Plavix, 75 mg 100 pcs

Special Instructions

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

Because of the risk of bleeding and adverse blood effects (see side effects), if during treatment, clinical symptoms suspicious of bleeding occur, a complete clinical blood count, ACTV, platelet count, platelet function tests and other necessary tests should be performed promptly.

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

If a patient is going to have elective surgery and there is no need for antiplatelet effects, clopidogrel should be discontinued 5-7 days before surgery.

Clopidogrel prolongs bleeding time and should be used with caution in patients with diseases that predispose to bleeding (especially gastrointestinal and intraocular). Drugs that may cause gastrointestinal mucosal damage (such as ASA, NSAIDs) in patients taking clopidogrel should be used with caution.

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

Very rare cases of TTP, characterized by thrombocytopenia and microangiopathic hemolytic anemia, accompanied by neurological disorders, impaired renal function and fever, have been reported after clopidogrel use (sometimes even short-term). TTP is a potentially life-threatening condition requiring immediate treatment, including plasmapheresis.

The combination of ASA and clopidogrel has been shown to increase the risk of major bleeding in patients with recent transient cerebral haemorrhage or stroke with a high risk of recurrent ischemic complications. Therefore, such combination therapy should be used with caution and only if there is clinical evidence of benefit from its use.

Cases of acquired hemophilia have been reported with clopidogrel administration. If an isolated increase in ACTV is confirmed, with or without bleeding, the possibility of acquired hemophilia should be considered. Patients with a confirmed diagnosis of acquired hemophilia should be monitored and treated by specialists in this disease and discontinue clopidogrel.

. In patients with low CYP2C19 isoenzyme activity, the use of clopidogrel at recommended doses produces less of the active metabolite clopidogrel and its antiaggregant effect is less pronounced; therefore, a higher incidence of cardiovascular complications may occur with commonly recommended doses of clopidogrel in acute coronary syndrome or percutaneous coronary intervention than in patients with normal CYP2C19 isoenzyme activity. Tests are available to determine the CYP2C19 genotype. These tests can be used to assist in the choice of therapeutic strategy. The use of higher doses of clopidogrel in patients with low CYP2C19 activity is being considered (see Pharmacokinetics, subsection Pharmacogenetics, Caution, Dosage and administration). Patients should have a history of previous allergic and/or hematologic reactions to other thienopyridines (such as ticlopidine, prasugrel), since cross-allergic and/or hematologic reactions between thienopyridines have been reported (see “Adverse Effects”).

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

Hypatic function should be monitored during treatment. In case of severe liver lesions it is necessary to remember about the risk of hemorrhagic diathesis. Administration of clopidogrel is not recommended in acute stroke less than 7 days old (since there are no data on its use in this condition).

Influence on ability to drive vehicles and engage in other potentially hazardous activities Plavix® has no significant effect on the ability to drive or engage in other potentially hazardous activities.

.

Contraindications

• Severe hepatic failure.
• Acute bleeding (e.g., peptic ulcer or intracranial hemorrhage).
• Pregnancy.
• Lactation period (breastfeeding).
• Children under 18 years of age (safety and effectiveness of use not established).
• High sensitivity to the drug’s components.
• Cautiously prescribe the drug in patients with liver and kidney diseases (including those with moderate hepatic and/or kidney failure), trauma, 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 one year or more.

In general, the tolerability of clopidogrel at a dose of 75 mg/day in the CAPRIE study was similar to that of acetylsalicylic acid (ASA) at a dose of 325 mg/day, regardless of patient age, sex, or race. Listed below are the clinically significant adverse effects observed in five large clinical trials: CAPRIE, CURE, CLARITY, COMMIT, and ACTIVE-A.

Bleeding and hemorrhage

Comparing clopidogrel and ASA monotherapy

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

The overall incidence of gastrointestinal bleeding in patients taking clopidogrel and patients taking ASA was 2% and 2.7%, respectively, including a rate of gastrointestinal bleeding requiring hospitalization of 0.7% and 1.1%, respectively.

The overall incidence of other localized bleeding was higher with clopidogrel compared with ASA administration (7.3% vs. 6.5%, respectively). However, the incidence of major bleeding with clopidogrel and ASA was comparable (0.6% or 0.4%, respectively). The most frequently reported bleeding events were: purpura/bleeding, nasal bleeding. Less commonly reported were hematoma, hematuria, and ocular hemorrhages (mainly conjunctival).

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

Comparing clopidogrel+ASC and placebo+ASC combination therapy

In the CURE clinical trial, patients taking clopidogrel+ASC compared with patients taking placebo+ASC had an increased rate of major bleeding (3.7% vs. 2.7%), and minor bleeding (5.1% vs. 2.4%). The main sources of major bleeding were the GI tract and arterial puncture sites.

The incidence of life-threatening bleeding was not significantly different in patients taking clopidogrel+ASC compared with patients taking placebo+ASC (2.2% and 1.8%, respectively); the incidence of fatal bleeding was similar (0.2% for both therapies).

The incidence of non-life-threatening major bleeding was significantly higher in patients taking clopidogrel+ASC compared with patients taking placebo+ASC (1.6% and 1%, respectively), but the incidence of intracranial hemorrhage was similar (0.1% for both therapies).

The incidence of major bleeding in the clopidogrel+ASC group depended on the dose of ASA (<100 mg, 2.6%; 100-200 mg, 3.5%; >200 mg, 4.9%), as did the incidence of major bleeding in the placebo+ASC group (< 100 mg, 2.0%; 100-200 mg, 2.3%; >200 mg, 4%).

In patients who discontinued antiplatelet therapy more than 5 days before aortocoronary bypass surgery, there was no increase in the incidence of major bleeding within 7 days after intervention (4.4% in the clopidogrel+ASC group and 5.3% in the placebo+ASC group). In patients who continued antiplatelet therapy for the last 5 days before coronary artery bypass grafting, the incidence of these events after intervention was 9.6% (in the clopidogrel+ASC group) and 6.3% (in the placebo+ASC 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+ASC and placebo+ASC) was comparable (1.3% versus 1.1% in the clopidogrel+ASC and placebo+ASC groups, respectively). It was similar in patient subgroups separated by baseline characteristics and by type of fibrinolytic therapy or heparin therapy.

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

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

In the ACTIVE-A clinical trial, the incidence of major bleeding was higher in the clopidogrel+ASC group than in the placebo+ASC group (6.7% vs. 4.3%, respectively). Major bleeding was mainly extracranial in both groups (5.3% vs. 3.5%), mainly from the GI tract (3.5% vs. 1.8%). There were more intracranial hemorrhages in the clopidogrel+ASC group compared to the placebo+ASC 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% versus 0.7%) and hemorrhagic stroke (0.8% versus 0.6%).

Hematopoietic system

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

Two of the 9599 patients taking clopidogrel had a complete absence of neutrophils in the peripheral blood, which was not observed in any of the 9586 patients taking ASA. Although the risk of myelotoxicity with clopidogrel is quite low, the patient should be evaluated for possible neutropenia if the patient taking clopidogrel has fever or other signs of infection.

In one case of treatment with clopidogrel, the development of aplastic anemia has been observed.

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 comparable numbers of patients with thrombocytopenia or neutropenia in both treatment groups.

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

The frequency of adverse reactions observed during the above clinical trials is presented according to the WHO classification: Very common (≥10%), common (≥1% and < 10%), infrequent (≥0.1% and < 1%), rare (≥0.01% and < 0.1%), very rare (< 0.01%), unknown frequency (it is not possible to determine the frequency of the side effect from the available data).

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

Digestive system disorders:often – dyspepsia, abdominal pain, diarrhea; infrequently – nausea, gastritis, bloating, constipation, vomiting, peptic ulcer, duodenal ulcer.

Dermatological reactions: infrequent – rash, itching.

Hematopoietic system disorders: infrequent – decreased number of platelets in peripheral blood, leukopenia, decreased number of neutrophils in peripheral blood, eosinophilia.

With the blood coagulation system:infrequent – increased bleeding time.

Postmarketing experience with the drug

Hemorrhagic disorders:. unknown frequency – cases of serious bleeding, mainly subcutaneous, musculoskeletal, ocular hemorrhages (conjunctival, tissue and retina), respiratory bleeding (hemoptysis, pulmonary bleeding), Nasal bleeding, hematuria, and bleeding from postoperative wounds and cases of fatal bleeding (particularly intracranial hemorrhage, gastrointestinal hemorrhage, and retroperitoneal hemorrhage).

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 hematologic reactions with other thienopyridines (such as ticlopidine, prazugrel).

Psychiatric disorders:unknown frequency – confusion, hallucinations.

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

Cardiovascular system disorders:unknown frequency – vasculitis, decreased BP.

Involved respiratory system: unknown frequency – bronchospasm, interstitial pneumonia, eosinophilic pneumonia.

Ingestive system disorders: 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, bulla

.

Overdose

Symptoms:Overdose of clopidogrel may lead to increased bleeding time with subsequent complications in the form of bleeding.

Treatment:In the event of bleeding, appropriate treatment measures are required. An antidote for clopidogrel has not been established. If rapid recovery of prolonged bleeding time is necessary, platelet transfusion is recommended.

.

Similarities

Clopidogrel, Zilt, Egithromb, Lopirel, Plagril, Clopidex, Clopidogrel-SZ