 cytochrome P450 inducers, are not expected to significantly affect the pharmacokinetics of the active metabolite.

Morphine and other opioids. In patients with ACS receiving morphine, delayed and reduced exposure to oral P2Y12 inhibitors, including prasugrel and its active metabolite, was observed. This interaction may be related to decreased gastrointestinal motility and may apply to other opioids. The clinical significance is unknown, but available data suggest a potential reduction in the efficacy of prasugrel in patients receiving concomitant prasugrel and morphine. In patients with ACS for whom morphine therapy cannot be discontinued and rapid P2Y12 inhibition is considered critical, administration of a parenteral P2Y12 inhibitor may be considered.

Effect of prasugrel on other medicinal products

Digoxin. Prasugrel has no clinically significant effect on the pharmacokinetics of digoxin.

Medicinal products metabolized by CYP2C9. Prasugrel does not inhibit CYP2C9, as it did not affect the pharmacokinetics of S-warfarin. Due to the potential increased risk of bleeding, concomitant use of warfarin and prasugrel should be exercised with caution (see section "Special precautions for use").

Medicinal products metabolized by CYP2B6. Prasugrel is a weak inhibitor of CYP2B6. In healthy subjects, prasugrel reduced exposure to hydroxybupropion – a metabolite of bupropion formed via CYP2B6 – by 23%. This effect may be clinically significant only when prasugrel is used concomitantly with medicinal products whose metabolism is mediated solely by CYP2B6 and which have a narrow therapeutic index (e.g., cyclophosphamide, efavirenz).

Special precautions.

Risk of bleeding. In clinical trials (TRITON), key exclusion criteria for patients included an increased risk of bleeding, anemia, thrombocytopenia, and history of intracranial pathology. In patients with ACS who underwent PCI and received prasugrel and aspirin, an increased risk of major and minor bleeding was observed according to the TIMI (Thrombolysis In Myocardial Infarction) classification. Therefore, prasugrel should be used in patients with an increased risk of bleeding only when the benefit of preventing ischemic events outweighs the risk of serious bleeding.

This is particularly relevant for patients:

• aged ≥75 years (see below);
• with a predisposition to bleeding (e.g., due to recent trauma, recent surgery, recent or recurrent gastrointestinal bleeding, or active peptic ulcer disease);
• with body weight <60 kg (see sections "Dosage and administration" and "Adverse reactions") (maintenance dose of 10 mg is not recommended for such patients; a maintenance dose of 5 mg should be used);
• who are concomitantly taking medicinal products that may increase the risk of bleeding, including oral anticoagulants, clopidogrel, NSAIDs, and fibrinolytics.

For patients with active bleeding in whom neutralization of the pharmacological effect of prasugrel is required, platelet transfusion may be beneficial.

During treatment with Cordipraz, menstrual flow may increase. In such cases, patients are advised to consult their physician. The drug should not be discontinued without medical advice.

Prasugrel is generally not recommended for patients aged ≥75 years. It should be used with caution only after careful individual assessment of benefit/risk ratio by the physician, if the benefit of preventing ischemic events outweighs the risk of serious bleeding. In clinical trials, such patients had a higher risk of bleeding, including fatal bleeding, compared to patients under 75 years of age. If prescribed, a lower maintenance dose (5 mg) should be used – a maintenance dose of 10 mg is not recommended.

Therapeutic experience with prasugrel in patients with renal impairment (including those on dialysis) and in patients with moderate hepatic impairment is limited. An increased risk of bleeding may occur in these patients. Therefore, prasugrel should be used with caution in such patients.

Patients should be informed that during treatment with prasugrel (in combination with aspirin), it may take longer than usual to stop bleeding, and they should report any unusual bleeding (site or duration) to their physician.

Timing-related bleeding risk with loading dose in NSTE-ACS. In a clinical trial (ACCOAST) involving patients with NSTE-ACS, where coronary angiography was planned within 2–48 hours after randomization, administration of a loading dose of prasugrel approximately 4 hours before coronary angiography increased the risk of major and minor periprocedural bleeding compared to administration of the loading dose during PCI. Therefore, patients with NSTE-ACS undergoing coronary angiography within 48 hours after hospitalization should receive the loading dose during PCI (see sections "Dosage and administration" and "Adverse reactions").

Surgery. Patients should be advised to inform their physicians and dentists that they are taking prasugrel before any planned surgical procedure and before starting any new medication. If a patient requires elective surgery and antiplatelet effect is undesirable, prasugrel should be discontinued at least 7 days prior to the surgical procedure. In patients undergoing coronary artery bypass grafting (CABG) within 7 days after discontinuation of prasugrel, an increased frequency (by 3 times) and severity of bleeding may occur (see section "Adverse reactions"). Careful assessment of benefit and risk of prasugrel use is necessary for patients in whom coronary anatomy has not been defined and in whom emergency CABG may be required.

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 recommended in patients with a history of allergy to thienopyridines (see section "Adverse reactions").

Thrombotic thrombocytopenic purpura (TTP). Cases of TTP have been reported with prasugrel use. TTP is a serious condition requiring immediate treatment.

Morphine and other opioids. A reduced efficacy of prasugrel has been observed in patients who received concomitant morphine (see section "Interaction with other medicinal products and other forms of interaction").

Stearate of sucrose. This medicinal product should not be used in patients with rare hereditary conditions such as fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency.

Use during pregnancy or breastfeeding.

Clinical studies in pregnant or breastfeeding women have not been conducted.

Pregnancy. Animal studies did not reveal any direct harmful effects on pregnancy, embryonic/fetal development, parturition, or postnatal development. Since results of reproductive toxicity studies in animals do not always predict outcomes in humans, prasugrel should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

Breastfeeding. It is unknown whether prasugrel is excreted in human breast milk. Animal studies have shown that prasugrel is excreted in milk. Prasugrel is not recommended during breastfeeding.

Fertility. Prasugrel had no effect on fertility in male and female rats when administered orally at exposures approximately 240 times higher than the recommended human maintenance daily doses (on a mg/m² basis).

Ability to affect reaction speed when driving or operating machinery.

Prasugrel is expected to have no effect or negligible effect on the ability to drive vehicles or operate machinery.

Method of Administration and Dosage

Dosage

Adults. Treatment with prasugrel should be initiated with a single 60 mg loading dose, followed by 10 mg once daily. In patients with NSTE-ACS undergoing coronary angiography within 48 hours after hospitalization, the loading dose should be administered only during PCI. Patients receiving prasugrel should also take daily aspirin (75–325 mg).

In patients with acute coronary syndrome who have undergone PCI, premature discontinuation of any antiplatelet agent, including prasugrel, may increase the risk of thrombosis, myocardial infarction, or death due to the underlying condition. Treatment should be continued for up to 12 months unless there is a compelling reason to discontinue prasugrel.

Patients aged ≥75 years. Prasugrel is generally not recommended for patients aged ≥75 years. If, after careful individual assessment of benefit/risks, the physician decides that treatment is necessary for a patient aged ≥75 years, a reduced maintenance dose of 5 mg should be prescribed following the 60 mg loading dose. Patients aged ≥75 years have increased sensitivity to bleeding and higher exposure to the active metabolite of prasugrel.

Patients with body weight <60 kg. Prasugrel should be administered as a single 60 mg loading dose, followed by 5 mg once daily. A maintenance dose of 10 mg is not recommended. This is due to increased exposure to the active metabolite of prasugrel and a higher risk of bleeding in patients with body weight <60 kg when receiving 10 mg once daily compared to patients with body weight ≥60 kg.

Renal impairment. Dose adjustment is not required in patients with renal impairment, including those with end-stage renal disease. However, therapeutic experience in patients with renal impairment is limited.

Hepatic impairment. Dose adjustment is not required in patients with mild or moderate hepatic impairment (Child–Pugh class A or B). Therapeutic experience in such patients is limited. Prasugrel is contraindicated in patients with severe hepatic impairment (Child–Pugh class C).

Method of Administration

For oral use. Cordipraz can be taken independently of food intake. Administration of the 60 mg prasugrel loading dose on an empty stomach may provide the fastest onset of action.

The 5 mg tablet must not be split or crushed. The 10 mg tablet may be divided into equal doses by splitting it only once; the tablet must not be crushed.

Children.

The safety and efficacy of prasugrel in children (under 18 years of age) have not been established. Limited data are available in children with sickle cell anemia.

Overdose.

Overdose with prasugrel may lead to prolonged bleeding time and an increased risk of bleeding complications. There are no data on the neutralization of prasugrel's pharmacological effect. However, if rapid correction of prolonged bleeding time is required, platelet transfusion and/or other blood products may be considered.

Adverse reactions.

The safety of patients with ACS who underwent PCI was evaluated in one study with clopidogrel as control (TRITON), in which 6741 patients received treatment with prasugrel (loading dose 60 mg and maintenance dose 10 mg once daily) for a median duration of 14.5 months (5802 patients were treated for over 6 months, and 4136 patients for more than 1 year). The rate of treatment discontinuation due to adverse events according to the study protocol was 7.2% for prasugrel and 6.3% for clopidogrel. Bleeding was the most common adverse reaction leading to discontinuation of the study drug (2.5% for prasugrel and 1.4% for clopidogrel).

Bleeding not related to CABG

Table 1 shows the frequency of bleeding events not related to CABG in patients enrolled in the TRITON study. The frequency of major bleeding (by TIMI criteria), not related to CABG, including life-threatening and fatal bleeding, as well as minor bleeding (by TIMI criteria), was statistically significantly higher in patients treated with prasugrel compared to clopidogrel in both the population with NSTE-ACS and in the overall ACS population. No significant differences were observed in the STEMI population. Spontaneous bleeding most commonly occurred in the gastrointestinal tract (1.7% for prasugrel and 1.3% for clopidogrel), while procedural bleeding most commonly occurred at the arterial puncture site (1.3% for prasugrel and 1.2% for clopidogrel).

Table 1

Frequency of bleeding events not related to CABG (% of patients)

Adverse reaction	All GCS		NS/IMBPST		IMZPST
	Prasugrelb + ASA (N=6741)	Clopidogrelb + ASA (N=6716)	Prasugrelb + ASA (N=5001)	Clopidogrelb + ASA (N=4980)	Prasugrelb + ASA (N=1740)	Clopidogrelb + ASA (N=1736)
Major bleeding by TIMIs	2.2	1.7	2.2	1.6	2.2	2.0
Life-threateningd	1.3	0.8	1.3	0.8	1.2	1.0
Fatal	0.3	0.1	0.3	0.1	0.4	0.1
CVFe with clinical manifestations	0.3	0.3	0.3	0.3	0.2	0.2
Requires inotropes	0.3	0.1	0.3	0.1	0.3	0.2
Requires surgical intervention	0.3	0.3	0.3	0.3	0.1	0.2
Requires transfusion (≥4 units)	0.7	0.5	0.6	0.3	0.8	0.8
Minor bleeding by TIMIf	2.4	1.9	2.3	1.6	2.7	2.6

a Defined according to TIMI criteria.

b Other standard therapies were used as needed.

c Any intracranial hemorrhage or any clinically evident bleeding associated with a decrease in hemoglobin level ≥5 g/dL.

d Life-threatening bleeding – a subgroup of major TIMI bleeds, including the types listed below. Patients may be counted in more than one category.

e ICH = intracranial hemorrhage.

f Clinically evident bleeding associated with a decrease in hemoglobin level ≥3 g/dL but <5 g/dL.

Patients aged ≥75 years

Table 2

Incidence of major or minor bleeding (by TIMI criteria), unrelated to CABG surgery

Age	Prasugrel 10 mg	Clopidogrel 75 mg
≥75 years (N=1785)*	9.0% (1.0% fatal)	6.9% (0.1% fatal)
<75 years (N=11672)*	3.8% (0.2% fatal)	2.9% (0.1% fatal)
<75 years (N=7180)**	2.0% (0.1% fatal)a	1.3% (0.1% fatal)
	Prasugrel 5 mg	Clopidogrel 75 mg
≥75 years (N=2060)**	2.6% (0.3% fatal)	3.0% (0.5% fatal)

* TRITON study in ACS patients undergoing PCI.

** TRILOGY-ACS study in patients not undergoing PCI.

a 10 mg prasugrel; 5 mg prasugrel for body weight <60 kg.

Patients <60 kg

Table 3

Frequency of major or minor bleeding (according to TIMI), unrelated to CABG

Body weight	Prasugrel 10 mg	Clopidogrel 75 mg
<60 kg (N=664)*	10.1% (0% fatal)	6.5% (0.3% fatal)
≥60 kg (N=12672)*	4.2% (0.3% fatal)	3.3% (0.1% fatal)
≥60 kg (N=7845)**	2.2% (0.2% fatal)а	1.6% (0.2% fatal)
	Prasugrel 5 mg	Clopidogrel 75 mg
<60 kg (N=1391)**	1.4% (0.1% fatal)	2.2% (0.3% fatal)

* TRITON trial in patients with ACS who underwent PCI.

** TRILOGY-ACS trial in patients who did not undergo PCI.

a 10 mg prasugrel; 5 mg prasugrel if age ≥75 years.

Patients ≥60 kg and age <75 years

In patients with body weight ≥60 kg and age <75 years, the rate of major or minor bleeding (according to TIMI criteria), not related to CABG, was 3.6% for prasugrel and 2.8% for clopidogrel. The rate of fatal bleeding was 0.2% for prasugrel and 0.1% for clopidogrel.

Bleeding related to CABG

During phase 3 clinical trials, 437 patients underwent CABG. In these patients, the rate of major or minor bleeding (according to TIMI criteria) related to CABG was 14.1% in the prasugrel group and 4.5% in the clopidogrel group. The increased risk of bleeding in patients receiving prasugrel treatment persisted up to 7 days after the last dose of the investigational drug. In patients who received thienopyridine within 3 days prior to CABG, major or minor bleeding (according to TIMI criteria) occurred at a rate of 26.7% (12 out of 45 patients) in the prasugrel group compared to 5.0% (3 out of 60 patients) in the clopidogrel group. In patients who received the last dose of thienopyridine 4–7 days before CABG, the bleeding rate decreased to 11.3% (9 out of 80 patients) in the prasugrel group and 3.4% (3 out of 89 patients) in the clopidogrel group. After 7 days from drug discontinuation, the rate of CABG-related bleeding was similar between treatment groups.

Bleeding risk related to timing of loading dose in NSTE-ACS

In a clinical trial (ACCOAST) involving patients with NSTE-ACS who were scheduled for coronary angiography within 2 to 48 hours after randomization, patients who received a 30 mg loading dose of prasugrel at a median of 4 hours before coronary angiography followed by a second 30 mg loading dose at the time of PCI had an increased risk of periprocedural bleeding not related to CABG, with no additional clinical benefit compared to patients who received a 60 mg loading dose only at the time of PCI.

Table 4

Rate of bleeding (according to TIMI criteria), not related to CABG, observed in patients during 7 days

Adverse reaction	Prasugrel before coronary angiographya (N=2037), %	Prasugrel during PCIa (N=1996), %
Major bleeding according to TIMIb	1.3	0.5
Life-threateningc	0.8	0.2
Fatal	0.1	0.0
CABGd with clinical manifestations	0.0	0.0
Requires inotropes	0.3	0.2
Requires surgical intervention	0.4	0.1
Requires transfusion (≥4 units)	0.3	0.1
Minor bleeding according to TIMIe	1.7	0.6

a Other standard therapies were applied as needed. The clinical study protocol stipulated that all patients would receive aspirin and a daily maintenance dose of prasugrel.

b Any intracranial hemorrhage or any clinically evident bleeding with a decrease in hemoglobin level ≥5 g/dL.

c Life-threatening bleeding – a subgroup of major bleeding according to TIMI criteria, including the types listed below. Patients could be counted in more than one category.

d ICH = intracranial hemorrhage.

e Clinically evident bleeding with a decrease in hemoglobin level ≥3 g/dL, but <5 g/dL.

Summary of adverse reactions

Below is a summary of hemorrhagic and non-hemorrhagic adverse reactions observed in the TRITON study or reported spontaneously. Adverse reactions are listed by system organ class and frequency of occurrence. Frequencies are categorized as follows: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000); frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders: common – anemia; rare – thrombocytopenia; frequency not known – thrombotic thrombocytopenic purpura (see section "Special warnings and precautions for use").

Immune system disorders: uncommon – hypersensitivity, including angioedema.

Eye disorders: uncommon – ocular hemorrhage.

Vascular disorders: common – hematoma.

Respiratory, thoracic and mediastinal disorders: common – epistaxis; uncommon – hemoptysis.

Gastrointestinal disorders: common – gastrointestinal hemorrhage; uncommon – retroperitoneal hemorrhage, rectal hemorrhage, hematochezia, gingival bleeding.

Skin and subcutaneous tissue disorders: common – rash, ecchymosis.

Renal and urinary disorders: common – hematuria.

General disorders and administration site conditions: common – vascular puncture site hematoma, bleeding at puncture site.

Injury, poisoning and procedural complications: common – contusion; uncommon – post-procedural bleeding; rare – subcutaneous hematoma.

Table 5

Incidence of stroke during the clinical study in patients with or without a history of TIA or stroke (see section "Special warnings and precautions for use")

History of TIA or stroke	Prasugrel	Clopidogrel
Yes (N=518)	6.5% (2.3% BAR*)	1.2% (0% BAR*)
No (N=13090)	0.9% (0.2% BAR*)	1.0% (0.3% BAR*)

*ICH = intracerebral hemorrhage.

Reporting of suspected adverse reactions. All cases of suspected adverse reactions and lack of drug efficacy should be reported at: https://aisf.dec.gov.ua/.

Shelf life. 2 years.

Storage conditions. Store at a temperature not exceeding 25 °C. Keep out of reach and sight of children.

Packaging.

10 tablets per blister, 3 or 9 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

PLIVA Hrvatska d.o.o.

Manufacturer's address and location of business operations.

Baruna Filipovića 25, 10000 Zagreb, Croatia.