PLAVIX

Clopidogrel bisulfate is a thienopyridine class inhibitor of P2Y 12 ADP platelet receptors.

Chemically it is methyl (+)-( S )-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4 H )-­acetate sulfate (1:1).

The molecular formula of clopidogrel bisulfate is C 16 H 16 ClNO 2 S•H 2 SO and its molecular weight is 419.9.

The structural formula is as follows

Clopidogrel bisulfate USP is a white to off-white powder.

It is practically insoluble in water at neutral pH but freely soluble at pH 1.

It also dissolves freely in methanol, dissolves sparingly in methylene chloride, and is practically insoluble in ethyl ether.

It has a specific optical rotation of about +56°.

Clopidogrel tablets, USP for oral administration are provided as pink colored, round, biconvex, beveled edge, debossed, film-coated tablets containing 97.875 mg of clopidogrel bisulfate which is the molar equivalent of 75 mg of clopidogrel base.

Each film-coated tablet contains crospovidone, hydrogenated castor oil, hydroxypropyl cellulose low substituted, hypromellose 15cP, iron oxide red, lactose monohydrate, mannitol, microcrystalline cellulose, polyethylene glycol 6000, titanium dioxide, and triacetin as inactive ingredients.

Acute coronary syndrome, terminal arteries, patients who had already suffered a stroke, coronary artery disease, cardiac stroke.

Patients with bleed disorders or plate problems.

Patients with anal fibrillation.

Patients with a cytocrom

CYP2C19 function.

Clupidogrel pregnant woman can be used if needed and under the supervision of the doctor.

Clupidogrel of the breast-feeding infant is unknown if it is separated with mother's milk, so it must be done under the supervision of the doctor.

Clopidogrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y 12 class of ADP receptors on platelets. 12.2 Pharmacodynamics Clopidogrel must be metabolized by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation.

The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y 12 receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation.

This action is irreversible.

Consequently, platelets exposed to clopidogrel’s active metabolite are affected for the remainder of their lifespan (about to 10 days).

Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP.

Dose-dependent inhibition of platelet aggregation can be seen 2 hours after single oral doses of clopidogrel.

Repeated doses of 75 mg clopidogrel per day inhibit ADP-induced platelet aggregation on the first day, and inhibition reaches steady state between Day and Day 7.

At steady state, the average inhibition level observed with a dose of 75 mg clopidogrel per day was between 40% and 60%.

Platelet aggregation and bleeding time gradually return to baseline values after treatment is discontinued, generally in about 5 days.

Elderly (≥75 years) and young healthy subjects had similar effects on platelet aggregation.

After repeated doses of 75 mg clopidogrel per day, patients with severe renal impairment (creatinine clearance from to 15 mL/min) and moderate renal impairment (creatinine clearance from to 60 mL/min) showed low (25%) inhibition of ADP-induced platelet aggregation.

After repeated doses of 75 mg clopidogrel per day for 10 days in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that observed in healthy subjects.

In a small study comparing men and women, less inhibition of ADP-induced platelet aggregation was observed in women. 12.3 Pharmacokinetics Clopidogrel is a prodrug and is metabolized to a pharmacologically active metabolite and inactive metabolites.

After single and repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed.

Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.

Effect of food

Clopidogrel can be administered with or without food.

In a study in healthy male subjects when clopidogrel 75 mg per day was given with a standard breakfast, mean inhibition of ADP-induced platelet aggregation was reduced by less than 9%.

The active metabolite

AUC 0-24 was unchanged in the presence of food, while there was a 57% decrease in active metabolite C max.

Similar results were observed when a clopidogrel 300 mg loading dose was administered with a high-fat breakfast.

Clopidogrel is extensively metabolized by two main metabolic pathways: one mediated by esterases and leading to hydrolysis into an inactive carboxylic acid derivative (85% of circulating metabolites) and one mediated by multiple cytochrome P450 enzymes.

Cytochromes first oxidize clopidogrel to a 2-oxo-clopidogrel intermediate metabolite.

Subsequent metabolism of the 2-oxo-clopidogrel intermediate metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel.

The active metabolite is formed mostly by CYP2C19 with contributions from several other CYP enzymes, including CYP1A2, CYP2B6 and CYP3A.

The active thiol metabolite binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation for the lifespan of the platelet.

C max of the active metabolite is twice as high following a single 300 mg clopidogrel loading dose as it is after four days of 75 mg maintenance dose.

C max occurs approximately to 60 minutes after dosing.

In the to 300 mg dose range, the pharmacokinetics of the active metabolite deviates from dose proportionality: 4-fold the dose results in 2-fold and 2.7-fold the C max and AUC, respectively.

Following an oral dose of 14 C-labeled clopidogrel in humans, approximately 50% of total radioactivity was excreted in urine and approximately 46% in feces over the 5 days post dosing.

After a single, oral dose of 75 mg, clopidogrel has a half-life of approximately 6 hours.

The half-life of the active metabolite is about 30 minutes.

Drug Interactions Effect of other drugs on clopidogrel Clopidogrel is metabolized to its active metabolite in part by CYP2C19.

CYP2C19 inducers Concomitant use of strong inducers of CYP2C19 results in increased plasma concentration of the active metabolite of clopidogrel and an increase in platelet inhibition.

Coadministration of rifampin 300 mg twice daily for 7 days with 600 mg loading dose of clopidogrel in healthy adults increased the mean AUC and C max of clopidogrel’s thiol metabolites by 3.8-fold.

Mean inhibition of platelet aggregation at 4 hours post dose was 34% higher in the presence of rifampin compared to clopidogrel administered alone.

CYP2C19 inhibitors Concomitant use of certain inhibitors of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition.

Proton pump inhibitors (PPI) The effect of proton pump inhibitors (PPI) on the systemic exposure to the clopidogrel active metabolite following multiple doses of clopidogrel 75 mg evaluated in dedicated drug interaction studies is presented in Figure 1.

Pharmacodynamic and pharmacokinetic parameters measured in these studies showed that the interaction was highest with omeprazole and least with dexlansoprazole.

Coadministration of 5 mg intravenous morphine with 600 mg loading dose of clopidogrel in healthy adults decreased the AUC and C max of clopidogrel’s thiol metabolites by 34%.

Mean platelet aggregation was higher up to to 4 hours with morphine coadministration.

Effect of clopidogrel on other drugs

In vitro studies have shown that the glucuronide metabolite of clopidogrel is a strong inhibitor of CYP2C8.

Concomitant administration of repaglinide with clopidogrel increased the systemic exposure to repaglinide (AUC 0-∞ ) by 5.1-fold following the loading dose (300 mg) and by 3.9-fold on day of the maintenance dose (75 mg) of clopidogrel.

Figure 1 12.5 Pharmacogenomics CYP2C19 is involved in the formation of both the active metabolite and the 2-oxo-clopidogrel intermediate metabolite.

Clopidogrel active metabolite pharmacokinetics and antiplatelet effects, as measured by ex vivo platelet aggregation assays, differ according to CYP2C19 genotype.

Patients who are homozygous for nonfunctional alleles of the CYP2C19 gene are termed “CYP2C19 poor metabolizers.” Approximately 2% of White and 4% of Black patients are poor metabolizers; the prevalence of poor metabolism is higher in Asian patients (e.g., 14% of Chinese).

Tests are available to identify patients who are CYP2C19 poor metabolizers.

A crossover study in 40 healthy subjects, 10 each in the four CYP2C19 metabolizer groups, evaluated pharmacokinetic and antiplatelet responses using 300 mg followed by 75 mg per day and 600 mg followed by 150 mg per day, each for a total of 5 days.

Decreased active metabolite exposure and diminished inhibition of platelet aggregation were observed in the poor metabolizers as compared to the other groups.

Table 3: Active Metabolite Pharmacokinetics and Antiplatelet Responses by CYP2C19 Metabolizer Status * Intermediate metabolizers have one but not two nonfunctional alleles. † Ultrarapid metabolizers have at least one gain-of-function allele. ‡ Inhibition of platelet aggregation with 5 mcM ADP; larger value indicates greater platelet inhibition. § Vasodilator-stimulated phosphoprotein – platelet reactivity index; smaller value indicates greater platelet inhibition.

Values are mean (SD).

Poor (n=10) Intermediate* (n=10) Normal (n=10) Ultrarapid † (n=10) C max (ng/mL) 300 mg (24 h) 11 23 32 24 600 mg (24 h) 17 39 44 36 75 mg (Day 5) 4 12 13 12 150 mg (Day 5) 7 18 19 16 IPA (%) ‡ 300 mg (24 h) 24 37 39 40 600 mg (24 h) 32 56 49 51 75 mg (Day 5) 37 60 58 56 150 mg (Day 5) 61 74 73 68 VASP-PRI (%) § 300 mg (24 h) 91 78 68 73 600 mg (24 h) 85 56 48 51 75 mg (Day 5) 83 50 39 40 150 mg (Day 5) 61 29 24 20.

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The following serious adverse reactions are discussed below and elsewhere in the labeling: Bleeding Thrombotic thrombocytopenic purpura Bleeding, including life-threatening and fatal bleeding, is the most commonly reported adverse reaction.

To report SUSPECTED ADVERSE

REACTIONS, contact Aurobindo Pharma USA, Inc.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions and durations of follow-up, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clopidogrel has been evaluated for safety in more than 54,000 patients, including over 21,000 patients treated for one year or more.

The clinically important adverse reactions observed in trials comparing clopidogrel plus aspirin to placebo plus aspirin and trials comparing clopidogrel alone to aspirin alone are discussed below.

CURE, clopidogrel use with aspirin was associated with an increase in major bleeding (primarily gastrointestinal and at puncture sites) compared to placebo with aspirin.

The incidence of intracranial hemorrhage (0.1%) and fatal bleeding (0.2%) were the same in both groups.

Other bleeding events that were reported more frequently in the clopidogrel group were epistaxis, hematuria, and bruise.

The overall incidence of bleeding is described in Table 1.

Table 1: CURE Incidence of Bleeding Complications (% patients) Event Clopidogrel (+ aspirin) (n=6259) Placebo (+ aspirin) (n=6303) * Life-threatening and other major bleeding. † Led to interruption of study medication.

Major bleeding * 3.7 2.7 Life-threatening bleeding 2.2 1.8 Fatal 0.2 0.2 5 g/dL hemoglobin drop 0.9 0.9 Requiring surgical intervention 0.7 0.7 Hemorrhagic strokes 0.1 0.1 Requiring inotropes 0.5 0.5 Requiring transfusion (≥4 units) 1.2 1 Other major bleeding 1.6 1 Significantly disabling 0.4 0.3 Intraocular bleeding with significant loss of vision 0.05 0.03 Requiring to 3 units of blood 1.3 0.9 Minor bleeding † 5.1 2.4 COMMIT In COMMIT, similar rates of major bleeding were observed in the clopidogrel and placebo groups, both of which also received aspirin.

Table 2: Incidence of Bleeding Events in COMMIT (% patients) Type of Bleeding Clopidogrel (+ aspirin) (n=22961) Placebo (+ aspirin) (n=22891) p-value * Major bleeds were cerebral bleeds or noncerebral bleeds thought to have caused death or that required transfusion.

Major* noncerebral or cerebral bleeding 0.6 0.5 0.59 Major noncerebral 0.4 0.3 0.48 Fatal 0.2 0.2 0.90 Hemorrhagic stroke 0.2 0.2 0.91 Fatal 0.2 0.2 0.81 Other noncerebral bleeding (nonmajor) 3.6 3.1 0.005 Any noncerebral bleeding 3.9 3.4 0.004 CAPRIE (Clopidogrel vs Aspirin) In CAPRIE, gastrointestinal hemorrhage occurred at a rate of 2% in those taking clopidogrel versus 2.7% in those taking aspirin; bleeding requiring hospitalization occurred in 0.7% and 1.1%, respectively.

The incidence of intracranial hemorrhage was 0.4% for clopidogrel compared to 0.5% for aspirin.

Other bleeding events that were reported more frequently in the clopidogrel group were epistaxis and hematoma.

Other Adverse Events In CURE and

CHARISMA, which compared clopidogrel plus aspirin to aspirin alone, there was no difference in the rate of adverse events (other than bleeding) between clopidogrel and placebo.

In CAPRIE, which compared clopidogrel to aspirin, pruritus was more frequently reported in those taking clopidogrel.

No other difference in the rate of adverse events (other than bleeding) was reported. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of clopidogrel.

Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hemorrhages, including those with fatal outcome, have been reported in patients treated with clopidogrel.

Blood and lymphatic system disorders

Agranulocytosis, aplastic anemia/pancytopenia, thrombotic thrombocytopenic purpura (TTP), acquired hemophilia A Gastrointestinal disorders: Colitis (including ulcerative or lymphocytic colitis), pancreatitis, stomatitis, gastric/duodenal ulcer, diarrhea General disorders and administration site condition: Fever Hepatobiliary disorders: Acute liver failure, hepatitis (noninfectious), abnormal liver function test Immune system disorders: Hypersensitivity reactions, anaphylactoid reactions, serum sickness, insulin autoimmune syndrome, which can lead to severe hypoglycemia Musculoskeletal, connective tissue and bone disorders: Myalgia, arthralgia, arthritis Nervous system disorders: Taste disorders, headache, ageusia Psychiatric disorders: Confusion, hallucinations Respiratory, thoracic and mediastinal disorders: Bronchospasm, interstitial pneumonitis, eosinophilic pneumonia Renal and urinary disorders: Increased creatinine levels Skin and subcutaneous tissue disorders: Maculopapular, erythematous or exfoliative rash, urticaria, bullous dermatitis, eczema, toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis (AGEP), angioedema, drug-induced hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), erythema multiforme, lichen planus, generalized pruritus Vascular disorders: Vasculitis, hypotension.

Platelet inhibition by clopidogrel is irreversible and will last for the life of the platelet.

Overdose following clopidogrel administration may result in bleeding complications.

A single oral dose of clopidogrel at 1500 or 2000 mg/kg was lethal to mice and to rats and at 3000 mg/kg to baboons.

Symptoms of acute toxicity were vomiting, prostration, difficult breathing, and gastrointestinal hemorrhage in animals.

Based on biological plausibility, platelet transfusion may restore clotting ability.

Active pathological bleeding, such as peptic ulcer or intracranial hemorrhage Hypersensitivity to clopidogrel or any component of the product 4.1 Active Bleeding Clopidogrel tablets are contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage. 4.2 Hypersensitivity Clopidogrel tablets are contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to clopidogrel or any component of the product.

Acute coronary syndrome – Initiate clopidogrel tablets with a single 300 mg oral loading dose and then continue at 75 mg once daily. – Initiating clopidogrel tablets without a loading dose will delay establishment of an antiplatelet effect by several days.

MI, recent stroke, or established peripheral arterial disease: 75 mg once daily orally without a loading dose. 2.1 Acute Coronary Syndrome In patients who need an antiplatelet effect within hours, initiate clopidogrel tablets with a single 300 mg oral loading dose and then continue at 75 mg once daily.

Initiating clopidogrel tablets without a loading dose will delay establishment of an antiplatelet effect by several days. 2.2 Recent MI, Recent Stroke, or Established Peripheral Arterial Disease 75 mg once daily orally without a loading dose.

USP, 75 mg are pink colored, round, biconvex, beveled edge, film-coated tablets debossed with ‘E’ on one side and ‘34’ on the other side.

Bottles of 30 NDC 65862-357-30 Bottles of 90 NDC 65862-357-90 Bottles of 100 NDC 65862-357-01 Bottles of 500 NDC 65862-357-05 Bottles of 1,000 NDC 65862-357-99 10 x 10 Unit-dose Tablets NDC 65862-357-10 Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) .

Protect from moisture.

Preserve in well-closed containers.

Available data from cases reported in published literature and postmarketing surveillance with clopidogrel use in pregnant women have not identified any drug-associated risks for major birth defects or miscarriage.

There are risks to the pregnant woman and fetus associated with myocardial infarction and stroke.

No evidence of fetotoxicity was observed when clopidogrel was administered to pregnant rats and rabbits during organogenesis at doses corresponding to and 78 times the recommended daily human dose.

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown.

All pregnancies have a background risk of birth defects, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Disease-associated maternal and/or embryo/fetal risk Myocardial infarction and stroke are medical emergencies.

Therapy for the pregnant woman should not be withheld because of potential concerns regarding the effects of clopidogrel on the fetus.

Labor or delivery

Clopidogrel use during labor or delivery will increase the risk of maternal bleeding and hemorrhage.

Avoid neuraxial blockade during clopidogrel use because of the risk of spinal hematoma.

When possible, discontinue clopidogrel to 7 days prior to labor, delivery, or neuraxial blockade.

Data Human data

The available data from published case reports over two decades of postmarketing use have not identified an association with clopidogrel use in pregnancy and major birth defects, miscarriage, or adverse fetal outcomes.

Animal data

Embryo-fetal developmental toxicology studies were performed in pregnant rats and rabbits with doses up to and 300 mg/kg/day, respectively, administered during organogenesis.

These doses, corresponding to and 78 times the recommended daily human dose, respectively, on a mg/m 2 basis, revealed no evidence of impaired fertility or fetotoxicity due to clopidogrel.

Safety and effectiveness in pediatric populations have not been established.

A randomized, placebo-controlled trial (CLARINET) did not demonstrate a clinical benefit of clopidogrel in neonates and infants with cyanotic congenital heart disease palliated with a systemic-to-pulmonary arterial shunt.

Possible factors contributing to this outcome were the dose of clopidogrel, the concomitant administration of aspirin, and the late initiation of therapy following shunt palliation.

It cannot be ruled out that a trial with a different design would demonstrate a clinical benefit in this patient population.

Of the total number of subjects in the CAPRIE and CURE controlled clinical studies, approximately 50% of patients treated with clopidogrel were 65 years of age and older, and 15% were 75 years and older.

In COMMIT, approximately 58% of the patients treated with clopidogrel were 60 years and older, 26% of whom were 70 years and older.

The observed risk of bleeding events with clopidogrel plus aspirin versus placebo plus aspirin by age category is provided in Table and Table for the CURE and COMMIT trials, respectively.

No dosage adjustment is necessary in elderly patients.