Sagrada

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SAGRADE® (SAGRADA)

Composition:

Active substance: prasugrel;

1 tablet contains prasugrel 10 mg;

Excipients: crospovidone (type A), lactose monohydrate, sodium croscarmellose, microcrystalline cellulose (E 460), sucrose stearate.

Film-coating mixture: Opadry II 32K230012 Orange*

* Dry film-coating mixture contains: hypromellose (E 464) (hydroxypropylmethylcellulose), 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 characteristics: film-coated, oval-shaped tablets with a biconvex surface, marked with «F2» on one side.

Pharmacotherapeutic group. Antithrombotic agents. Platelet aggregation inhibitors, excluding heparin. Prasugrel.

ATC code B01A C22.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Prasugrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to P2Y₁₂ ADP receptors on platelets. Since platelets are involved in the initiation and/or progression of thrombotic complications of atherosclerotic disease, inhibition of platelet function may reduce the incidence of cardiovascular events such as death, myocardial infarction, or stroke.

Following a 60 mg loading dose of prasugrel, inhibition of ADP-induced platelet aggregation occurs within 15 minutes with 5 µM ADP and within 30 minutes with 20 µM ADP. Maximum inhibition of ADP-induced platelet aggregation by prasugrel is 83% with 5 µM ADP and 79% with 20 µM AD, with at least 50% inhibition achieved in 89% of healthy subjects and patients with stable atherosclerosis within 1 hour in both cases. Prasugrel-mediated inhibition of platelet aggregation demonstrates low inter-subject (9%) and intra-subject (12%) variability when using either 5 µM or 20 µM ADP. Mean steady-state inhibition of platelet aggregation was 74% and 69% for 5 µM ADP and 20 µM ADP, respectively, achieved within 3–5 days after administration of the 10 mg maintenance dose following a 60 mg loading dose. More than 98% of subjects had ≥20% inhibition of platelet aggregation during maintenance therapy.

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

Data on Transition from One Medicinal Product to Another

After receiving 75 mg clopidogrel once daily for 10 days, 40 healthy subjects were switched to prasugrel 10 mg once daily with or without a 60 mg loading dose. Similar or greater inhibition of platelet aggregation was observed with prasugrel. Transitioning with a 60 mg loading dose of prasugrel resulted in faster and stronger platelet inhibition. After receiving a loading dose of clopidogrel (with ASA) 900 mg, 56 ACS patients received prasugrel 10 mg once daily or clopidogrel 150 mg once daily for 14 days, then crossed over to clopidogrel 150 mg or prasugrel 10 mg for another 14 days. Greater inhibition of platelet aggregation was observed in patients switched to prasugrel 10 mg compared to those receiving clopidogrel 150 mg. In a study involving 276 ACS (acute coronary syndrome) patients undergoing PCI (percutaneous coronary intervention), switching from an initial 600 mg loading dose of clopidogrel or placebo administered upon hospital presentation before coronary angiography to a 60 mg loading dose of prasugrel administered during percutaneous coronary intervention resulted in a similar enhancement of platelet aggregation inhibition over the 72-hour study period.

Clinical Efficacy and Safety

Acute Coronary Syndrome (ACS)

In the phase 3 TRITON trial, prasugrel was compared with clopidogrel, both administered with acetylsalicylic acid (ASA) and other medications according to standard treatment practices. TRITON was a multicenter, international, randomized, double-blind, parallel-group study involving 13,608 patients with ACS at moderate or high risk of developing unstable angina (UA)/non-ST-elevation myocardial infarction (NSTEMI) and ST-elevation myocardial infarction (STEMI), who underwent PCI.

Patients with UA/NSTEMI within 72 hours of symptom onset or STEMI within 12 hours to 14 days of symptom onset were randomized after evaluation of coronary anatomy. Patients with STEMI within 12 hours of symptom onset who were scheduled for primary PCI could be enrolled without prior coronary anatomy assessment. All patients received a loading dose at any time between randomization and within 1 hour after leaving the catheterization laboratory.

Patients randomized to receive prasugrel (60 mg loading dose, followed by 10 mg once daily) or clopidogrel (300 mg loading dose, followed by 75 mg once daily) were treated for a mean of 14.5 months (maximum 15 months, minimum 6 months). All patients also received ASA (75–325 mg once daily). Exclusion criteria included use of any thienopyridine within 5 days prior to enrollment. Other therapies, such as heparin and GPIIb/IIIa inhibitors, were administered at the physician’s discretion. Approximately 40% of patients (in each treatment group) received GPIIb/IIIa inhibitors during PCI (no information on the specific type of GPIIb/IIIa inhibitor used). Approximately 98% of patients (in each treatment group) received antithrombotics (heparin, low-molecular-weight heparin, bivalirudin, or other agents) during PCI.

The primary efficacy endpoint was time to first occurrence of non-fatal myocardial infarction (MI), non-fatal stroke, or cardiovascular death. Analysis of the composite endpoint in the overall ACS patient population (combined UA/NSTEMI and STEMI population) showed a statistically significant benefit of prasugrel over clopidogrel in the UA/NSTEMI patient group (p < 0.05).

Overall ACS Population

Prasugrel demonstrated greater efficacy than clopidogrel in reducing the incidence of the primary composite endpoint as well as secondary endpoints, including stent thrombosis (see Table 1). The benefit of prasugrel was evident within the first 3 days and persisted throughout the study. The increased efficacy was associated with a higher incidence of major bleeding (see sections "Special Warnings and Precautions for Use" and "Adverse Reactions"). 92% of the patient population were Caucasian, 26% were women, and 39% were aged ≥65 years. The efficacy of prasugrel was independent of concomitant therapy, including heparin/low-molecular-weight heparins, bivalirudin, intravenous GPIIb/IIIa inhibitors, lipid-lowering agents, beta-blockers, and ACE inhibitors. The efficacy of prasugrel was also independent of ASA dose (75–325 mg once daily). The use of oral anticoagulants, investigational antiplatelet agents, and NSAIDs (long-term use) was not permitted in the TRITON study. In the overall ACS population, prasugrel was associated with a lower incidence of cardiovascular death, non-fatal MI, 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 due to a significant reduction in non-fatal MI (see Table 1). Patients with diabetes also showed a significant reduction in the incidence of the primary and all secondary composite endpoints.

The benefit of prasugrel therapy was less pronounced in patients aged ≥75 years compared to those <75 years. Patients aged ≥75 years had an increased risk of bleeding, including fatal bleeding (see sections "Dosage and Administration", "Special Warnings and Precautions for Use", and "Adverse Reactions").

For patients aged ≥75 years with diabetes, STEMI, high risk of stent thrombosis, or disease recurrence, the benefit of prasugrel is more evident.

In patients with a history of TIA or ischemic stroke more than 3 months prior to initiation of prasugrel therapy, no reduction in the primary composite endpoint was observed.

Table 1

Patients with outcomes in the primary analysis of TRITON

In the overall ACS population, analysis of each secondary endpoint demonstrated significant advantages (p < 0.001) of prasugrel compared with clopidogrel. These included the incidence of definite or probable stent thrombosis at the end of the study (0.9% vs. 1.8%, respectively; hazard ratio 0.498; CI 0.364, 0.683); cardiovascular death, non-fatal MI, or need for urgent revascularization of the target vessel within 30 days (5.9% vs. 7.4%, respectively; HR 0.784; CI 0.688, 0.894); all-cause mortality, non-fatal MI, or non-fatal stroke at the end of the study (10.2% vs. 12.1%, respectively; OR 0.831; CI 0.751, 0.919); cardiovascular death, non-fatal MI, non-fatal stroke, or recurrent hospitalization due to ischemic cardiac event at the end of the study (11.7% vs. 13.8%, respectively; OR 0.838; CI 0.762, 0.921). Analysis of all-cause mortality did not reveal any significant differences between prasugrel and clopidogrel in the overall ACS patient population (2.76% vs. 2.90%, respectively), in the population of patients with NSTE-ACS (2.58% vs. 2.41%, respectively), or in the STEMI population (3.28% vs. 4.31%, respectively).

Prasugrel use was associated with a 50% reduction in stent thrombosis over the 15-month observation period. The reduction in stent thrombosis incidence was observed both at initiation of prasugrel treatment and after 30 days of therapy, and for both bare-metal stents and drug-eluting stents.

In the analysis of patients who survived an ischemic event, prasugrel use was associated with a reduced incidence of subsequent primary endpoint events (7.8% with prasugrel vs. 11.9% with clopidogrel).

Although bleeding events increased with prasugrel use, analysis of the composite endpoint of all-cause mortality, non-fatal MI, non-fatal stroke, and non-CABG-related major bleeding according to the TIMI (Thrombolysis In Myocardial Infarction) scale favored prasugrel over clopidogrel (risk ratio 0.87, 95% CI 0.79–0.95, p = 0.004).

In the TRITON trial, for every 1000 patients treated with prasugrel, there were 22 fewer patients with myocardial infarction and 5 more with non-CABG-related major bleeding according to the TIMI scale compared to patients treated with clopidogrel.

Results from a pharmacodynamic/pharmacogenomic study involving 720 Asian patients with ACS undergoing PCI demonstrated that prasugrel achieves a higher level of platelet inhibition compared to clopidogrel, and that prasugrel at a loading dose of 60 mg/maintenance dose of 10 mg is an appropriate dosing regimen for Asian subjects with body weight less than 60 kg and age less than 75 years (see section "Dosage and Administration").

In a 30-month study (TRILOGY-ACS) involving 9326 patients with NSTE-ACS managed medically without revascularization (an unapproved indication), prasugrel did not significantly reduce the rate of the composite endpoint of cardiovascular death, MI, or stroke compared to clopidogrel. The rate of major bleeding according to the TIMI scale (including life-threatening, fatal, and intracranial bleeding) was similar in patients receiving prasugrel and those receiving clopidogrel. In a blinded randomization, patients aged over 75 years or with body weight less than 60 kg (N = 3022) were assigned to receive 5 mg prasugrel. As in patients aged < 75 years and with body weight ≥ 60 kg receiving 10 mg prasugrel, there was no difference in cardiovascular event rates between the group receiving 5 mg prasugrel and the group receiving 75 mg clopidogrel. The rate of major bleeding 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 over 75 years and in patients with body weight less than 60 kg (see sections "Dosage and Administration", "Special Warnings and Precautions", and "Adverse Reactions").

In a 30-day study (ACCOAST) involving 4033 patients with NSTE-ACS and elevated troponin levels scheduled for coronary angiography followed by PCI within 2–48 hours after randomization, subjects who received prasugrel at a loading dose of 30 mg on average 4 hours before coronary angiography followed by a second 30 mg loading dose at the time of PCI (n = 2037) had an increased risk of post-procedural non-CABG-related bleeding and showed no additional benefit compared to patients who received a 60 mg loading dose at the time of PCI (n = 1996). Specifically, prasugrel did not significantly reduce the rate of the composite endpoint of cardiovascular death (CVD), myocardial infarction (MI), stroke, urgent revascularization (UR), or treatment with GP IIb/IIIa inhibitors within 7 days after randomization in subjects receiving prasugrel before coronary angiography compared to those receiving full loading dose prasugrel at the time of PCI. The achievement of the key safety endpoint—major bleeding according to the TIMI scale (CABG-related and non-CABG-related events) within 7 days after randomization—was significantly higher in subjects receiving prasugrel before coronary angiography compared to those receiving full loading dose prasugrel at the time of PCI. Therefore, in patients with NSTE-ACS undergoing coronary angiography within 48 hours of hospitalization, the loading dose should be administered at the time of PCI (see sections "Dosage and Administration", "Special Warnings and Precautions", and "Adverse Reactions").

Pediatric population

In a Phase III study, prasugrel (n = 171) was compared with placebo (n = 170) for the prevention of vaso-occlusive crisis in patients aged 2 to 18 years with sickle cell anemia. The study did not meet either primary or secondary endpoints. Overall, no new safety findings were identified with prasugrel use (as monotherapy in this patient group).

Pharmacokinetics

Prasugrel is a prodrug and is rapidly metabolized in vivo into active and inactive metabolites. The area under the plasma concentration-time curve (AUC) of the active metabolite 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 underwent PCI.

Absorption

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

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. In the TRITON trial, prasugrel was administered without regard to food intake. Thus, prasugrel can be taken independently of food; however, 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. It is rapidly hydrolyzed in the intestine to a thiolactone intermediate, 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 inactivated via S-methylation or cysteine conjugation.

In healthy volunteers and in patients with stable atherosclerotic disease or post-PCI receiving prasugrel, no effect of genetic variations in CYP2B6, CYP2C9, CYP2C19, or CYP3A5 isoenzymes on prasugrel pharmacokinetics or platelet aggregation inhibition 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 populations

Elderly patients. Studies in healthy volunteers aged 20 to 80 years indicate that the pharmacokinetics of prasugrel or platelet aggregation inhibition are not age-dependent. The AUC of the active metabolite is 19% higher in elderly patients (aged ≥75 years) compared to patients under 75 years. Prasugrel should be used with caution in patients aged 75 years and older due to the potential risk of bleeding (see sections "Special Warnings and Precautions" and "Dosage and Administration"). In a study involving patients with stable atherosclerotic disease, the AUC of the active metabolite in individuals aged ≥75 years receiving 5 mg prasugrel was approximately half that in individuals aged ≥65 years receiving 10 mg prasugrel, and the antiplatelet effect was reduced in patients receiving 5 mg prasugrel.

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

Renal impairment. Dose adjustment is not required in patients with renal impairment, including those with end-stage renal disease (ESRD). Pharmacokinetics and platelet aggregation inhibition of prasugrel are similar in patients with moderate renal impairment (GFR 30–50 mL/min/1.73 m² body surface area) and healthy volunteers. Platelet aggregation inhibition by prasugrel was 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 ESRD patients.

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. Prasugrel should be used with caution in patients with body weight less than 60 kg due to the potential risk of bleeding (see section "Special Warnings and Precautions"). In a study involving patients with stable atherosclerosis, the mean AUC of the active metabolite in individuals with body weight < 60 kg receiving 5 mg prasugrel was 38% lower than in individuals with body weight ≥ 60 kg receiving 10 mg prasugrel, yet the antiplatelet effect at 5 mg prasugrel was comparable to that at 10 mg prasugrel.

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

Gender. 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 (see section "Dosage and Administration").

Clinical characteristics

Indications

Prasugrel in combination with acetylsalicylic acid (ASA) is indicated for the prevention of atherothrombotic events in adult patients with acute coronary syndrome (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).

The medicinal product Sagrada®, 10 mg, is used in adults with body weight above 60 kg and age under 75 years.

For additional information see 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 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), or 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 blockers. Although prasugrel has not been studied in specific interaction trials, in phase 3 clinical trials it was administered together with low-molecular-weight heparins, bivalirudin, and GP IIb/IIIa inhibitors (information on the type of GP IIb/IIIa inhibitor used is not available) without evidence of clinically significant adverse interactions.

Effect of other medicinal products on prasugrel

ASA. Prasugrel should be taken together with ASA. Although a pharmacodynamic interaction with ASA may increase the risk of bleeding, 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. Prasugrel also does not significantly affect the anticoagulant effect of heparin. Thus, both medicinal products can be used concomitantly. However, an increased risk of bleeding may occur 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. Therefore, 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. Daily co-administration of ranitidine (H2-receptor blocker) or lansoprazole (proton pump inhibitor) did not alter 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 use of proton pump inhibitors or H2-receptor blockers. Administration of a 60 mg loading dose of prasugrel without concomitant use of proton pump inhibitors may ensure the fastest onset of action.

CYP3A inhibitors. Ketoconazole (400 mg/day), a selective and potent inhibitor of CYP3A4 and CYP3A5, did not affect prasugrel-mediated inhibition of platelet aggregation or AUC and Tmax of the active metabolite of prasugrel, but reduced Cmax by 34% to 46%. Therefore, CYP3A inhibitors such as antifungal agents (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.

Cytochrome P450 inducers. 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 be characteristic of other opioids. The clinical significance is unknown, but available data suggest a potential reduction in prasugrel efficacy when co-administered with morphine. When morphine is required in patients with ACS in whom rapid P2Y12 inhibition is considered critical, parenteral P2Y12 inhibitors should 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 does 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 of 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 Warnings and 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 who underwent PCI and received prasugrel together with ASA, there was an increased risk of major and minor bleeding according to the TIMI scale. 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 applies to the following patient groups:

• aged 75 years and older (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 "Posology and Method of Administration" and "Undesirable Effects"). In these patients, a maintenance dose of 10 mg is not recommended; a maintenance dose of 5 mg should be used;
• concurrently using medicinal products that may increase the risk of bleeding, including oral anticoagulants, clopidogrel, NSAIDs, and fibrinolytics.

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

The use of prasugrel in patients aged 75 years and older is generally not recommended and should be used with caution and only after careful individual benefit/risk assessment by the physician, demonstrating that the benefits of preventing ischemic events outweigh the risk of serious bleeding. In phase 3 clinical trials, this patient group had a higher risk of bleeding, including fatal bleeding, compared to patients under 75 years of age. If necessary, a lower maintenance dose (5 mg) should be used; a maintenance dose of 10 mg is not recommended (see sections "Posology and Method of Administration" and "Undesirable 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 may 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 report any unusual bleeding (site or duration) to their physician.

Risk of bleeding associated with timing of loading dose in patients with STEMI

In a clinical trial involving patients with STEMI (ACCOAST study), where patients were scheduled to undergo coronary angiography 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 a loading dose given at the time of PCI. Therefore, in patients with NSTE-ACS/STEMI undergoing coronary angiography within 48 hours of presentation, the loading dose should be administered at the time of PCI (see sections "Pharmacodynamics", "Posology and Method of Administration", and "Undesirable Effects").

Surgery

Patients should inform their physician, including their dentist, about taking prasugrel when planning surgical procedures or starting new medications.

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 CABG, there may be an increased frequency (3-fold) and severity of bleeding 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 receiving prasugrel, including in patients with a history of hypersensitivity reaction to other thienopyridines.

Thrombotic thrombocytopenic purpura (TTP)

Cases of TTP have been reported during prasugrel treatment. 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 received prasugrel concomitantly with morphine (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Important Information on Excipients

Lactose

If you have been diagnosed with an intolerance to certain sugars, consult your doctor before taking this medicinal product.

Sodium croscarmellose

This medicinal product contains 30 mg of sodium per tablet. Caution is advised when administering to patients on a sodium-controlled diet.

Use during Pregnancy or Breastfeeding

Clinical studies in pregnant or breastfeeding women 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 pregnant woman outweighs the potential risk to the fetus.

Breastfeeding

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 did not affect 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 Time While Driving or Operating Machinery
Prasugrel is expected to have no effect or a negligible effect on the ability to drive or operate machinery.

Method of Administration and Dosage

Adults

Treatment with prasugrel is initiated with a single 60 mg loading dose. This is followed by a daily maintenance dose of 10 mg. Patients with NSTE-ACS (non-ST-segment elevation acute coronary syndrome) undergoing coronary angiography within 48 hours after hospitalization should receive the loading dose only at the time of PCI (percutaneous coronary intervention). Patients taking prasugrel should also receive daily aspirin (75–325 mg/day).

In patients with ACS who have undergone PCI, premature discontinuation of any antiplatelet therapy, including prasugrel, may increase the risk of thrombosis, myocardial infarction, or death due to the underlying disease. Continued treatment for up to 12 months is recommended, unless there are reasons necessitating discontinuation of prasugrel (see sections "Pharmacodynamics" and "Special Warnings and Precautions for Use").

This medicinal product at this dosage strength is not recommended for patients aged 75 years and older.

This medicinal product at this dosage strength is not recommended for patients with body weight less than 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 classes 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 is taken orally, independent of food intake. It is not recommended to break the tablet before administration. Administration of the 60 mg prasugrel loading dose on an empty stomach may provide the fastest onset of action.

Children

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

Overdose

Symptoms: prolonged bleeding time and related complications are possible.

Treatment: there is no specific information on the reversibility of prasugrel's pharmacological effect. However, if rapid reduction of bleeding time is required, transfusion of platelet concentrates and/or other blood products may be considered.

Adverse Reactions

The safety of use in patients with acute coronary syndrome who underwent PCI was evaluated in one controlled trial with clopidogrel (TRITON), in which 6741 patients received prasugrel (60 mg loading dose and 10 mg once daily maintenance dose) for a mean duration of 14.5 months (5802 patients were treated for more than 6 months, 4136 patients 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 (2.5% with prasugrel and 1.4% with clopidogrel).

Bleeding

Bleeding not related to CABG

The incidence of bleeding not related to CABG was assessed in the TRITON trial (see Table 2). The rate of TIMI major bleeding not related to CABG, including life-threatening and fatal bleeds, as well as TIMI minor bleeding, was significantly higher with prasugrel than with clopidogrel in patients with NSTE-ACS and in all ACS populations. No significant difference was observed in the STEMI patient population. The most common spontaneous bleeds were gastrointestinal (1.7% in the prasugrel group vs. 1.3% in the clopidogrel group); the most frequent site of procedural bleeding was the arterial puncture site (1.3% in the prasugrel group vs. 1.2% in the clopidogrel group).

Table 2

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

a. Cases were identified according to the criteria of the TIMI (Thrombolysis In Myocardial Infarction) Study Group classification.

b. Other standard therapies were used as needed. In phase 3 clinical trials, all patients also received aspirin (ASA) according to protocol.

c. Any intracranial hemorrhage or bleeding with clinical manifestations associated with a decrease in hemoglobin ≥ 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 counted in more than one category.

e. Intracranial hemorrhage (ICH).

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

Table 3

Frequency of major and minor non-CABG-related bleeding according to TIMI classification in patients over 75 years of age

* 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 body weight < 60 kg.

Table 4

Frequency of major and minor TIMI-defined bleeding events unrelated to CABG, by patient body weight

* TRITON study in ACS patients who underwent PCI.

** TRILOGY-ACS study 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 under 75 years

In patients with body weight ≥ 60 kg and age under 75 years, non-CABG-related major or minor bleeding events according to TIMI classification were 3.6% with prasugrel and 2.8% with clopidogrel; the frequency of fatal bleeding was 0.2% and 0.1%, respectively.

CABG-related bleeding

In phase 3 clinical trials, 437 patients underwent CABG. The frequency of CABG-related major or minor bleeding events according to the TIMI scale in these patients was 14.1% in the prasugrel group and 4.5% in the clopidogrel group. The higher 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 frequency of major or minor bleeding according to the TIMI scale 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. For patients who received the last dose of thienopyridine 4–7 days before CABG, the frequency 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 before CABG, the frequency of CABG-related bleeding was similar in both treatment groups.

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

In a clinical trial involving patients with STEMI (ACCOAST study), where coronary angiography was scheduled within 2–48 hours after randomization, a loading dose of 30 mg was administered on average 4 hours before coronary angiography, followed by a second 30 mg loading dose during PCI. This dosing regimen is associated with an increased risk of periprocedural bleeding (non-CABG-related) and provides no additional benefit compared to the regimen where a 60 mg loading dose is administered during PCI (see sections "Special precautions" and "Dosage and administration").

Table 5

Frequency of non-CABG-related TIMI bleeding events during 7 days of treatment

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

b Any intracranial hemorrhage or any clinically evident bleeding associated with a drop in hemoglobin ≥ 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 could be counted in more than one category.

d ICH – intracranial hemorrhage.

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

Summary table of adverse reactions

Table 6 presents information on hemorrhagic and non-hemorrhagic adverse reactions (from the TRITON study), as well as those reported spontaneously. Adverse reactions are categorized by frequency and by system organ class. Frequency categories 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); frequency not known (cannot be estimated from available data).

Table 6

Hemorrhagic and non-hemorrhagic adverse reactions

Table 7

Frequency of stroke occurrence in phase 3 of the clinical trial in patients with or without history of TIA or stroke (see section "Special instructions for use")

* ICH – intracerebral hemorrhage.

Reporting of suspected adverse reactions

Reporting of adverse reactions after registration of the medicinal product is of great importance. It allows 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 of the medicinal product via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging. 14 tablets in a blister pack, 2 blisters per carton.

Prescription status. Prescription only.

Manufacturer: Neuraxpharm Farmacéuticas, S.L.

Manufacturer's address and place of business

Avda. de Barcelona, 69, Sant Joan Despí, Barcelona, 08970, Spain