plavix tablet drug Uses, Dosage, Side Effects, Precautions & Warnings

WHAT IS plavix generic name
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plavix tablet Generic drug of the therapeutic class: Hemostasis and blood
active ingredients: Clopidogrel

WHAT IS plavix generic name?

plavix generic name IS Clopidogrel

What Plavix is used for and indication ?

Secondary prevention of atherothrombotic events:
Clopidogrel is indicated:

  • In adult patients with myocardial infarction (a few days to less than 35 days old), ischemic stroke (more than 7 days old and less than 6 months old) or arterial occlusive disease lower limbs established.
  • In adult patients with acute coronary syndrome:
    • ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), including patients undergoing coronary angioplasty with stenting, in combination with acetylsalicylic acid (ASA).
    • ST segment elevation acute myocardial infarction in combination with ASA in medically treated patients eligible for thrombolytic therapy.

Prevention of atherothrombotic and thromboembolic events in atrial fibrillation:

In adult patients with atrial fibrillation who have at least one risk factor for vascular events, who can not be treated with vitamin K antagonist (AVK) and who have a low risk of bleeding, clopidogrel is indicated in combination with ASA, in the prevention of atherothrombotic and thromboembolic events, including stroke.

For more information, see Pharmacodynamics .

plavix dosage

Prevention of atherothrombotic events

Clopidogrel is indicated:

in adult patients with myocardial infarction (a few days to less than 35 days old), ischemic stroke (more than 7 days old and less than 6 months old) or arterial occlusive disease lower limbs established.

in adult patients with acute coronary syndrome:

  1. – ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), including patients undergoing coronary angioplasty with stenting, in combination with acetylsalicylic acid (ASA).
  2. – ST segment elevation acute myocardial infarction, in combination with ASA in medically treated patients eligible for thrombolytic therapy.

Prevention of atherothrombotic and thromboembolic events in atrial fibrillation In adult patients with atrial fibrillation, who have at least one risk factor for vascular events, who can not be treated with antivitamin K (AVK) and who are at low risk bleeding, clopidogrel is indicated, in combination with ASA, for the prevention of atherothrombotic and thromboembolic events, including stroke.

For more information see section Pharmacodynamic properties .

Contraindications

  • Hypersensitivity to the active substance or to any of the excipients listed in section 2 or in section Composition .
  • Severe hepatic impairment.
  • Active bleeding lesion such as peptic ulcer or intracranial hemorrhage.

How it works Plavix?

Pharmacotherapeutic group: Platelet Aggregation Inhibitors Excluding Heparin, ATC Code: B01AC-04.

Mechanism of Action

Clopidogrel is a prodrug of which one of the metabolites is an inhibitor of platelet aggregation. Clopidogrel must be metabolized by cytochrome P450 enzymes to synthesize its active metabolite, which inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its P2Y 12 platelet receptor ,and therefore the activation of the GPIIb / IIIa complex caused by ADP, so that platelet aggregation is inhibited. Following this irreversible fixation, the platelet function is modified for the rest of their lifespan (approximately 7 to 10 days) and the restoration of a normal platelet function corresponds to the platelet renewal period. Platelet aggregation caused by other ADP agonists is also inhibited by neutralizing the amplification of platelet activation by released ADP.

Since the active metabolite is synthesized by cytochrome P450 enzymes, some of which are polymorphic or inhibited by other drugs, not all patients will have adequate platelet inhibition.

Pharmacodynamic effects

Repeated 75 mg per day administration resulted in a significant inhibition of platelet aggregation induced by ADP from 1 st  day of treatment; this inhibition gradually increases to reach a plateau of equilibrium between the 3 rd  and the 7 th  day. At steady state, the daily dose of 75 mg per day resulted in an average inhibition rate of 40% to 60%. Platelet aggregation and bleeding time gradually returned to baseline, usually within 5 days of stopping treatment.

Efficacy and clinical safety The safety

and efficacy of clopidogrel have been evaluated in five double-blind studies in more than 88,000 patients: the CAPRIE trial, which compared clopidogrel with ASA and the CURE studies, CLARITY, COMMIT and ACTIVE-A who compared clopidogrel to placebo, both drugs being administered in combination with ASA and other conventional treatments.

Recent myocardial infarction (MI), recent stroke or peripheral arterial occlusive disease established

The CAPRIE study included 19,185 patients with atherothrombosis localization that was manifested by recent myocardial infarction (<35 days), recent ischemic stroke (7 days to 6 months), or arterial occlusive disease. lower limbs (AOMI) established. The patients were randomly assigned to both treatment groups: clopidogrel 75 mg / day or ASA 325 mg / day, followed for 1 to 3 years. In the subgroup of patients included for myocardial infarction, most received ASA for the first few days following the acute phase of myocardial infarction.

Clopidogrel significantly reduced the frequency of new ischemic events (endpoint combining myocardial infarction, ischemic stroke, and vascular death) compared with ASA. In the intent-to-treat analysis, 939 events were observed in the clopidogrel group and 1,020 events in the ASA group (relative risk reduction (RRR) 8.7%, [95% CI: 0.2 to 16.4, p = 0.045). This allows, compared to the ASA, to avoid in 10 additional patients (CI: 0 to 20), out of 1000 treated for 2 years, the occurrence of a new ischemic event. The analysis of total mortality (secondary endpoint) shows no significant difference between clopidogrel (5.8%) and ASA (6.0%).

In a subgroup analysis by qualifying event (myocardial infarction, ischemic stroke, peripheral arterial occlusive disease), the benefit appeared to be greater (reaching a statistical significance of p = 0.003) in patients included for arterial disease. obliterating lower limbs (especially those with a history of myocardial infarction) (RRR = 23.7%, CI: 8.9 to 36.2) and lower (not significantly different from ASA) in patients included for stroke (RRR = 7.3%, CI: -5.7 to 18.7 [p = 0.258]). In patients who were included in the study with only recent myocardial infarction as a criterion, the result under clopidogrel was numerically lower, but not statistically different from that under AAS (RRR = -0.4%, CI: -22.5 to 11.7 [p = 0.639]). In addition, a subgroup-by-age analysis suggested that the benefit of clopidogrel in patients over 75 years of age was lower than that seen in patients aged 75 years or younger.

Since the CAPRIE study was not designed to have the statistical power to evaluate efficacy in each of the subgroups, it is not clear that the differences observed in the relative risk reduction as a function of the qualifying event are real or the result of chance.

Acute coronary syndrome

The CURE study included 12,562 patients with acute coronary syndrome without ST elevation (unstable angina or non-Q-wave myocardial infarction) presenting within 24 hours of the onset of the most recent episode of angina or symptoms related to ischemia. Patients had to have ECG changes consistent with a new ischemic episode or elevated cardiac enzymes or troponins I or T greater than at least twice the upper limit of normal. Patients were randomized to clopidogrel (loading dose of 300 mg followed by 75 mg per day, N = 6,259) or placebo (N = 6,303), with both groups receiving ASA (75 325 mg daily) and other standard treatments. Patients were treated for up to 1 year. In CURE, 823 patients (6.6%) were concomitantly treated with GPIIb-IIIa anti-drugs. Heparin therapy was administered in more than 90% of patients and the relative risk of bleeding between clopidogrel and placebo was not significantly influenced by concomitant heparin therapy.

The number of patients with one of the components of the primary endpoint [cardiovascular death (CV), myocardial infarction (MI) or stroke) was 582 (9.3%) in the clopidogrel group and 719 (11.4%) in the placebo group, corresponding to a relative risk reduction (RRR) of 20% (95% CI: 10% -28%, p = 0.00009) in favor of the treated group by clopidogrel (RRR of 17% in conservatively treated patients, 29% with coronary angioplasty with or without stenting, and 10% with coronary artery bypass). New cardiovascular events (primary endpoint) were avoided with a relative risk reduction of 22% (CI: 8.6 – 33.4), 32% (CI: 12.8 – 46.4), 4% (CI : -26.9 – 26.7), 6% (CI: -33, 5 – 34.3) and 14% (CI: -31.6-44.2) during the following respective intervals: 0-1 months, 1-3 months, 3-6 months, 6-9 months and 9-12 month. Thus, after 3 months of treatment, the benefit observed in the clopidogrel + ASA group did not increase while the haemorrhagic risk persisted.Warnings and precautions for use ).

The use of clopidogrel in CURE was associated with a decrease in the use of thrombolytic therapy (RRR = 43.3%, CI: 24.3% -57.5%) and anti GPIIb-IIIa (RRR = 18.2 % CI: 6.5% -28.3%).

The number of patients with one of the components of the primary co-endpoint (CV death, MI, cerebrovascular accident, or refractory ischemia) was 1,035 (16.5%) in the clopidogrel group and 1,187 (18.8%) in the placebo group, corresponding to a 14% relative risk reduction (95% CI: 6% – 21%, p = 0.0005) in favor of the clopidogrel group . This benefit was mainly related to the statistically significant reduction in the incidence of myocardial infarction [287 (4.6%) in the clopidogrel group and 363 (5.8%) in the placebo group]. No effect on the frequency of rehospitalizations for unstable angina was observed.

The results obtained on patient populations with different characteristics (such as unstable angina or non-Q-wave IDM, low to high risk level, diabetes, need for revascularization, age, sex, etc.) were consistent with the results of the main analysis. In particular, in a post-hoc analysis of 2,172 patients (17% of the total population of the CURE study) who received stent-placement (Stent-CURE), the data showed a significant reduction in relative risk of 26.2% in favor of clopidogrel compared to placebo on the main endpoint (CV death, MI, cerebrovascular accident), as well as a significant reduction in relative risk of 23.9% on the co-criterion of main judgment (CV death, IDM, cerebrovascular accident or refractory ischemia). In addition, the safety profile of clopidogrel in this subgroup of patients did not raise any particular problem. Thus, the results of this subgroup are consistent with the results of the entire study.

The benefit observed with clopidogrel was independent of other acute or long-term cardiovascular therapies (such as heparin / LMWH, GPIIb-IIIa, lipid-lowering, beta blockers, and IEC). The efficacy of clopidogrel was observed regardless of the dose of aspirin (75 to 325 mg daily).

In patients with acute ST segment elevation MI, the safety and efficacy of clopidogrel were evaluated in two randomized, double-blind, placebo-controlled studies: CLARITY and COMMIT.

The CLARITY study included 3,491 patients presenting within the first 12 hours of an ST segment elevation MI and for whom thrombolytic therapy was scheduled. Patients received clopidogrel (loading dose of 300 mg then 75 mg / day, n = 1752) or placebo (n = 1739), in combination for the 2 groups with ASA (150 to 325 mg then 75 to 162 mg / day), to a fibrinolytic agent and, if indicated, heparin. The patients were followed for 30 days. The primary endpoint was defined as the combined outcome of occlusion of the artery responsible for infarction seen with coronary angiography performed prior to discharge from hospital, death or recurrence of an MI before coronary angiography. For patients who have not had coronarography,th day before the release of the hospital. In the study population, 19.7% of patients included were women and 29.2% of patients were 65 years or older. In total, 99.7% of patients received fibrinolytics (fibrin-specific: 68.7%, nonspecific fibrin: 31.1%), 89.5% heparin, 78.7% beta-blockers, 54.7% of angiotensin converting enzyme inhibitors and 63% of statins.

Fifteen percent (15.0%) of patients in the clopidogrel group and 21.7% of the placebo group experienced an event of the primary endpoint representing an absolute risk reduction of 6.7% and a reduction of odds of 36%. favor of clopidogrel (95% CI: 24-47%, p <0.001), mainly due to a decrease in the occlusion rate of the artery responsible for the infarction. This benefit was consistent across pre-specified subgroups including age and sex of patients, location of infarction, and type of fibrinolytic or heparin used.

The COMMIT study was conducted using a 2×2 factorial design and included 45,852 patients with suspicion of MI, within 24 hours after onset of symptoms associated with ECG abnormalities (ST segment elevation). ST segment offset or left branch block). Patients received clopidogrel (75 mg / day, n = 22,961) or placebo (n = 22,891) in combination with ASA (162 mg / day) for 28 days or until discontinuation. hospital. The 2 main criteria of evaluation were deaths from all causes and 1 stoccurrence of a combined endpoint event involving recurrent infarction, stroke or death. In the study population 27.8% of patients included were women, 58.4% of patients were 60 or older (26% were 70 years of age or older) and 54.5% of patients received fibrinolytic therapy .

Clopidogrel significantly reduced the relative risk of all-cause death by 7% (p = 0.029) and the relative risk of the combined endocardial infarct recurrence, stroke or death criterion by 9% (p = 0.002), representing absolute risk reduction of 0.5% and 0.9% respectively. This benefit was homogeneous regardless of age, gender and the presence or absence of fibrinolytic therapy and this benefit was observed from the first 24 hours.

Atrial fibrillation

The ACTIVE-W and ACTIVE-A studies, which are independent studies of the overall ACTIVE program, included patients with atrial fibrillation (AF) who had at least one risk factor for vascular events. According to the inclusion criteria, physicians included patients in the ACTIVE-W study if they were candidates for treatment with vitamin K antagonist (AVK), such as warfarin. Patients were included in the ACTIVE-A study if they were not candidates for treatment with VKA, either because of their inability to follow treatment or their reluctance to treatment with VKA.

The ACTIVE-W study demonstrated that AVK therapy is more effective than clopidogrel + ASA.

The ACTIVE-A study (n = 7554) is a multicentre, randomized, double-blind, placebo-controlled study that compared the combination of clopidogrel 75 mg / day and ASA (n = 3772) with placebo and AAS combination (n = 3782). The recommended dose of ASA was 75 to 100 mg daily. Patients were treated for up to 5 years.

Patients randomized to the ACTIVE program had documented FA, that is, permanent AF, at least 2 episodes of intermittent AF in the last 6 months, and had at least one of the following risk factors: age ≥ 75 years old;age 55-74 years associated with either type 2 diabetes requiring drug therapy, documented history of MI, or documented coronary artery disease; treated high blood pressure; history of stroke, transient ischemic attack (TIA) or systemic embolism outside the CNS; left ventricular dysfunction with LVEF <45%;documented peripheral vascular disease. The average CHADS score was 2.0 (range 0 to 6).

The main exclusion criteria were: peptic ulcer documented in the last 6 months; history of intracranial hemorrhage; significant thrombocytopenia (platelets <50 x 10 9 / l); need for treatment with clopidogrel or oral anticoagulant (ACO); intolerance to one of the two substances.

73% of the patients included in the ACTIVE-A study could not be treated with AVK according to the doctor’s assessment, due to a patient’s incapacity to respect the constraints related to the follow-up of the INR (international normalised ratio), a predisposition to falls or head trauma, or a particular risk of bleeding; for 26% of patients, the doctor’s decision was based on the patient’s reluctance to undergo AVK treatment.

41.8% of the patients were women. The average age was 71 years, 41.6% of patients were 75 years of age or older. 23.0% of patients were treated with antiarrhythmic agents, 52.1% with betablockers, 54.6% with ACE inhibitors and 25.4% with statins.

832 patients (22.1%) presented one of the components of the primary efficacy endpoint (stroke, IDM, systemic embolism outside the CNS or vascular death) in the clopidogrel + ASA group versus 924 patients (24.4%). %) in the placebo + ASA group (a relative risk reduction of 11.1%, 95% CI: 2.4-19.1%, p = 0.013).This difference is mainly due to a significant decrease in the number of strokes. 296 patients (7.8%) in the clopidogrel + ASA group had a stroke versus 408 patients (10.8%) in the placebo + ASA group (a 28.4% relative risk reduction, 95% CI: 16 , 8% -38.3%, p = 0.00001).

Pediatric population

A titration titration study of clopidogrel (PICOLO study) was performed in 86 neonates or infants up to 24 months of age at risk for thrombosis; at consecutive doses of 0.01, 0.1 and 0.2 mg / kg in neonates and infants, and 0.15 mg / kg in neonates only.

The dose of 0.2 mg / kg achieved an average percentage inhibition of 49.3% (ADP-induced platelet aggregation of 5 (μM), a result comparable to that seen in adults treated with 75 mg per day of Plavix.

In a randomized (CLARINET), double-blind, parallel-group study in 906 neonates and infants with cyanotic congenital heart defects corrected by aortopulmonary arterial anastomosis were randomized to receive either clopidogrel 0.2 mg / kg (n = 467) or placebo (n = 439) in combination with concomitant background therapy to the second surgical stage.

The mean duration between the pulmonary arterial anastomosis and the first administration of the study drug was 20 days.

Approximately 88% of patients received acetylsalicylic acid (ASA) in combination at a dose of 1 to 23 mg / kg / day).

No significant difference between the treatment groups was observed on the composite endpoint of death, thrombosis of the anastomosis or intervention attributable to cardiac disease before a delay of 120 days after a thrombotic event, respectively (89 [19.1%] in the clopidogrel group and 90 [20.5%] in the placebo group).

Bleeding was the most commonly reported adverse event in both groups (clopidogrel and placebo).

However, no significant difference in bleeding rates was observed between the two groups.

When monitoring the long-term safety of this study, 26 patients whose anastomosis was still in place at one year received clopidogrel for up to 18 months.

No new tolerance events were observed during the long-term follow-up of this study.

The CLARINET and PICOLO studies were performed using a reconstituted solution of clopidogrel. A relative bioavailability study in adults showed that the reconstituted solution of clopidogrel had similar exposure and a slightly faster rate of absorption based on the main circulating metabolite (inactive) compared to the approved tablet.

What are side effects of Plavix?

Tolerance Profile Summary

The safety of clopidogrel has been studied in more than 44,000 patients in clinical trials, of whom more than 12,000 have been treated for one year or more. In the CAPRIE study, the safety of clopidogrel 75 mg / day was broadly comparable to that of ASA 325 mg / day, regardless of age, sex and race. The clinically significant adverse events recorded in the CAPRIE, CURE, CLARITY, COMMIT and ACTIVE-A studies are presented below. In addition to experience in clinical studies, side effects have been reported spontaneously.

Bleeding is the most commonly reported adverse reaction in both clinical studies and since marketing. They are mainly reported during the first month of treatment.

In CAPRIE, in patients treated with clopidogrel or ASA, the overall bleeding rate was 9.3%. The frequency of severe episodes was similar for clopidogrel and ASA.

In CURE, there was no increase in major bleeding with clopidogrel + ASA in the 7 days following CABG in patients who discontinued more than 5 days before surgery. In patients who remained on treatment during these 5 days, this frequency was 9.6% for the clopidogrel + ASA group and 6.3% for the placebo + ASA group.

In CLARITY, an overall increase in bleeding was observed in the clopidogrel + ASA group vs the placebo + ASA group. The frequency of major bleeding was similar between the 2 groups. This was homogeneous in the subgroups of patients defined by the initial characteristics of the patients and the type of fibrinolytic treatment or heparin.

In COMMIT, the overall rate of major non-cerebral haemorrhages and cerebral hemorrhages was low and similar in both groups.

In ACTIVE-A, the rate of major bleeding was higher in the clopidogrel + ASA group compared to the placebo + ASA group (6.7% versus 4.3%). Major bleeding was predominantly extracranial in both groups (5.3% in the clopidogrel + ASA group versus 3.5% in the placebo + ASA group), mainly of gastrointestinal origin (3.5% vs 1.8%). There was more intracranial bleeding in the clopidogrel + ASA group than in the placebo + ASA group (1.4% versus 0.8%, respectively). There was no statistically significant difference between the 2 groups, or fatal bleeding (1.1% in the clopidogrel + ASA group versus 0.7% in the placebo + ASA group), nor in stroke. bleeding (0.8% versus 0.6%, respectively).

Table of adverse effects

Adverse reactions occurring either during clinical studies or spontaneously reported are presented in the table below. Their frequency is defined using the following convention: frequent (> 1/100 to <1/10);uncommon (> 1/1000 to <1/100); rare (> 1/10 000 to <1/1000); very rare (<1 / 10,000), not known (can not be estimated based on available data). For each class of organ system, adverse effects are presented in descending order of severity.

Class-organ system Frequent Rare Rare Very rare, undetermined frequency *
affections

hematologic and lymphatic system

T hrombocytopenia,

leukopenia,

eosinophilia

neutropenia,

including

neutropenia

severe

Thrombocytopenic purpura

thrombotic (PTT) (seeWarnings and precautions for use ), bone marrow suppression, pancytopenia , agranulocytosis, severe thrombocytopenia,

acquired hemophilia A,granulocytopenia, anemia

System conditions

i mmunity

Serum sickness,anaphylactoid reactions, allergic cross reactions between thienopyridines (such as ticlopidine, prasugrel) (see Warnings and Precautions section ) *
Psychiatric disorders Hallucinations, confusion
System conditions

nervous

Hemorrhage

intracranial (some fatal cases have been reported),

headache ,

paresthesia,

stun

Taste disorders
Eye disorders Bleeding

ocular

(conjunctival,intraocular

retinal)

Affections of the ear and labyrinth Fear of heights
Vascular disorders Hey matome Serious hemorrhage, bleeding from an operative wound, vasculitis, hypotension
Respiratory, thoracic and mediastinal disorders Epistaxis Bleeding from the airways (haemoptysis, pulmonary hemorrhage), bronchospasm, interstitial lung disease, eosinophilic pneumonia
Class-organ system Frequent Rare Rare Very rare, undetermined frequency *
Gastrointestinal disorders Gastrointestinal haemorrhage

intestinal ,

diarrhea,

pain

abdominaldyspepsia

Gastric ulcer and duodenal ulcer,

gastritis

vomiting,

nausea,

constipation,flatulence

Hemorrhage retro-

peritoneal

Gastrointestinal and retro-peritoneal haemorrhage with fatal outcome,

pancreatitis , colitis (including ulcerative colitis and lymphocytic colitis), stomatitis

Hepatobiliary disorders Acute hepatic insufficiency, hepatitis, abnormal liver function tests
Skin and subcutaneous tissue disorders Contusion Rash, pruritus, skin bleeding (purpura) Bullous Eruption (Lyell’s Syndrome)

Stevens-Johnson, erythema multiforme), angioedema, drug hypersensitivity syndrome, DRESS syndrome (cutaneous rash with eosinophilia andsystemic symptoms ) ,

erythematous rash, skin exfoliation, urticaria, eczema, lichen planus

Musculoskeletal disorders

Skeletal, systemic and bony

Muscle bleeding

articular (hemarthrosis),

arthritis, arthralgia, myalgia

Kidney disorders and

Urinary tract

hematuria glomerulonephritis,

Elevation of serum creatinine

General disorders and administrative abnormalities Bleeding at the injection site Fever
Investigations (biological examinations) Prolonged bleeding time, decrease Noshadow

neutrophils, decreased platelet count

* Information on clopidogrel, with frequency “indeterminate”.

plavix interactions

Drugs Associated with Risk of Bleeding: There is an increased risk of bleeding due to the potential additive effect. Co-administration of drugs with a risk ofbleeding should be made with caution.

  • Oral anticoagulants: Concomitant  administration of clopidogrel and oral anticoagulants is not recommended, as these combinations may increase the intensity of bleeding (see Warnings and Precautions section ).Although 75 mg / day of clopidogrel did not affect the pharmacokinetic parameters of S-warfarin, nor the INR (International Normalized Ratio) in long-term warfarin patients, the combination of Clopidogrel and warfarin increases the risk of bleeding, due to their independent effects on hemostasis.
  • Anti GPIIb-IIIa : Clopidogrel should be used with caution in patients treated with GPIIb-IIIa (see Warnings and Precautions ).
  • Acetylsalicylic acid (ASA): ASA did not affect clopidogrel inhibition of ADP-induced platelet aggregation, while clopidogrel potentiated ASA activity on platelet aggregation induced by collagen. However, concomitant administration of 500 mg ASA twice daily for one day did not significantly affect  the lengthening of bleeding time caused by clopidogrel. A pharmacodynamic interaction between clopidogrel and ASA is possible, leading to an increased risk of bleeding. Therefore, simultaneous administration of these two products should be undertaken with caution (see Warnings and Precautions section).). However, clopidogrel and ASA have been administered in combination for periods of up to one year.
  • Heparin : In a clinical study in healthy subjects, no change in heparin dosage was required and heparin activity on coagulation was not impaired. Concomitant administration of heparin did not alter the inhibition of platelet aggregation due to clopidogrel. A pharmacodynamic interaction between clopidogrel and heparin is possible, leading to an increased risk of bleeding. Therefore, the simultaneous administration of these two products should be undertaken with caution (see Warnings and Precautions ).
  • Thrombolytics:  The safety of concomitant administration of clopidogrel, fibrin-specific or non-fibrin thrombolytic agents and heparins has been studied in patients with acute myocardial infarction. The frequency of clinically significant bleeding was similar to that seen with concomitant administration of thrombolytics and heparin with ASA (see section 4.8 ).
  • NSAIDs : A clinical study in healthy volunteers has shown that concomitant administration of clopidogrel and naproxen increased the frequency of occult gastrointestinal bleeding. However, due to the lack of interaction studies with other NSAIDs, it is not currently clear whether the risk of increased gastrointestinal bleeding exists with all NSAIDs. Therefore, the combination of clopidogrel / NSAID including Cox-2 inhibitors requires caution (see Warnings and Precautions ).
  • Selective Serotonin Reuptake Inhibitors (SSRIs) : Because SSRIs have an effect on platelet activation and increase the risk of bleeding, co-administration of SSRIs with clopidogrel should be undertaken with caution.
  • Interaction with other medicinal products: As clopidogrel is converted to the active metabolite in part by CYP2C19, the use of drugs that inhibit the activity of this enzyme may decrease the level of the active metabolite of clopidogrel. The clinical relevance of this interaction is uncertain. As a precaution, the combination of potent or moderate CYP2C19 inhibitors should be discouraged (see sections Warnings and Precautions and Pharmacokinetic Properties ). The following drugs are examples of potent or moderate CYP2C19 inhibitors omerazole and eomerazole, fluvoxamine, fluoxeine, moclobide, voriconazole, fluconazole,
    ticlopidine, carbamazeine and efavirenz.
  • Proton Pump Inhibitors (PPIs):The administration of omeprazole 80 mg once daily, at the same time as clopidogrel, 12 hours apart, decreased exposure to the active metabolite of 45% (at the loading dose) and 40% (at the maintenance dose). Inhibition of platelet aggregation was also decreased by 39% (at the loading dose) and 21% (at the maintenance dose). Similar interaction is expected with esomeprazole.


Conflicting data on the clinical consequences of this pharmacokinetic (PK) / pharmacodynamic (PD) interaction in terms of the occurrence of major cardiovascular events have been reported in observational and clinical studies. As a precaution, the combination of omeprazole or esomeprazole should be discouraged (see Warnings and Precautions ).

A less pronounced decrease in exposure to the active metabolite was observed with pantoprazole or lansoprazole.
Plasma concentrations of the active metabolite decreased by 20% (at the loading dose) and 14% (at the maintenance dose) when 80 mg pantoprazole was added once daily.
Mean inhibition of platelet aggregation also decreased by 15% and 11%, respectively. These results indicate that pantoprazole may be associated with clopidogrel.

There is no evidence that other drugs that reduce gastric acidity such as H2 antihistamines or antacids interfere with the antiplatelet activity of clopidogrel.

Other drugs: Several other clinical studies have been conducted to determine potential pharmacodynamic and pharmacokinetic interactions between clopidogrel and other concurrently administered drugs. No clinically significant pharmacodynamic interaction has been observed with clopidogrel and atenolol, nifedipine, or both. In addition, the pharmacodynamic activity of clopidogrel did not change significantly with simultaneous administration of phenobarbital or estrogen.

Concomitant administration of clopidogrel did not alter the pharmacokinetic parameters of digoxin or those of theophylline. Antacids did not influence the

Data from the CAPRIE trial show that the combination of tolbutamide and phenytoin (which are metabolized by CYP2C9) with clopidogrel is well tolerated.

CYP2C8 Substrates: Clopidogrel has been shown to increase repaglinide exposure in healthy volunteers. In vitro studies  have shown that the increase in repaglinide exposure is due to inhibition of CYP2C8 by the glucuronide metabolite of clopidogrel. Due to the potential for increased plasma concentrations, concomitant administration of clopidogrel with medicinal products that are predominantly metabolized by CYP2C8 (eg, repaglinide, paclitaxel) should be performed with caution ( see Warnings and Precautions section). of employment ).

Apart from the specific drug interactions described above, no other interaction studies between clopidogrel and certain drugs commonly used in patients with atherothrombotic disease have been performed. However, patients included in clinical studies of clopidogrel received many combination drugs including diuretics, beta-blockers, ACE inhibitors, calcium channel blockers, cholesterol-lowering drugs, coronary vasodilators, antidiabetic agents (including insulin), anti-epileptic drugs and anti-GPIIb-IIIa notable clinically significant drug interaction.

Plavix Warnings and Precautions

Bleeding and hematological disorders

  • Because of the risk of bleeding and hematologic adverse events, Blood Count and / or other appropriate tests should be considered promptly whenever clinical signs suggestive of bleeding occur during treatment . Clopidogrel, like other antiplatelet agents, should be used with caution in patients with increased risk of bleeding due to trauma, surgery, or other causes, and in patients treated with ASA, heparin, anti-GPIIb IIIa, Non-Steroidal Anti-Inflammatory (NSAID) including Cox-2 inhibitors or selective serotonin reuptake inhibitor (SSRI), or with another drug that has a risk of bleeding such as pentoxifylline (see ,Interactions with other medicinal products and other forms of interaction ). Careful investigation of any signs of bleeding, including occult bleeding, should be performed especially during the first few weeks of treatment and / or after invasive cardiac procedures or surgery. The concomitant administration of clopidogrel with oral anticoagulants is not recommended since it may increase the intens ity bleeding (see section Interactions with other drugs and other forms of interaction ).
  • In the case of a scheduled surgical procedure, if a platelet anti-aggregating effect is temporarily not desirable, treatment with clopidogrel should be discontinued 7 days before surgery. Patients should inform their doctors and dentists of clopidogrel treatment before scheduled surgery and before prescribing a new medicine. Clopidogrel prolongs bleeding time and should be used with caution in patients with bleeding lesions (particularly gastrointestinal and intraocular).
  • Patients should be informed that treatment with clopidogrel (taken alone or in combination with ASA) may prolong bleeding time and that they should consult a physician in the event of abnormal bleeding (by location or duration).

Thrombotic Thrombocytopenic Purpura (PTT)

  • Very rare cases of thrombotic thrombocytopenic purpura (TTP) have been reported during the use of clopidogrel, sometimes after a short period of exposure. This condition is characterized by thrombocytopenia and microangiopathic haemolytic anemia associated with neurological disorders, renal function disorders or fever. PTT is a potentially fatal condition requiring rapid treatment including plasmapheresis.

Acquired haemophilia

  • Cases of acquired hemophilia have been reported during the use of clopidogrel. If confirmation of prolongation of isolated activated partial thromboplastin time (APTT), with or without bleeding, acquired hemophilia should be considered. Patients diagnosed with confirmed hemophilia should be referred to a specialist and treatment with clopidogrel should be discontinued.

Recent ischemic stroke

In the absence of data, clopidogrel is not recommended in the first 7 days after an acute ischemic stroke.

Cytochrome P450 2C19 (CYP2C19)

  • Pharmacogenetics: In patients who are poor metabolisers of CYP2C19, clopidogrel at the recommended doses results in less active metabolite formation of clopidogrel and has a lower platelet aggregation-inhibiting effect . There are tests to identify the CYP2C19 genotype of patients.
  • Since clopidogrel is converted to the active metabolite in part by CYP2C19, the use of drugs that inhibit the activity of this enzyme is likely to result in a decrease in the level of the active metabolite of clopidogrel. The clinical relevance of this interaction is uncertain. As a precaution, the combination of strong or moderate CYP2C19 inhibitors should be discouraged (see section Interaction with other drugs and other forms of interaction for a list of CYP2C19 inhibitors, see also section Pharmacokinetic properties ).

CYP2C8 substrates

  • Caution should be exercised in patients receiving concomitant treatment with clopidogrel and a CYP2C8 substrate drug (see Interaction with other medicinal products and other forms of interaction ).

Cross-reactions between thienopyridines

  • Since cross-reactions between thienopyridines have been reported, patients should be screened for any history of hypersensitivity to thienopyridine (such as clopidogrel, ticlopidine, prasugrel) . 
  • Thienopyridines may cause mild to severe allergic reactions such as rash, angioedema, or hematologic reactions such as thrombocytopenia or neutropenia. Patients with a history of allergic reaction and / or hematologic reaction to a thienopyridine have an increased risk of experiencing the same or another reaction with another thienopyridine. It is recommended to monitor the occurrence of signs of hypersensitivity in patients with a history of

Renal failure

  • Limited data are available on the use of clopidogrel in patients with renal impairment. Clopidogrel will therefore be used with caution in this type of patient (see section Dosage and method of administration ).

Hepatic insufficiency

  • Similarly, the experience with clopidogrel is limited in patients with moderate hepatic impairment likely to result in a bleeding diathesis. Clopidogrel will therefore be used with caution in this population (see section Dosage and method of administration ).

excipients

  • Plavix contains lactose. Patients with rare hereditary conditions such as: galactose intolerance, lactase deficiency, or glucose or galactose malabsorption should not take this medicine.
  • This medication contains hydrogenated castor oil which can cause stomach upset and diarrhea.

Drive and use machines

  • Clopidogrel has no or negligible effect on the ability to drive and use machines.

Plavix and PREGNANCY / BREAST FEEDING / FERTILITY:

Pregnancy

  • Since there are no clinical data on the use of clopidogrel during pregnancy as a precaution, it is best not to use clopidogrel during pregnancy.
  • Studies in animals have not shown any direct or indirect harmful effects on pregnancy, embryonic or fetal development, childbirth or postnatal development ( see Preclinical Safety ).

Breastfeeding

  • In the human species, there are no data on the excretion of clopidogrel in breast milk.
  • Studies in animals have shown excretion of clopidogrel in breast milk. As a precaution, breastfeeding should not be continued if treated with Plavix.

Fertility

  • Studies in animals have not shown any impairment of fertility with clopidogrel.

What happens if I overdose from Plavix ?

  • Overdose can lead to longer bleeding time and bleeding complications. Appropriate treatment should be considered if bleeding occurs.
  • There is no known antidote to the pharmacological activity of clopidogrel. If rapid correction of prolonged bleeding time is required, platelet transfusion may correct the effects of clopidogrel.

What is  Forms and Composition Plavix?

FORMS
  • 300 mg film-coated tablet (oblong, engraved “300” on one side and “1332” on the other side, pink):   Box of 30 x 1, in blister packs for single delivery. 75 mg film-coated tablet (round, biconvex, engraved “75” on one side and “1171” on the other side, pink):   Box of 30, under blister packs. Hospital model: Box of 50 x 1, in blister packs for single delivery.
COMPOSITION
  p cp
Clopidogrel (INN) hydrogen sulfate expressed as clopidogrel 300 mg
or 75 mg
  • Excipients (common): mannitol (E421), macrogol 6000, microcrystalline cellulose, hydrogenated castor oil, low substituted hydroxypropylcellulose. Coating: hypromellose (E464), lactose monohydrate, triacetin (E1518), titanium dioxide (E171), red ferric oxide (E172). Polishing agent: carnauba wax.
  • Excipients with known effect: lactose (12 mg / cp 300 mg, 3 mg / cp 75 mg); hydrogenated castor oil (13.2 mg / cp 300 mg, 3.3 mg / cp 75 mg).

NOT’s

Edrug-online contains comprehensive and detailed information about drugs available in the medical field, and is divided into four sections:

general information:

  • Includes a general description of the drug, its use, brand names, FAQs, and relevant news and articles

Additional information:

  • General explanation about dealing with the medicine: how to take the medicine, the doses and times of it, the start and duration of its effectiveness, the recommended diet during the period of taking the medicine, the method of storage and storage, recommendations in cases for forgetting the dose and instructions to stop taking the drug and take additional doses.

Special warnings:

  • For pregnant and breastfeeding women, the elderly, boys and drivers, and use before surgery.

Side effects:

  • It treats possible side effects and drug interactions that require attention and its effect on continuous use.
  • The information contained in this medicine is based on medical literature, but it is not a substitute for consulting a doctor.

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