Agregal (Tablets) Instructions for Use

Marketing Authorization Holder

Nizhpharm JSC (Russia)

Manufactured By

FP Obolenskoe, JSC (Russia)

ATC Code

B01AC04 (Clopidogrel)

Active Substance

Clopidogrel (Rec.INN registered by WHO)

Dosage Form

Agregal

Film-coated tablets, 75 mg: 14 or 28 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets pinkish-cream in color, round, biconvex; a cross-section shows two layers.

Excipients: potato starch, lactose, microcrystalline cellulose, hypromellose (hydroxypropyl methylcellulose), macrogol 6000 (polyethylene glycol 6000), stearic acid, magnesium stearate.

Film coating composition: hypromellose (hydroxypropyl methylcellulose), titanium dioxide, macrogol 6000 (polyethylene glycol 6000), iron oxide red.

14 pcs. – blister packs (1) – cardboard cartons.
14 pcs. – blister packs (2) – cardboard cartons.

Clinical-Pharmacological Group

Antiplatelet agent

Pharmacotherapeutic Group

Antiaggregant agent

Pharmacological Action

Antiplatelet agent.

Clopidogrel prevents platelet aggregation by selectively blocking the binding of adenosine diphosphate (ADP) to its receptor on platelets and the activation of the GPIIb/IIIa complex. It inhibits platelet aggregation induced by other agonists by eliminating the activity of platelets released by ADP and does not affect PDE activity.

Changes in platelet ADP receptors caused by clopidogrel are irreversible: platelets remain non-functional throughout their lifespan, and the antiplatelet effect persists for this entire period. Normal function is restored as platelets are renewed (approximately after 7 days).

In the presence of atherosclerotic vascular lesions, Clopidogrel prevents the development of atherothrombosis regardless of the location of the vascular process (cerebrovascular, cardiovascular, or peripheral lesions).

Pharmacokinetics

Absorption

After oral administration of 75 mg of clopidogrel, the drug is rapidly absorbed from the gastrointestinal tract, but the plasma concentration is low and 2 hours after administration does not reach the measurement limit (0.025 µg/L), while platelet aggregation inhibition reaches 40%. The maximum effect (60% suppression of aggregation) develops after 4-7 days of continuous use of the drug at a dose of 98 mg/day (equivalent to Clopidogrel – 75 mg/day).

C_max of the metabolite after repeated doses of clopidogrel 75 mg is about 3 mg/L and is observed approximately 1 hour after administration.

Distribution

Plasma protein binding of clopidogrel and its main metabolite is 98-94%, respectively.

Metabolism

The drug is metabolized in the liver. The main metabolite is an inactive carboxylic acid derivative.

Excretion

About 50% of the dose is excreted in the urine and approximately 46% in the feces (within 120 hours after administration). T_1/2 of the main metabolite after single and repeated administration of the drug is 8 hours.

Pharmacokinetics in special clinical cases

The plasma concentration of the main metabolite after administration of clopidogrel 75 mg/day is lower in patients with severe kidney disease (CrCl 5-15 ml/min) compared to patients with moderate kidney disease (CrCl from 30 to 60 ml/min) and healthy individuals.

C_max of the drug in plasma is higher in patients with liver cirrhosis, both after a single dose and at steady state. However, the safety and tolerability of the drug in such patients do not change when using 75 mg/day of clopidogrel for 10 days.

Indications

Prevention of ischemic disorders (myocardial infarction, stroke, peripheral arterial thrombosis, sudden vascular death) in patients with atherosclerosis, incl.

• After myocardial infarction;
• After ischemic stroke;
• With diagnosed peripheral arterial diseases;
• With acute coronary syndrome without ST-segment elevation (unstable angina, myocardial infarction without Q wave), in combination with acetylsalicylic acid;
• During percutaneous coronary angioplasty.

ICD codes

Dosage Regimen

The drug should be taken orally, 1 tablet once a day, regardless of meals.

Treatment should be started within a period from several days to 35 days in patients after myocardial infarction and from 7 days to 6 months in patients after ischemic stroke.

In acute coronary syndrome without ST-segment elevation (unstable angina, myocardial infarction without Q wave), treatment should be started with a single loading dose – 4 tablets of Agregal (300 mg of clopidogrel), then continue with 1 tablet/day (75 mg of clopidogrel) with simultaneous administration of acetylsalicylic acid at a dose of 75-375 mg/day.

The maximum course of combined use of Agregal and acetylsalicylic acid is 1 year (safety with longer use has not been studied).

The choice of regimen and duration of treatment with Agregal during percutaneous coronary angioplasty is determined by the doctor depending on the type of stent and the timing of the procedure.

Adverse Reactions

From the blood coagulation system: gastrointestinal bleeding (2%; required hospitalization in 0.7% of cases); sometimes – hematomas, hematuria, conjunctival hemorrhage.

From the hematopoietic system: severe neutropenia (granulocyte count <450/µL; observed in 0.04%); severe thrombocytopenia (platelet count <80,000/µL; observed in 0.2%).

From the digestive system: abdominal pain, dyspepsia (constipation, diarrhea, nausea), gastritis; rarely – changes in liver function tests.

From the central and peripheral nervous system: headache, dizziness, paresthesia.

Dermatological reactions: skin rash, itching.

Allergic reactions: very rarely – bronchospasm, angioedema, anaphylactic reactions.

Other: thrombocytopenic purpura (1/200,000).

Other clinically significant side effects noted in a number of large international studies, with a frequency of >0.1%, as well as all severe side effects are presented below, in accordance with the WHO classification. Their frequency is defined as follows: common (> 1/100, but <1/10); uncommon (>1/1000, but < 1/100); rare (>1/10,000, but <1/1000).

From the central and peripheral nervous system: common – headache, dizziness, paresthesia; rare – vertigo.

From the digestive system: common – diarrhea, abdominal pain; uncommon – nausea, gastritis, flatulence, constipation, vomiting, gastric and duodenal ulcer.

From the blood coagulation system: uncommon – prolonged bleeding time.

From the hematopoietic system: uncommon – leukopenia, decreased neutrophil count, eosinophilia, decreased platelet count.

Dermatological reactions: uncommon – rash and itching.

Contraindications

• Severe hepatic impairment;
• Acute bleeding (e.g., peptic ulcer or intracranial hemorrhage);
• Pregnancy;
• Lactation (breastfeeding);
• Childhood;
• Hypersensitivity to the components of the drug.

With caution, the drug should be prescribed to patients with an increased risk of bleeding (trauma, before surgical interventions), moderate hepatic and/or renal impairment (development of hemorrhagic diathesis is possible).

Use in Pregnancy and Lactation

The use of the drug during pregnancy and breastfeeding is contraindicated due to the lack of safety data.

Use in Hepatic Impairment

Contraindicated in severe hepatic impairment.

Use with caution in moderate hepatic impairment.

Use in Renal Impairment

The drug should be used with caution in renal impairment.

Pediatric Use

Contraindicated: childhood.

Special Precautions

In case of combining Agregal with acetylsalicylic acid, other NSAIDs, heparin, glycoprotein IIb/IIIa inhibitors, or fibrinolytics, blood tests should be performed during the first week of treatment (APTT, platelet count and functional activity).

Treatment with Agregal should be discontinued 7 days before planned surgery.

The patient should be warned that it is necessary to inform the doctor about every case of bleeding.

Overdose

No cases of overdose have been reported.

Treatment: platelet transfusion. There is no specific antidote.

Drug Interactions

Concomitant use of Agregal with warfarin is not recommended, as it may increase the intensity of bleeding.

Concomitant use of Agregal with glycoprotein IIb/IIIa inhibitors requires caution.

Acetylsalicylic acid does not change the inhibitory effect of Agregal on ADP-induced platelet aggregation, but Agregal enhances the effect of acetylsalicylic acid on collagen-induced platelet aggregation. The combined use of these drugs requires caution.

According to a clinical trial conducted on healthy individuals, Clopidogrel does not change either the need for heparin or the effect of heparin on blood coagulation. Simultaneous use of heparin did not change the inhibitory effect of clopidogrel on platelet aggregation. However, the safety of such a combination has not yet been established and simultaneous use of these drugs requires caution.

The safety of simultaneous use of clopidogrel, recombinant tissue plasminogen activator (rt-PA), and heparin was studied in patients with recent myocardial infarction. The frequency of clinically significant bleeding was similar to that observed in the case of simultaneous use of rt-PA and heparin. The safety of the combined use of clopidogrel with other fibrinolytics has not yet been established and simultaneous use of these drugs requires caution.

Concomitant use of Agregal with NSAIDs requires caution due to a possible increased risk of bleeding.

No clinically significant pharmacodynamic interaction was found when using clopidogrel concomitantly with atenolol, nifedipine, phenobarbital, cimetidine, estrogens, digoxin, theophylline, phenytoin, tolbutamide, and antacids. However, there is evidence that Clopidogrel inhibits the activity of one of the CYP2C9 isoenzymes and may change the concentration of drugs metabolized via CYP2C9 (including phenytoin, tolbutamide).

Storage Conditions

List B. The drug should be stored out of the reach of children, in a dry, light-protected place at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 2 years.

Dispensing Status

The drug is dispensed by prescription.

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.