Trombasel

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

Composition:

Active substance: prasugrel;

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

Excipients: crospovidone (type A); lactose monohydrate; sodium croscarmellose; microcrystalline cellulose; sucrose stearate (type III);

Coating mixture for 5 mg tablets Opadry II 32K220036 Yellow: hypromellose (E 464); lactose monohydrate; titanium dioxide (E 171); triacetin (E 1518); talc; iron oxide yellow (E 172).

Coating mixture for 10 mg tablets Opadry II 32K230012 Orange: hypromellose (E 464); lactose monohydrate; titanium dioxide (E 171); triacetin (E 1518); talc; iron oxide yellow (E 172); iron oxide red (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

5 mg tablets: elongated, biconvex tablets with "F1" imprint on one side.

10 mg tablets: elongated, biconvex tablets with "F2" imprint on one side.

Pharmacotherapeutic group. Antithrombotic agents. Platelet aggregation inhibitors, excluding heparin. Prasugrel. 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 P2Y12 class of ADP receptors on platelets. Since platelets play a role in the development of atherosclerotic complications, inhibition of their function reduces the frequency of cardiovascular complications (such as myocardial infarction, stroke, and cardiovascular death).

In 89% of healthy volunteers and patients with atherosclerotic arterial disease, inhibition of platelet aggregation of at least 50% is achieved within 1 hour after administration of a 60 mg loading dose of prasugrel. After 3–5 days of treatment with the maintenance dose of prasugrel 10 mg/day (following prior administration of the loading dose), i.e., at steady-state conditions, inhibition of platelet aggregation reaches approximately 70%.

Platelet aggregation gradually returns to baseline values after discontinuation of prasugrel therapy: within 7–9 days after a single 60 mg loading dose of prasugrel and within 5 days after discontinuation of the maintenance dose at steady state.

Data on switching from one medicinal product to another.

Switching to prasugrel after treatment with 75 mg daily of clopidogrel for 10 days results in similar or greater inhibition of platelet aggregation. In a study of patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI), switching from an initial 600 mg loading dose of clopidogrel or placebo administered prior to coronary angiography to a 60 mg loading dose of prasugrel given during PCI resulted in similar inhibition of platelet aggregation over 72 hours.

Efficacy and safety.

Acute coronary syndrome (ACS). In a clinical trial involving patients with ACS at risk of unstable angina (UA)/non-ST-elevation myocardial infarction (NSTEMI) and patients with ST-elevation myocardial infarction (STEMI) undergoing PCI, prasugrel was compared with clopidogrel, both administered with acetylsalicylic acid (ASA) and other medications according to standard treatment practices. Patients received either prasugrel (60 mg loading dose, followed by 10 mg daily) or clopidogrel (300 mg loading dose, followed by 75 mg daily), with a mean treatment duration of 14.5 months and subsequent follow-up for at least 6 months. Patients received ASA (75–325 mg once daily). The efficacy endpoint was time to first occurrence of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. Analysis of the composite endpoint in the overall ACS patient population (combined UA/NSTEMI and STEMI populations) demonstrated a statistically significant advantage of prasugrel over clopidogrel in the UA/NSTEMI subgroup (p < 0.05).

All patients receiving ASA. Prasugrel demonstrated greater efficacy than clopidogrel in reducing the incidence of the primary composite endpoint as well as secondary endpoints, including stent thrombosis. The benefit of prasugrel was evident within the first 3 days and persisted throughout the study. This superior efficacy was accompanied by an increased incidence of "major" bleeding (see sections "Special precautions for use" and "Adverse reactions"). The efficacy of prasugrel was independent of age, sex, body weight, geographic region, concomitant therapy—including heparin, bivalirudin, intravenous (IV) GPIIb/IIIa inhibitors, lipid-lowering agents, beta-blockers, and angiotensin-converting enzyme (ACE) inhibitors—and ASA dosage (75–325 mg once daily). Prasugrel was associated with a lower incidence of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke compared to clopidogrel, regardless of baseline characteristics such as age, sex, body weight, geographic region, use of GPIIb/IIIa inhibitors, or stent type. The benefit was primarily driven by a significant reduction in fatal myocardial infarction.

The advantages of prasugrel therapy were evident in a significant reduction in the incidence of non-fatal myocardial infarction. In patients with diabetes, a significant reduction in the incidence of the primary and all secondary composite endpoints (non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death) was observed. These advantages of prasugrel are less pronounced in patients aged 75 years and older compared to those under 75 years of age (see sections "Pharmacokinetics", "Dosage and administration", "Special precautions for use", and "Adverse reactions"). For patients with diabetes, STEMI, high risk of stent thrombosis, or disease recurrence, the benefit of prasugrel is more pronounced even in those aged 75 years and older. In the overall ACS patient population, analysis of each secondary endpoint showed a significant advantage of prasugrel over clopidogrel in the incidence of confirmed or probable stent thrombosis at study end, cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, urgent target vessel revascularization within 30 days, or rehospitalization due to coronary ischemic events before study end. Analysis of all-cause mortality showed no significant difference between prasugrel and clopidogrel in the overall ACS patient population. Prasugrel use was associated with a 50% reduction in stent thrombosis during a 15-month follow-up period, both for bare-metal stents and drug-eluting stents.

Despite the increased bleeding risk with prasugrel therapy, analysis of the composite endpoint of all-cause death, non-fatal myocardial infarction, non-fatal stroke, and non–coronary artery bypass graft (CABG)-related "major" bleeding, according to TIMI classification (TIMI—Thrombolysis In Myocardial Infarction), demonstrated an overall advantage of prasugrel over clopidogrel.

In a study involving 720 Asian patients with body weight ≥60 kg and age ≤75 years undergoing PCI and receiving ASA, a higher level of platelet inhibition was observed in the prasugrel group compared to the clopidogrel group (prasugrel loading dose 60 mg, maintenance dose 10 mg). In a 30-month study involving 9326 patients with UA/NSTEMI receiving ASA without revascularization (unapproved indications), prasugrel did not significantly reduce the rate of the composite endpoint of cardiovascular death, MI, or stroke compared to clopidogrel. The incidence of major bleeding (TIMI) was similar in the prasugrel and clopidogrel groups. Patients aged ≥75 years or with body weight <60 kg received 5 mg prasugrel. Patients under 75 years of age and with body weight >60 kg received 10 mg prasugrel.

There was no difference between the groups receiving 5 mg prasugrel and 75 mg clopidogrel in cardiovascular outcomes. The incidence of major bleeding (TIMI) was similar in patients receiving 5 mg prasugrel and those receiving 75 mg clopidogrel. Prasugrel 5 mg demonstrated greater antiplatelet effect than clopidogrel 75 mg. Prasugrel should be used with caution in patients aged ≥75 years and in patients with body weight <60 kg.

In a study involving 4033 patients with NSTEMI and elevated troponin levels who were scheduled for coronary angiography followed by PCI within 2–48 hours after randomization, patients who received a 30 mg loading dose of prasugrel approximately 4 hours before coronary angiography, followed by 30 mg during PCI, had an increased risk of non–CABG-related periprocedural bleeding and showed no benefit compared to administration of 60 mg prasugrel at the time of PCI. Specifically, prasugrel did not significantly reduce the incidence of the composite endpoint of cardiovascular death, myocardial infarction, stroke, urgent revascularization, or use of a glycoprotein (GP) IIb/IIIa inhibitor at 7 days after randomization in patients who received prasugrel before coronary angiography compared to those who received the full dose at the time of PCI; the incidence of key safety outcomes, major bleeding (TIMI) (CABG-related and non–CABG-related), at 7 days was significantly higher in patients who received prasugrel before coronary angiography compared to those who received the full loading dose during PCI. Therefore, in patients with UA/NSTEMI undergoing coronary angiography within 48 hours, the loading dose should be administered at the time of PCI.

Pediatric population. A phase III study evaluated the use of prasugrel (n = 171) versus placebo (n = 170) in patients aged 2 to 18 years with sickle cell anemia to reduce vaso-occlusive crises. The study did not meet either of its primary or secondary endpoints. Overall, no new safety findings were observed with prasugrel use (as monotherapy in this patient group).

Pharmacokinetics.

Prasugrel is a prodrug and is rapidly metabolized in vivo to active and inactive metabolites. The area under the plasma concentration-time curve (AUC) shows low to moderate inter-individual (27%) and intra-individual (19%) variability. Pharmacokinetic parameters of prasugrel are similar in healthy volunteers, patients with stable atherosclerotic disease, and patients who have undergone PCI.

Absorption.

After oral administration, prasugrel is rapidly absorbed and metabolized. The time to reach maximum plasma concentration (Tmax) of the active metabolite is approximately 0.5 hours after dosing. The AUC of the active metabolite increases proportionally with the therapeutic dose of the drug.

In healthy volunteers, a high-fat, high-calorie meal does not affect the AUC of the active metabolite, but reduces Cmax by 49% and increases Tmax from 0.5 to 1.5 hours. Administration of the loading dose on an empty stomach may provide a faster onset of action (see section "Dosage and administration").

Distribution.

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

Metabolism.

Prasugrel is not detectable in plasma after oral administration. Prasugrel is rapidly hydrolyzed in the intestine to a thiolactone, which is then converted to the active metabolite primarily by cytochrome P450 isoenzymes, mainly CYP3A4 and CYP2B6, and to a lesser extent by CYP2C9 and CYP2C19. The active metabolite is further converted to two inactive metabolites via S-methylation or cysteine conjugation.

In healthy volunteers, patients with stable atherosclerotic disease, and patients undergoing PCI who received prasugrel, no effect of genetic variations in CYP2B6, CYP2C9, CYP2C19, and CYP3A5 isoenzymes on the pharmacokinetic parameters of prasugrel or inhibition of platelet aggregation was observed.

Elimination.

Approximately 68% of prasugrel is excreted in urine and about 27% in feces as inactive metabolites. The elimination half-life (T1/2) of the active metabolite is approximately 7.4 hours (range: 2 to 15 hours).

Special patient groups.

Elderly patients. A study in healthy volunteers aged 20 to 80 years shows that the pharmacokinetics of prasugrel or inhibition of platelet aggregation are not dependent on patient age. The AUC of the active metabolite is 19% higher in elderly patients (aged ≥75 years) compared to those under 75 years. Prasugrel should be used with caution in patients aged ≥75 years due to the potential risk of bleeding in this population (see sections "Special precautions for use" and "Dosage and administration"). In a study of patients with stable atherosclerotic disease, the AUC of the active metabolite in patients aged ≥75 years receiving 5 mg prasugrel was approximately half that in patients aged ≥65 years receiving 10 mg prasugrel, and antiplatelet activity was reduced in patients receiving 5 mg prasugrel.

Hepatic impairment. Dose adjustment is not required for patients with mild to moderate hepatic impairment (Child-Pugh class A and B). The pharmacokinetics of prasugrel and its inhibitory effect on platelet aggregation are similar in patients with mild to moderate hepatic impairment and healthy volunteers. The pharmacokinetics and pharmacodynamics of prasugrel have not been studied in patients with severe hepatic impairment (Child-Pugh class C). Prasugrel is contraindicated in these patients (see section "Contraindications").

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 (GFR [glomerular filtration rate] 30–50 mL/min/1.73 m² body surface area) and healthy volunteers. Inhibition of platelet aggregation by prasugrel was also comparable in patients with ESRD requiring hemodialysis and healthy volunteers, despite a 51% and 42% reduction in Cmax and AUC of the active metabolite, respectively, in patients with ESRD.

Body weight. The AUC of the active metabolite of prasugrel is approximately 30–40% higher in healthy volunteers and patients with body weight <60 kg compared to those with body weight ≥60 kg.

Ethnicity. In clinical pharmacology studies, the AUC of the active metabolite (adjusted for body weight) was approximately 19% higher in Mongoloid race individuals compared to Caucasians. No differences were observed between Chinese, Japanese, and Korean nationalities. Exposure in individuals of Negroid race and Latin American origin was comparable to that in Caucasians. Dose adjustment based on ethnicity is not required.

Sex. Pharmacokinetic parameters of prasugrel do not differ between men and women in healthy volunteers and patients.

Children and adolescents (under 18 years of age). The pharmacokinetics and pharmacodynamics of prasugrel have not been studied in children and adolescents.

Clinical characteristics.

Indications.

Prasugrel in combination with acetylsalicylic acid (ASA) is indicated for the prevention of atherothrombotic complications in adult patients with acute coronary syndrome [i.e. unstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI), or ST-segment elevation myocardial infarction (STEMI)] undergoing primary or delayed percutaneous coronary intervention (PCI).

See also section "Pharmacological properties".

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
• Active 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 potentially increased risk of bleeding, warfarin (or other coumarin derivatives) and prasugrel should be used with caution (see section "Special precautions for use").

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

Prasugrel may be administered concomitantly with medicinal products metabolized by cytochrome P450 enzymes (including statins), and with medicinal products that are inducers or inhibitors of P450 enzymes. Prasugrel may also be used concomitantly with ASA, heparin, digoxin, and agents that increase gastric pH, including proton pump inhibitors and H2-receptor antagonists. Although prasugrel has not been studied in specific interaction trials, it was administered concurrently in phase 3 clinical trials with low-molecular-weight heparins, bivalirudin, and GP IIb/IIIa inhibitors (information on the type of GP IIb/IIIa inhibitor used is lacking) without evidence of clinically significant adverse interactions.

Effect of other medicinal products on prasugrel.

ASA. Prasugrel should be taken concomitantly with ASA. Although pharmacodynamic interaction with ASA increases the risk of bleeding, the efficacy and safety of prasugrel have been demonstrated in patients taking prasugrel together with ASA.

Heparin. A single intravenous bolus dose of unfractionated heparin (100 IU/kg) does not significantly alter prasugrel-mediated inhibition of platelet aggregation. Prasugrel also does not significantly affect the anticoagulant effect of heparin. Therefore, both medicinal products can be used concomitantly. The risk of bleeding is increased when prasugrel is used concomitantly with heparin.

Statins. Atorvastatin (80 mg/day) did not alter the pharmacokinetics of prasugrel or prasugrel-mediated inhibition of platelet aggregation. Thus, no effect of statins, which are substrates of CYP3A, on the pharmacokinetics of prasugrel or prasugrel-mediated inhibition of platelet aggregation is expected.

Medicinal products that increase gastric pH. Concomitant daily administration of ranitidine (H2-receptor antagonist) 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 phase 3 clinical trials, prasugrel was administered regardless of concomitant administration of a proton pump inhibitor or H2-receptor antagonist. Administration of a 60 mg loading dose of prasugrel without concomitant use of proton pump inhibitors may ensure the most rapid onset of action.

Inhibitors of CYP3A. Ketoconazole (400 mg/day), 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% to 46%. Therefore, CYP3A inhibitors such as antifungal azole derivatives, 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/day), a potent inducer of CYP3A and CYP2B6 and an inducer of CYP2C9, CYP2C19, and CYP2C8, does not significantly alter the pharmacokinetics of prasugrel. Therefore, known CYP3A inducers 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. Delayed and reduced effect of oral P2Y12 inhibitors, including prasugrel and its active metabolite, has been observed in patients with ACS who received morphine. This interaction may be related to decreased gastrointestinal motility and may also apply to other opioids. The clinical significance is unknown, but available data suggest a potential reduction in the efficacy of prasugrel when co-administered with morphine. When morphine administration is necessary in patients with ACS for whom rapid P2Y12 inhibition is considered critical, consideration should be given to using a parenteral P2Y12 inhibitor.

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 potentially increased risk of bleeding, warfarin and prasugrel should be used with caution (see section "Special precautions for use").

Medicinal products metabolized by CYP2B6. Prasugrel is a weak inhibitor of CYP2B6. In healthy volunteers, prasugrel reduced the exposure to hydroxybupropion, a CYP2B6-mediated metabolite of bupropion, by 23%. This effect is likely to be clinically relevant only when prasugrel is used concomitantly with medicinal products for which CYP2B6 is the sole metabolic pathway and which have a narrow therapeutic index (e.g., cyclophosphamide, efavirenz).

Special precautions for use.

Risk of bleeding.

In the phase 3 clinical trials (TRITON), key exclusion criteria included an increased risk of bleeding, anemia, thrombocytopenia, and a history of pathological intracranial lesions. In patients with ACS undergoing PCI who received prasugrel and aspirin (ASA), the risk of major and minor bleeding was increased according to the TIMI classification. Therefore, prasugrel should be considered for patients at increased risk of bleeding only when the benefit of preventing ischemic events outweighs the risk of serious bleeding. This applies to the following patient groups:

• aged 75 years or older (see below);
• with a predisposition to bleeding (e.g., due to recent trauma, recent surgery, recent or recurrent gastrointestinal bleeding, active peptic ulcer disease);
• with body weight < 60 kg (see sections "Dosage and administration" and "Side effects"). For these patients, a maintenance dose of 10 mg is not recommended— a maintenance dose of 5 mg should be used;
• who are concurrently taking medications that increase the risk of bleeding, including oral anticoagulants, clopidogrel, NSAIDs, and fibrinolytics.

For patients with active bleeding who require reversal of the pharmacological effect of prasugrel, platelet transfusion may be beneficial.

Prasugrel is generally not recommended for patients aged 75 years or older. Prasugrel should be prescribed to these patients with caution and only after careful individual assessment of benefit/risk, when the benefits of preventing ischemic events outweigh the risk of serious bleeding. In phase 3 clinical trials, patients aged 75 years or older had a higher risk of bleeding, including fatal bleeding, compared to patients younger than 75 years. If necessary, a lower maintenance dose (5 mg) should be used—a maintenance dose of 10 mg is not recommended (see sections "Dosage and administration" and "Side effects").

Therapeutic experience with prasugrel in patients with renal impairment, including those on dialysis, and in patients with moderate hepatic impairment is limited. These patients have an increased risk of bleeding. Therefore, prasugrel should be used with caution in such patients.

Patients should be informed that it may take longer than usual to stop bleeding while taking prasugrel (in combination with ASA), and that they should inform their physician about any unusual bleeding (site or duration).

Risk of bleeding related to timing of loading dose in patients with STEMI. In a clinical trial of patients with STEMI (ACCOAST study), where coronary angiography was planned within 2–48 hours after randomization, a loading dose of prasugrel administered a median of 4 hours before coronary angiography increased the risk of major and minor periprocedural bleeding compared to administration of the loading dose during PCI. Therefore, in patients with NSTE-ACS/STEMI undergoing coronary angiography within 48 hours of admission, the loading dose should be administered during PCI (see sections "Pharmacodynamics", "Dosage and administration", and "Side effects").

Surgery.

Patients should inform their physician, including their dentist, about taking prasugrel if surgical procedures are planned or if new medications are prescribed. If a patient requires elective surgery and antiplatelet effect is undesirable, prasugrel should be discontinued 7 days prior to the surgical procedure. In patients undergoing CABG, an increased frequency (by 3 times) and severity of bleeding may occur within 7 days after discontinuation of prasugrel.

The benefit and risk of prasugrel use should be carefully evaluated in patients in whom coronary anatomy has not been defined and who may require emergency CABG.

Hypersensitivity, including angioedema.

Cases of hypersensitivity, including angioedema, have been reported in patients taking prasugrel, including patients with a history of hypersensitivity reaction to other thienopyridines.

Thrombotic thrombocytopenic purpura (TTP).

Cases of TTP have been reported during treatment with prasugrel. TTP is a serious condition that can be fatal and requires urgent treatment.

Morphine and other opioids.

Reduced efficacy of prasugrel has been observed in patients who took prasugrel concomitantly with morphine (see section "Interaction with other medicinal products and other forms of interaction").

Important information about excipients.

Lactose. If a patient has been diagnosed with intolerance to certain sugars, they should consult their physician before taking this medicinal product.

Use during pregnancy or breastfeeding.

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

Pregnancy.

Animal studies have not shown any direct adverse effects on pregnancy, embryonic, or postnatal development. Prasugrel may be prescribed during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus.

Lactation.

It is unknown whether prasugrel is excreted in human breast milk. Animal studies have shown excretion of prasugrel into breast milk. The use of this medicinal product is not recommended during breastfeeding.

Fertility.

Prasugrel had no effect on fertility in male and female rats following oral administration at doses up to 240 times the recommended daily maintenance dose in humans (on a mg/m² basis).

Ability to affect reaction speed when driving or operating machinery.

The effect of prasugrel on the ability to drive vehicles or operate machinery has not been established.

Method of Administration and Dosage

Adults

Treatment with prasugrel should be initiated with a single 60 mg loading dose, followed by a daily maintenance dose of 10 mg. Patients with NSTE-ACS (non-ST-elevation acute coronary syndrome) undergoing coronary angiography within 48 hours of hospitalization should receive the loading dose only at the time of PCI (percutaneous coronary intervention). Patients receiving prasugrel should also take acetylsalicylic acid (ASA) daily (75–325 mg/day).

In patients with ACS who have undergone PCI, premature discontinuation of any antiplatelet therapy, including prasugrel, increases the risk of stent thrombosis, myocardial infarction, or death due to the underlying condition. Treatment should be continued for up to 12 months unless there are compelling reasons to discontinue prasugrel.

This dosage of the medicinal product is not recommended for patients aged 75 years and older. This dosage is also not recommended for patients with body weight below 60 kg.

Renal Impairment

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

Hepatic Impairment

Dose adjustment is not required in patients with mild to moderate hepatic impairment (Child–Pugh class A and B). Limited experience exists with prasugrel in patients with mild to moderate hepatic dysfunction (see section "Special Warnings and Precautions for Use"). Prasugrel is contraindicated in patients with severe hepatic impairment (Child–Pugh class C).

Method of Administration

The medicinal product should be taken orally, independent of food intake. It is not recommended to break the tablet before administration. Administration of the 60 mg loading dose of prasugrel on an empty stomach may provide the fastest onset of action.

Pediatric Population

The safety and efficacy of prasugrel in children and adolescents (under 18 years of age) have not been established.

Overdose

Symptoms: prolonged bleeding time and related complications may occur.

Treatment: there is no specific antidote to reverse the pharmacological effect of prasugrel. However, if urgent reduction of bleeding time is required, transfusion of platelet concentrates and/or other blood products may be considered.

Adverse Reactions

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

Bleeding

Bleeding not related to CABG

The incidence of bleeding events not related to CABG is shown in the TRITON trial (Table 1). The rate of major bleeding (TIMI), not related to CABG, including life-threatening and fatal bleeding, as well as minor bleeding (TIMI), was significantly higher with prasugrel compared to clopidogrel in patients with NSTE-ACS and in the overall treatment population. No significant difference was observed in the population of patients with STEMI. The most common spontaneous bleeding events were gastrointestinal (1.7% in the prasugrel group and 1.3% in the clopidogrel group); the most frequent site of procedural bleeding was the arterial puncture site (1.3% in the prasugrel group and 1.2% in the clopidogrel group).

Incidence of complications and bleeding events not related to CABG (% of patients):

Table 1

a. Cases recorded according to the criteria of the TIMI classification — the Thrombolysis In Myocardial Infarction trial group.

b. Other standard therapies were used if necessary. In phase 3 clinical trials, all patients also received aspirin (ASA) as per protocol.

c. Any intracranial hemorrhage or bleeding with clinical manifestations associated with a hemoglobin decrease of ≥ 5 g/dL.

d. Life-threatening bleeding — a subgroup of major bleeding according to the TIMI classification, including the types of bleeding listed below. Patients could be included in more than one category.

e. Intracranial hemorrhage (ICH).

f. Bleeding with clinical manifestations associated with a hemoglobin decrease of ≥ 3 g/dL but < 5 g/dL.

In patients aged 75 years and older, the incidence of major and minor bleeding events according to the TIMI classification, unrelated to CABG, was as follows:

Table 2

• TRITON trial in ACS patients undergoing PCI.

** TRILOGY-ACS trial in patients not undergoing PCI:

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

Patients < 60 kg. Frequency of major and minor TIMI bleeding events unrelated to CABG:

Table 3

* TRITON trial in patients with ACS who underwent PCI.

** TRILOGY-ACS trial in patients who did not undergo PCI: 10 mg prasugrel; 5 mg prasugrel if ≥ 75 years of age.

Patients with body weight ≥ 60 kg and age ≥ 75 years.

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

Bleeding events related to CABG.

In phase 3 clinical trials, 437 patients underwent CABG. The incidence of major or minor TIMI bleeding events related to CABG in these patients was 14.1% in the prasugrel group and 4.5% in the clopidogrel group. The increased risk of bleeding in patients receiving prasugrel persisted up to 7 days after the last dose of the investigational drug. In patients who received thienopyridines within 3 days prior to CABG, the incidence of major or minor TIMI bleeding was 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 prior to CABG, the incidence 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. In patients who received the last dose of thienopyridine more than 7 days prior to CABG, the incidence of CABG-related bleeding was similar between treatment groups.

Bleeding events temporally associated with the loading dose in patients with STEMI.

In a clinical trial (ACCOAST), in which patients with STEMI underwent coronary angiography within 2–48 hours after randomization, patients received a 30 mg loading dose on average 4 hours before coronary angiography, followed by an additional 30 mg loading dose at the time of PCI. This regimen increased the risk of periprocedural bleeding (not related to CABG) and provided no additional benefit compared to a 60 mg loading dose administered at the time of PCI (see sections "Special precautions" and "Dosage and administration").

The incidence of TIMI bleeding events not related to CABG at 7 days was as follows:

Table 4

a Other standard therapies were used as needed. In the phase 3 clinical trials, all patients received aspirin (ASA) as per protocol.

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

c Life-threatening bleeding, a subgroup of major bleeding according to the TIMI classification, including the types of bleeding listed below. Patients may be included in more than one category.

d ICH — intracranial hemorrhage.

e Bleeding with clinical manifestations accompanied by a decrease in hemoglobin level of ≥ 3 g/dL but < 5 g/dL.

Summary table of adverse reactions.

Table 5 lists hemorrhagic and non-hemorrhagic adverse reactions observed in the TRITON study, as well as spontaneously reported adverse reactions. Adverse reactions are classified by organ systems and frequency. Frequency is defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

Hemorrhagic and non-hemorrhagic adverse reactions.

Table 5

In patients with a history of TIA or stroke, or without such history, the incidence of stroke in phase 3 of the clinical trial was as follows (see section "Dosage and Administration"):

ICH — intracerebral hemorrhage.

Reporting of suspected adverse reactions.

Reporting of adverse reactions after marketing authorization of a medicinal product is of great importance. It enables continuous monitoring of the benefit/risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions. No special storage conditions required. Keep out of reach of children.

Packaging.

For 5 mg dosage: 10 tablets per blister, 3 blisters per cardboard box;

for 10 mg dosage: 10 tablets per blister, 3 blisters per cardboard box, or 14 tablets per blister, 7 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

NEURAXPHARM FARMACEUTICAS S.L.

Manufacturer's location and address of its business premises.

Avinguda de Barcelona 69, Poligono Industrial de La Fuenciana, Sant Joan Despí,
08970, Spain.