Plavix pills 75 mg, 100 pcs.

Composition

• Active ingredient
  • Clopidogrel hydrosulfate 97.875 mg in 1 tablet, which is equivalent to the content of clopidogrel base 75 mg.
• Auxiliary substances
  • Mannitol.
  • Macrogol 6000.
  • Microcrystalline cellulose.
  • Hydrogenated castor oil.
  • Low-substituted giprolose.
• The composition
  • of the Opadry shell is white (lactose, hypromellose, triacetin, titanium dioxide (E 171).
  • Iron oxide red (E 172)).

Clinical pharmacology

Inhibitor of platelet aggregation. Clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to platelet receptors and the activation of the GPIIb/IIIa complex by ADP, thus inhibiting platelet aggregation.

Clopidogrel also inhibits platelet aggregation caused by other agonists by blocking increased platelet activity with released ADP. Clopidogrel irreversibly binds to platelet ADP receptors.

Consequently, platelets that interact with it are immune to ADP stimulation for the entire duration of their life, and normal platelet function is restored at a rate corresponding to the rate of platelet renewal.

From the first day of use of the drug, there is a significant inhibition of platelet aggregation. Inhibition of platelet aggregation increases and a stable condition is achieved after 3-7 days.

At the same time, the average level of suppression of platelet aggregation with a daily dose of 75 mg is 40-60%. Platelet aggregation and bleeding time return to baseline on average 5 days after discontinuation of treatment.

The drug has a coronary dilating effect. If there is an atherosclerotic lesion of the vessel, it prevents the development of atherothrombosis, regardless of the localization of the process (brain, heart or peripheral vessels).

Indications

Prevention of atherothrombotic disorders in patients with severe atherosclerosis, including:

• After a previous myocardial infarction, ischemic stroke, or a diagnosed peripheral artery disease.
• In acute coronary syndrome without ST-segment elevation (unstable angina or myocardial infarction without abnormal Q wave) in combination with acetylsalicylic acid.
• In acute coronary syndrome with ST-segment elevation (acute myocardial infarction) in combination with acetylsalicylic acid, receiving medical treatment with the possible use of thrombolytic therapy.

Contraindications

• Severe hepatic insufficiency.
• Acute bleeding (for example, with a peptic ulcer or intracranial hemorrhage).
• Pregnancy.
• Lactation period (breastfeeding).
• Children under 18 years of age (safety and efficacy have not been established).
• Hypersensitivity to the components of the drug.
• With caution, the drug should be prescribed for liver and kidney diseases (including moderate hepatic and/or renal failure), injuries, and before surgery.

Side effects

The safety of clopidogrel has been studied in more than 44,000 patients, including more than 12,000 patients treated for a year or more.

Overall, the tolerability of clopidogrel 75 mg/day in the CAPRIE study was consistent with that of acetylsalicylic acid (ASA) 325 mg/day, regardless of age, gender, or race. The following are clinically significant adverse events observed in five large clinical trials: CAPRIE, CURE, CLARITY, COMMIT, and ACTIVE-A.

Bleeding and hemorrhage

Comparison of clopidogrel monotherapy with ASA

In the CAPRIE clinical trial, the overall incidence of all bleeding events in patients treated with clopidogrel and in patients treated with ASA was 9.3%. The incidence of severe bleeding with clopidogrel and ASA was comparable: 1.4% and 1.6%, respectively.

Overall, the incidence of gastrointestinal bleeding in patients treated with clopidogrel and in patients treated with ASA was 2% and 2.7%, respectively, including the incidence of gastrointestinal bleeding requiring hospitalization was 0.7% and 1.1%, respectively.

The overall incidence of non-local bleeding with clopidogrel compared to ASA was higher (7.3% vs.6.5%, respectively). However, the incidence of severe bleeding with clopidogrel and ASA was comparable (0.6% or 0.4%, respectively). The following bleeding events were most frequently reported: purpura / bruising, nosebleeds. Less frequently, hematomas, hematuria, and ocular hemorrhages (mainly conjunctival) were reported.

The incidence of intracranial hemorrhage with clopidogrel and ASA was comparable (0.4% or 0.5%, respectively).

Comparison of combination therapy with clopidogrel+ASA and placebo+ASA

In the CURE clinical trial, patients treated with clopidogrel+ASA experienced an increase in the incidence of major bleeding (3.7% vs.2.7%) and minor bleeding (5.1% vs.2.4%) compared to patients treated with placebo+ASA. The main sources of major bleeding were the gastrointestinal tract and arterial puncture sites.

The incidence of life-threatening bleeding in patients taking clopidogrel+ASA compared to patients taking placebo+ASA did not significantly differ (2.2% and 1.8%, respectively), the incidence of fatal bleeding was the same (0.2% with both types of therapy).

The incidence of non-life-threatening major bleeding was significantly higher in patients taking clopidogrel+ASA compared to patients taking placebo+ASA (1.6% and 1%, respectively), but the incidence of intracranial hemorrhage was the same (0.1% for both types of therapy).

The incidence of bleeding in a large group of clopidogrel+ASA was dependent on the dose of ask (<100 mg – 2.6%; 100-200 mg – 3.5%; >200 mg – 4.9%) and the incidence of large bleeding in the placebo+ASA (<100 mg – 2.0%; 100-200 mg – 2.3%; >200 mg – 4%).

Patients who stopped antiplatelet therapy more than 5 days before coronary artery bypass grafting did not experience an increase in major bleeding within 7 days after the intervention (4.4% in the clopidogrel+ASA group and 5.3% in the placebo+ASA group). In patients who continued antiplatelet therapy for the last 5 days before coronary artery bypass grafting, the incidence of these events after the intervention was 9.6% (in the clopidogrel+ASA group) and 6.3% (in the placebo+ASA group).

In the CLARITY clinical trial, the incidence of major bleeding (defined as intracranial bleeding or bleeding with a decrease in hemoglobin >5 g/dl) in both groups (clopidogrel+ASA and placebo+ASA) was comparable (1.3% vs.1.1% in the clopidogrel+ASA and placebo+ASA groups, respectively). It was the same in subgroups of patients divided by baseline characteristics and by types of fibrinolytic therapy or heparin therapy.

The incidence of fatal bleeding (0.8% vs.0.6%) and intracranial hemorrhage (0.5% vs.0.7%) with clopidogrel+ASA and placebo+ASA, respectively, was low and comparable in both treatment groups.

In the COMMIT clinical trial, the overall incidence of non-cerebral major bleeding or cerebral hemorrhage was low and similar (0.6% in the clopidogrel+ASA group and 0.5% in the placebo+ASA group).

In the ACTIVE-A clinical trial, the incidence of major bleeding in the clopidogrel+ASA group was higher than in the placebo+ASA group (6.7% vs.4.3%, respectively). Major hemorrhages were mostly extracranial in both groups (5.3% vs.3.5%), mainly from the gastrointestinal tract (3.5% vs.1.8%). There were more intracranial hemorrhages in the clopidogrel+ASA group than in the placebo+ASA group (1.4% vs.0.8%, respectively). There were no statistically significant differences between these treatment groups in the incidence of fatal bleeding (1.1% vs.0.7%) and hemorrhagic stroke (0.8% vs.0.6%).

From the hematopoietic system

In the CAPRIE study, severe neutropenia (<0.45×109/L) was observed in 4 patients (0.04%) treated with clopidogrel and 2 patients (0.02%) treated with ASA.

In 2 out of 9599 patients treated with clopidogrel, there was a complete absence of neutrophils in the peripheral blood, which was not observed in any of the 9586 patients treated with ASA. Although the risk of developing myelotoxic effects when taking clopidogrel is quite low, if the patient taking clopidogrel has a fever or other signs of infection, the patient should be examined for possible neutropenia.

In one case, the development of aplastic anemia was observed during treatment with clopidogrel.

The incidence of severe thrombocytopenia (<80-10%) was 0.2% in patients treated with clopidogrel and 0.1% in patients treated with ASA, very rare cases of platelet count reduction <30-10% were reported.

The CURE and CLARITY studies observed a comparable number of patients with thrombocytopenia or neutropenia in both treatment groups.

Other clinically significant adverse reactions observed in the CAPRIE, CURE, CLARITY, COMMIT, and ACTIVE clinical trials

The frequency of adverse reactions that were observed during the above clinical trials is presented in accordance with the WHO classification: very common (≥10%), common (≥1% and <10%), infrequent (≥0.1% and <1%), rare (≥0.01% and <0.1%), very rare (

Nervous system disorders: infrequently-headache, dizziness, paresthesia; rarely-vertigo.

From the digestive system: often-dyspepsia, abdominal pain, diarrhea; infrequently-nausea, gastritis, bloating, constipation, vomiting, stomach ulcer, duodenal ulcer.

Dermatological reactions: infrequently – rash, itching.

From the hematopoietic system: infrequently-a decrease in the number of platelets in the peripheral blood, leukopenia, a decrease in the number of neutrophils in the peripheral blood, eosinophilia.

From the side of the blood coagulation system: infrequently-increased bleeding time.

Post-marketing experience with the drug

Hemorrhagic disorders: unknown frequency – serious cases of bleeding, mainly subcutaneous, musculoskeletal, eye bleeding (conjunctival, in the tissue and the retina of the eye), bleeding from the airway (hemoptysis, pulmonary hemorrhage), nasal bleeding, hematuria, and bleeding from surgical wounds and cases of bleeding with fatal outcome (especially intracranial hemorrhage, gastrointestinal bleeding and retroperitoneal hemorrhage).

From the hematopoietic system: unknown frequency-agranulocytosis, granulocytopenia, aplastic anemia/pancytopenia, thrombotic thrombocytopenic purpura (TTP), acquired hemophilia A.

Allergic reactions: unknown frequency – anaphylactoid reactions, serum sickness; cross-allergic and hematological reactions with other thienopyridines (such as ticlopidine, prasugrel).

Mental disorders: unknown frequency – confusion, hallucinations.

Nervous system disorders: unknown frequency – disorders of taste perception.

From the cardiovascular system: unknown frequency – vasculitis, decreased blood pressure.

Respiratory system disorders: unknown frequency-bronchospasm, interstitial pneumonia, eosinophilic pneumonia.

From the digestive system: unknown frequency-colitis (including ulcerative colitis or lymphocytic colitis), pancreatitis, stomatitis, hepatitis (non-infectious), acute liver failure.

Dermatological reactions: unknown frequency-maculopapular, erythematous or exfoliative rash, urticaria, pruritus, angioedema, bull

Interaction

with drugs associated with the risk of bleeding: there is an increased risk of bleeding due to their potential additive effect with clopidogrel. Concomitant use of medications with clopidogrel that are associated with a risk of bleeding should be carried out with caution.

With warfarin: although taking clopidogrel 75 mg / day did not change the pharmacokinetics of warfarin (a substrate of the CYP2C9 isoenzyme) or INR in patients receiving long-term warfarin treatment, concomitant administration of clopidogrel increases the risk of bleeding due to its independent additional effect on blood clotting.

Therefore, caution should be exercised when taking warfarin and clopidogrel at the same time.

With IIb/IIIa receptor blockers: due to the possible pharmacodynamic interaction between clopidogrel and IIb/IIIa receptor blockers, their combined use requires caution, especially in patients with an increased risk of bleeding (due to injuries and surgical interventions or other pathological conditions) (see “Special Instructions”).

With ASK: It does not change the effect of clopidogrel, which inhibits ADP-induced platelet aggregation, but clopidogrel potentiates the effect of ASA on collagen-induced platelet aggregation. However, concomitant administration of ASA 500 mg twice daily for one day with clopidogrel did not significantly increase the bleeding time caused by clopidogrel, since there may be a pharmacodynamic interaction between clopidogrel and ASA, which leads to an increased risk of bleeding. Therefore, caution should be exercised when using them together. However, in clinical trials, patients received combination therapy with clopidogrel and ASA (75-325 mg once daily) for up to 1 year.

With heparin: according to a clinical study conducted with the participation of healthy individuals, clopidogrel did not require dose adjustment of heparin and did not change its anticoagulant effect. Concomitant use of heparin did not affect the antiplatelet effect of clopidogrel. There may be a pharmacodynamic interaction between clopidogrel and heparin, which may increase the risk of bleeding, so the simultaneous use of clopidogrel and heparin requires caution.

With thrombolytics: the safety of co-administration of clopidogrel, fibrin-specific or fibrin-specific thrombolytics and heparin was studied in patients with acute MI.

The frequency of clinically significant bleeding was similar to that observed in the case of co-administration of thrombolytics and heparin with ASA.

With NSAIDs: in a clinical study conducted in healthy volunteers, the combined use of clopidogrel and naproxen increased hidden blood loss through the gastrointestinal tract.

However, due to the lack of studies on the interaction of clopidogrel with other NSAIDs, it is currently unknown whether there is an increased risk of gastrointestinal bleeding when taking clopidogrel together with other NSAIDs. Therefore, the application NSAIDs, including COX-2 inhibitors in combination with clopidogrel, should be used with caution (see “Special instructions”).

WITH SSRIs: Since SSRIs interfere with platelet activation and increase the risk of bleeding, concomitant use of SSRIs is recommended. SSRIs with clopidogrel should be administered with caution.

With other simultaneous therapy

With strong to moderate inhibitors of the CYP2C9 isoenzyme Since clopidogrel is metabolized to the formation of its active metabolite partly by the CYP2C19 isoenzyme, the use of Drugs that inhibit this isoenzyme may lead to a decrease in the formation of the active metabolite of clopidogrel. The clinical significance of this interaction has not been established. As a precautionary measure, concomitant use of clopidogrel and strong or moderate inhibitors of the CYP2C9 isoenzyme should be avoided. Strong and moderate inhibitors of the CYP2C9 isoenzyme are omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine, chloramphenicol.

Concomitant use with clopidogrel of proton pump inhibitors that are strong or moderate inhibitors of the CYP2C19 isoenzyme (for example, omeprazole, esomeprazole) should be avoided (see “Pharmacokinetics”, subsection Pharmacogenetics, “Special Instructions”). If proton pump inhibitors are to be taken concomitantly with clopidogrel, a proton pump inhibitor with the least inhibition of the CYP2C19 isoenzyme, such as pantoprazole and lantoprazole, should be taken. A number of clinical studies have been conducted with clopidogrel and other concomitantly administered drugs to investigate possible pharmacodynamic and pharmacokinetic interactions that have shown: :

– that the use of clopidogrel in conjunction with atenolol, nifedipine, or a combination of clinically significant pharmacodynamic interactions were observed;

– simultaneous administration of phenobarbital or estrogen had no significant effect on the pharmacodynamics of clopidogrel;

– the pharmacokinetic parameters of digoxin or theophylline was not altered in their joint application with clopidogrel;

– antacids did not reduce the absorption of clopidogrel;

– phenytoin and tolbutamide can be safely administered concomitantly with clopidogrel (studyCAPRIE). It is unlikely that clopidogrel can affect the metabolism of other drugs, such as phenytoin and tolbutamide, as well as NSAIDs that are metabolized by the CYP2C9 isoenzyme of the cytochrome P450 family;

– ACE inhibitors, diuretics, beta-blockers, BCC, lipid-lowering agents, coronary vasodilators, hypoglycemic agents (including insulin), antiepileptic drugs, hormone replacement therapy, and GPIIb/IIIa receptor blockers: no clinically significant adverse interactions were identified in clinical studies.

With drugs that are substrates of the CYP2C8 isoenzyme, clopidogrel was shown to increase systemic exposure to repaglinide in healthy volunteers. In vitro studies have shown that increased systemic exposure to repaglinide is due to inhibition of the CYP2C8 isoenzyme by the glucuronide metabolite of clopidogrel.Caution should be exercised when concomitantly using clopidogrel and drugs that are mainly eliminated from the body by metabolism using the CYP2C8 isoenzyme (for example, repaglinide, paclitaxel) due to the risk of increasing their plasma concentrations.

How to take, course of administration and dosage

Inside, regardless of food intake.

Adults and the elderly

A tablet containing 300 mg of clopidogrel is intended for use as a loading dose in patients with acute coronary syndrome (see “Indications for use”).

Acute coronary syndrome without ST-segment elevation (unstable angina, MI without Q wave). Treatment with clopidogrel should be started with a single loading dose of 300 mg, and then continued with a dose of 75 mg once a day (in combination with ASA in doses of 75-325 mg/day). Since the use of higher doses of ASA is associated with an increased risk of bleeding, the recommended dose of ASA for this indication should not exceed 100 mg. The maximum beneficial effect is observed by the third month of treatment. The course of treatment is up to 1 year.

Acute ST-segment elevation coronary syndrome (acute ST-segment elevation MI).  Clopidogrel is prescribed once at a dose of 75 mg once a day with an initial single dose of 300 mg in combination with ASA and thrombolytics (or without them). Combination therapy should be initiated as early as possible after the onset of symptoms and continued for at least 4 weeks.

In patients over 75 years of age, treatment with clopidogrel should begin without taking its loading dose. As for the maintenance dose of clopidogrel, which is 75 mg, Plavix® 75 mg tablets are available for its administration.

Patients with a genetically determined decrease in the function of the CYP2C19 isoenzyme.  The status of a weak CYP2C19 metabolizer is associated with a decrease in the antiplatelet effect of clopidogrel. A high-dose regimen (600 mg as a loading dose, followed by 150 mg once daily) increases the antiplatelet effect of clopidogrel in weak metabolizers. However, the optimal dosage regimen for patients with reduced metabolism using the CYP2C19 isoenzyme in clinical trials for clinical outcomes has not yet been established

Overdose

Symptoms: overdose of clopidogrel can lead to an increase in bleeding time with subsequent complications in the form of bleeding.

Treatment: if bleeding occurs, appropriate treatment measures are required. The antidote of clopidogrel has not been established. If a rapid recovery of the prolonged bleeding time is required, platelet transfusion is recommended.

Special instructions

During treatment with clopidogrel, especially during the first weeks of treatment and/or after invasive cardiac procedures/surgery, patients should be carefully monitored for signs of bleeding, including hidden ones.

Due to the risk of bleeding and undesirable effects from the blood (see “Side effects”), if clinical symptoms appear during treatment that are suspicious of the occurrence of bleeding, a general clinical blood test should be performed urgently, APTT, platelet count, platelet functional activity indicators should be determined, and other necessary studies should be carried out.

Clopidogrel, as well as other antiplatelet agents, should be used with caution in patients who have an increased risk of bleeding associated with injuries, surgery or other pathological conditions, as well as in patients taking ASA, NSAIDs, including COX-2 inhibitors, heparin or glycoprotein IIb/IIIa inhibitors. Concomitant use of clopidogrel with warfarin may increase the risk of bleeding (see “Interaction”), so caution should be exercised when using clopidogrel and warfarin together.

If the patient is going to undergo elective surgery and there is no need for an antiplatelet effect, then clopidogrel should be discontinued 5-7 days before the operation.

Clopidogrel prolongs the bleeding time and should be used with caution in patients with diseases predisposing to the development of bleeding (especially gastrointestinal and intraocular). Medications that can cause damage to the gastrointestinal mucosa (such as ASA, NSAIDs) Caution should be exercised in patients taking clopidogrel.

Patients should be warned that it may take longer to stop bleeding when taking clopidogrel (alone or in combination with ASA), and that if they experience unusual (by location or duration) bleeding, they should inform their doctor about this. Patients should inform their doctor (including their dentist) about taking clopidogrel before any upcoming surgery and before starting any new medication.

Very rarely, after the use of clopidogrel (sometimes even for a short time), cases of TTP have been observed, which is characterized by thrombocytopenia and microangiopathic hemolytic anemia, accompanied by neurological disorders, impaired renal function and fever. TTP is a potentially life-threatening condition that requires immediate treatment, including plasmapheresis.

The combination of ASA and clopidogrel has been shown to increase the risk of major bleeding in patients with a recent transient cerebrovascular accident or stroke who are at high risk for recurrent ischemic events. Therefore, such combination therapy should be carried out with caution and only if there is clinical evidence of benefits from its use.

Cases of acquired hemophilia have been reported with clopidogrel. When isolated zoom is confirmed APTT, whether or not accompanied by the development of bleeding, should be considered the possibility of developing acquired hemophilia. Patients with a confirmed diagnosis of acquired hemophilia should be monitored and treated by specialists for this condition and stop taking clopidogrel.

In patients with low activity of the CYP2C19 isoenzyme, when using clopidogrel at the recommended doses, less of the active metabolite of clopidogrel is formed and its antiplatelet effect is less pronounced, and therefore, when taking the usually recommended doses of clopidogrel in acute coronary syndrome or percutaneous coronary intervention, a higher incidence of cardiovascular complications is possible than in patients with normal activity of the CYP2C19 isoenzyme. Tests are available to determine the CYP2C19 genotype. These tests can be used to help you choose a therapeutic strategy. The use of higher doses of clopidogrel in patients with low CYP2C19 activity is considered (see “Pharmacokinetics”, subsection” Pharmacogenetics”, “With caution”, “Method of administration and doses”). Patients should have a history of previous allergic and/or hematological reactions to other thienopyridines (such as ticlopidine, prasugrel), as cross-allergic and / or hematological reactions between thienopyridines have been reported (see “Side Effects”).

Thienopyridines can cause moderate to severe allergic reactions (such as rash, angioedema) or hematological reactions (such as thrombocytopenia and neutropenia). Patients who have previously experienced allergic and / or hematological reactions to one of the thienopyridine drugs may have an increased risk of developing similar reactions to another thienopyridine drug. Monitoring of cross-allergic and/or hematological reactions is recommended.

During treatment, it is necessary to monitor the functional state of the liver. With severe liver damage, you should be aware of the risk of developing hemorrhagic diathesis. Taking clopidogrel is not recommended for acute stroke with a duration of less than 7 days (since there are no data on its use in this condition).

Impact on the ability to drive vehicles and engage in other potentially dangerous activities.  Plavix® does not significantly affect the ability to drive a car or engage in other potentially dangerous activities.

Form of production

Tablets coated with a pink color, round, biconvex, with the inscription “75” on one side and “1171” – on the other side.

Active ingredient

Clopidogrel

Conditions of release from pharmacies

By prescription

Dosage form

of the tablet

Purpose

For adults as directed by your doctor

Indications

Prevention of thrombosis, Prevention of heart attacks and strokes

Weight

Weight: 24 gr.