Antagrex^® (Tablets) Instructions for Use

Marketing Authorization Holder

Egis Pharmaceuticals PLC (Hungary)

Manufactured By

Egis Pharmaceuticals PLC (Hungary)

Or

Nobel Ilac Sanayii Ve Ticaret, A.S. (Turkey)

ATC Code

B01AC22 (Prasugrel)

Active Substance

Prasugrel (Rec.INN registered by WHO)

Dosage Forms

	Antagrex®	Film-coated tablets, 5 mg: 28, 30, 56, 60, 84 or 90 pcs.
		Film-coated tablets, 10 mg: 28, 30, 56, 60, 84 or 90 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, round, slightly biconvex, with a stylized engraving “E 781” on one side; odorless or almost odorless; slight surface roughness is allowed.

Excipients: microcrystalline cellulose PH 101 – 125 mg, croscarmellose sodium – 20 mg, pregelatinized starch – 20 mg, microcrystalline cellulose PH 113 FMC – 16 mg, hypromellose – 10 mg, sodium stearyl fumarate – 4 mg.

Film coating composition Opadry II 33G28523 white (hypromellose 2910 – 40%, titanium dioxide E171 – 25%, lactose monohydrate – 21%, macrogol 3350 – 8%, triacetin – 6%) – 6 mg.

7 pcs. – blisters (4) – cardboard packs.
7 pcs. – blisters (8) – cardboard packs.
7 pcs. – blisters (12) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Film-coated tablets white or almost white, oval, slightly biconvex, with a stylized engraving “E 782” on one side; odorless or almost odorless; slight surface roughness is allowed.

Excipients: microcrystalline cellulose PH 101 – 250 mg, croscarmellose sodium – 40 mg, pregelatinized starch – 40 mg, microcrystalline cellulose PH 113 FMC – 32 mg, hypromellose – 20 mg, sodium stearyl fumarate – 8 mg.

Film coating composition Opadry II 33G28523 white (hypromellose 2910 – 40%, titanium dioxide E171 – 25%, lactose monohydrate – 21%, macrogol 3350 – 8%, triacetin – 6%) – 12 mg.

7 pcs. – blisters (4) – cardboard packs.
7 pcs. – blisters (8) – cardboard packs.
7 pcs. – blisters (12) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Clinical-Pharmacological Group

Antiplatelet agent

Pharmacotherapeutic Group

Antiaggregant agent

Pharmacological Action

Antiplatelet agent. A thienopyridine class adenosine diphosphate (ADP) receptor antagonist, it is a potent inhibitor of platelet activation and aggregation mediated by platelet P2Y₁₂ ADP receptors.

The action is due to the irreversible binding of prasugrel’s active metabolite to platelet P2Y₁₂ ADP receptors.

Since platelets play a role in the initiation and/or progression of thrombotic complications in atherosclerotic diseases, inhibition of platelet function leads to a reduction in mortality and the frequency of ischemic cardiovascular complications such as myocardial infarction or stroke.

Pharmacokinetics

Prasugrel is a prodrug and is rapidly metabolized to a pharmacologically active metabolite and inactive metabolites. The AUC values of the active metabolite are characterized by low to moderate variability: interindividual variability is 27%, intraindividual variability is 19%. The pharmacokinetic parameters of prasugrel are the same in healthy subjects, in patients with stable atherosclerosis, and in patients undergoing percutaneous coronary intervention.

After oral administration, absorption is 79% or more. Absorption and metabolism occur rapidly. The C_max of the active metabolite in plasma is reached approximately 30 minutes after administration. The AUC of the active metabolite increases proportionally to the dose within the therapeutic dose range. Clinical studies in healthy volunteers have shown that the AUC of the active metabolite does not change when prasugrel is taken with high-fat, high-calorie food, while C_max decreased by 49%, and the time to reach C_max increased from 0.5 h to 1.5 h.

Plasma protein binding is 98%. Prasugrel metabolites have limited permeability into red blood cells.

Prasugrel is not detected in plasma after oral administration. It is rapidly hydrolyzed in the intestine to a thiolactone, which is then converted to the active metabolite primarily by CYP3A4 and CYP2B6 and to a lesser extent by CYP2C9 and CYP2C19. The active metabolite undergoes further biotransformation via S-methylation or conjugation with cysteine to form 2 inactive compounds.

Approximately 68% of the dose is excreted in the urine and 27% in the feces as inactive metabolites. The T_1/2 of the active metabolite is about 7.4 h (2-15 h).

Clinical studies have shown that in elderly patients (75 years and older), the AUC values of the active metabolite were 16% higher compared to patients under 75 years of age.

The AUC values of the active metabolite are approximately 30-40% higher in healthy volunteers weighing less than 60 kg and in patients weighing less than 60 kg, compared to those weighing 60 kg or more.

Indications

Prevention of atherothrombotic complications (myocardial infarction, stroke, cardiovascular death) in patients with acute coronary syndrome (unstable angina with moderate to high risk, non-ST-segment elevation myocardial infarction, ST-segment elevation myocardial infarction) who undergo percutaneous coronary intervention.

ICD codes

Dosage Regimen

Take orally.

Initiate therapy with a single 60 mg loading dose.

Follow with a maintenance dose of 10 mg once daily.

Concomitantly administer acetylsalicylic acid at a daily dose of 75 mg to 325 mg.

For patients with a body weight less than 60 kg, consider using a 5 mg once daily maintenance dose.

In patients aged 75 years and older, use is generally not recommended due to an increased bleeding risk.

If treatment in this age group is necessary after individual benefit-risk assessment, use a 5 mg once daily maintenance dose; the 10 mg dose is not recommended.

Discontinue therapy at least 7 days prior to elective surgery if the antiplatelet effect is undesirable.

Do not use in patients with a history of transient ischemic attack or stroke.

Contraindicated in patients with severe hepatic impairment (Child-Pugh class C).

Use with caution in patients at increased risk of bleeding, including those with recent trauma, surgery, or active bleeding.

Avoid premature discontinuation of therapy, as this increases the risk of thrombotic events.

Adverse Reactions

From the blood coagulation system: frequent – bleeding of various locations.

From the hematopoietic system severe thrombocytopenia, anemia, leukopenia.

From the digestive system: liver function disorders, nausea, vomiting, diarrhea.

From the cardiovascular system arterial hypertension, arterial hypotension, atrial fibrillation, bradycardia.

From metabolism hypercholesterolemia/hyperlipidemia.

From the nervous system headache, dizziness.

From the respiratory system dyspnea, cough.

Other allergic reactions (including angioedema) back pain, weakness, non-cardiac chest pain, rash, fever, peripheral edema, limb pain; based on post-marketing studies – thrombotic thrombocytopenic purpura, hypersensitivity reactions, including anaphylactic reactions.

Contraindications

Acute pathological bleeding; history of transient ischemic attack or stroke; severe liver dysfunction (Child-Pugh class C); hypersensitivity to prasugrel.

Use in Pregnancy and Lactation

Adequate and strictly controlled studies of prasugrel in pregnant women have not been conducted. The use of prasugrel during pregnancy is possible only in cases where the expected benefit of therapy for the mother outweighs the potential risk to the fetus.

It is not known whether prasugrel is excreted in human breast milk. If it is necessary to use prasugrel during lactation, breastfeeding should be discontinued.

In experimental studies in animals, no direct damaging effect on fertility was detected. Prasugrel had no effect on fertility of male and female rats at oral doses up to 300 mg/kg/day, where the AUC of the active metabolite was approximately 1500 times higher than the values observed at the maintenance dose intended for humans. Prasugrel has been shown to be excreted in the milk of lactating rats.

Use in Hepatic Impairment

Contraindicated in severe liver dysfunction (Child-Pugh class C).

In patients with mild or moderate hepatic impairment (Child-Pugh classes A and B), dose adjustment is not required. The pharmacokinetics and pharmacodynamics of prasugrel in patients with severe liver disease have not been studied. Prasugrel should not be used in patients with severe liver disease due to the potential risk of bleeding in this patient population.

Use in Renal Impairment

Prasugrel should be used with caution in patients with severe renal impairment.

In patients with renal impairment (including patients with end-stage renal disease), dose adjustment is not required.

Pediatric Use

The efficacy and safety of prasugrel in children have not been established.

Geriatric Use

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 assessment of the benefit-risk ratio of therapy, i.e., the benefit in preventing ischemic complications and the risk of bleeding. If therapy is necessary in this category of patients, prasugrel should be used at a dose of 5 mg once/day; a dose of 10 mg/day is not recommended. It should be borne in mind that in clinical studies, patients aged 75 years and older had a higher risk of bleeding, including fatal bleeding, compared to patients under 75 years of age.

Special Precautions

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 assessment of the benefit-risk ratio of therapy, i.e., the benefit in preventing ischemic complications and the risk of bleeding. If therapy is necessary in this category of patients, prasugrel should be used at a dose of 5 mg once/day; a dose of 10 mg/day is not recommended. It should be borne in mind that in clinical studies, patients aged 75 years and older had a higher risk of bleeding, including fatal bleeding, compared to patients under 75 years of age.

Use prasugrel with caution in patients weighing less than 60 kg.

Prasugrel should be used with caution in patients with a likelihood of bleeding, including due to recent trauma, surgery, gastrointestinal bleeding, peptic ulcer in the acute phase, severe renal impairment.

Use prasugrel with caution concomitantly with drugs that can increase the risk of bleeding, including oral anticoagulants, NSAIDs and fibrinolytics.

In patients with acute coronary syndrome undergoing percutaneous coronary intervention, treatment with prasugrel was associated with an increased risk of bleeding. Therefore, in patients at increased risk of bleeding, the use of prasugrel should be considered only when the benefit of the course of prevention of ischemic complications outweighs the risk of serious bleeding.

Patients should be warned that during treatment with prasugrel, it may take longer to stop bleeding and that they must inform their doctor about all cases of bleeding.

In case of severe bleeding requiring suppression of the effects of prasugrel, platelet transfusion may be required.

Patients taking prasugrel should be advised to inform their doctor and dentist about this before any surgical procedure, as well as before starting any medication. If a patient is scheduled for elective surgery and the antiplatelet effect is undesirable, prasugrel should be discontinued at least 7 days before surgery. An increase in the frequency (3 times) and severity of bleeding may be observed in patients who have undergone coronary artery bypass grafting within 7 days after discontinuation of prasugrel. The benefit and risk of using prasugrel should be carefully weighed in patients in whom the anatomy of the coronary vessels is not precisely defined and there is a possibility of emergency coronary artery bypass surgery.

In patients with acute coronary syndrome undergoing percutaneous coronary intervention, premature discontinuation of any antithrombotic drug, including prasugrel, may lead to an increased risk of thrombosis, myocardial infarction, and death. Patients who require sudden discontinuation of prasugrel (e.g., due to severe bleeding) require clinical monitoring for cardiac complications. Once the patient’s condition has stabilized, under the close supervision of the attending physician, the possibility of resuming antithrombotic therapy may be considered.

In patients with renal impairment (including patients with end-stage renal disease), dose adjustment is not required.

In patients with mild or moderate hepatic impairment (Child-Pugh classes A and B), dose adjustment is not required. The pharmacokinetics and pharmacodynamics of prasugrel in patients with severe liver disease have not been studied. Prasugrel should not be used in patients with severe liver disease due to the potential risk of bleeding in this patient population.

Preclinical studies of prasugrel did not reveal any data indicating the possibility of carcinogenic and mutagenic effects.

Use in pediatrics

The efficacy and safety of prasugrel in children have not been established.

Drug Interactions

Concomitant use of prasugrel with warfarin, with NSAIDs increases the risk of bleeding.

Prasugrel can be used with drugs that are inducers or inhibitors of cytochrome P450 isoenzymes.

Prasugrel can be used concomitantly with acetylsalicylic acid (75-325 mg/day), heparin, glycoprotein GPIIb/IIIa receptor inhibitors, statins, digoxin and drugs that increase gastric pH, including proton pump inhibitors and histamine H₂-receptor blockers.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.