Clopidogrel (Tablets) Instructions for Use

ATC Code

B01AC04 (Clopidogrel)

Active Substance

Clopidogrel

Clinical-Pharmacological Group

Antiplatelet agent

Pharmacotherapeutic Group

Antithrombotic agents; antiplatelet agents, other than heparin

Pharmacological Action

Mechanism of action and pharmacodynamic effects

Clopidogrel is a prodrug, one of whose active metabolites is an inhibitor of platelet aggregation.

To form the active metabolite, which inhibits platelet aggregation, Clopidogrel must be metabolized by cytochrome P450 (CYP450) system isoenzymes.

The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to the P2Y12 platelet receptor and the subsequent ADP-mediated activation of the GPIIb/IIIa complex, leading to suppression of platelet aggregation.

Due to irreversible binding, platelets remain unresponsive to ADP stimulation for the remainder of their lifespan (approximately 7-10 days), and restoration of normal platelet function occurs at a rate corresponding to the platelet renewal rate.

Platelet aggregation caused by agonists other than ADP is also inhibited due to the blockade of enhanced platelet activation by released ADP.

Since the formation of the active metabolite occurs with the help of cytochrome P450 system isoenzymes, some of which may be polymorphic or inhibited by other drugs, adequate inhibition of platelet aggregation may not be possible in all patients.

With daily administration of clopidogrel at a dose of 75 mg, significant suppression of ADP-induced platelet aggregation is noted from the first day of administration, which gradually increases over 3-7 days and then reaches a constant level (upon reaching steady state).

At steady state, platelet aggregation is suppressed by an average of 40-60%.

After discontinuation of clopidogrel, platelet aggregation and bleeding time gradually return to baseline levels, on average, within 5 days.

Clinical efficacy and safety

The safety and efficacy of clopidogrel were evaluated in 7 double-blind studies involving more than 100,000 patients: the CAPRIE study, comparing clopidogrel with ASA, as well as the CURE, CLARITY, COMMIT, CHANCE, POINT and ACTIVE-A studies, which compared Clopidogrel with placebo; both drugs were prescribed in combination with ASA and other standard therapy.

Recent MI, recent stroke, and diagnosed PAD

The CAPRIE study included 19,185 patients with atherothrombosis manifested as a recent MI (< 35 days), recent ischemic stroke (from 7 days to 6 months), or established PAD.

Patients were randomized to receive Clopidogrel at a daily dose of 75 mg, or ASA at a daily dose of 325 mg, and were followed for 1-3 years.

In the subgroup of patients who had an MI, the majority of patients received ASA during the first few days after the acute MI.

Clopidogrel significantly reduced the incidence of new ischemic events (combined endpoint – MI, stroke and vascular death) compared with ASA.

Analysis of overall mortality, as a secondary endpoint, revealed no significant difference between clopidogrel (5.8%) and ASA (6.0%).

In the subgroup analysis using qualitative assessment of condition (MI, stroke and PAD), the greatest treatment effect was observed in patients enrolled in the study due to PAD (especially those with a history of MI) and a weaker effect (not significantly different from ASA) in patients who had a stroke.

In patients enrolled in the study solely on the basis of a recent MI, the outcome in the clopidogrel group was numerically worse, but not statistically different from ASA.

Furthermore, subgroup analysis by age suggests that the beneficial effect of clopidogrel in patients over 75 years of age was less pronounced than in patients aged ≤ 75 years.

ACS

The CURE study included 12,562 patients with non-ST-segment elevation ACS (unstable angina or non-Q-wave MI) who had chest pain or symptoms suggestive of ischemia within the last 24 hours.

For inclusion in the study, patients were required to have either ECG changes indicating new ischemic events, or elevated levels of cardiac enzymes, or a level of troponin I or T at least twice the upper limit of normal.

Patients were randomized to treatment with clopidogrel (loading dose – 300 mg, then 75 mg/day, n=6259) or placebo (n=6303), which were taken in combination with ASA (75-325 mg once/day) and other standard drugs.

Patients received treatment for a period of up to 1 year.

In the CURE study, 823 patients (6.6%) received concomitant therapy with GPIIb/IIIa receptor antagonists.

Heparin was administered to more than 90% of patients.

Concomitant heparin therapy did not significantly affect the relative incidence of bleeding with clopidogrel and placebo.

The number of patients who had the primary endpoint (death from cardiovascular disease (CVD), MI, or stroke) was 582 (9.3%) in the Clopidogrel group and 719 (11.4%) in the placebo group, and the relative risk was reduced by 20% in the Clopidogrel group (17% relative risk reduction with conservative patient management, 29% with percutaneous transluminal coronary angioplasty (PTCA) with or without stenting, and 10% with CABG).

After 3 months of treatment, the advantage observed in the Clopidogrel + ASA group did not increase further, while the risk of bleeding persisted.

The number of patients with the combined primary endpoint (death from CVD, MI, stroke or refractory ischemia) was 1035 (16.5%) in the Clopidogrel group and 1187 (18.8%) in the placebo group.

No effect on the frequency of rehospitalizations for unstable angina was observed.

The positive effects observed with clopidogrel were not altered by the short-term or long-term use of other cardiovascular drugs (such as heparin/low molecular weight heparin (LMWH), GPIIb/IIIa antagonists, lipid-lowering drugs, beta-blockers and ACE inhibitors).

The efficacy of clopidogrel did not depend on the dose of ASA (75-325 mg once/day).

In patients with acute ST-segment elevation MI, the safety and efficacy of clopidogrel were evaluated in 2 randomized placebo-controlled double-blind studies, CLARITY and COMMIT.

The CLARITY study involved 3491 patients who were hospitalized within 12 hours of the onset of ST-segment elevation MI and who were indicated for thrombolytic therapy.

Patients received Clopidogrel (loading dose – 300 mg, then 75 mg/day, n=1752) or placebo (n=1739), both in combination with ASA (from 150 to 325 mg as a loading dose, then from 75 to 162 mg/day), a fibrinolytic drug and, if necessary, heparin.

Patients were observed for 30 days.

The primary endpoint was the presence of occlusion in the infarct-related coronary artery on the angiogram before discharge, death or recurrent MI before coronary angiography was performed.

For patients who did not undergo angiography, the primary endpoint was death or recurrent MI by day 8 or hospital discharge.

15% of patients in the clopidogrel group and 21.7% in the placebo group reached the primary endpoint, representing an absolute reduction of 6.7% and a 36% reduction difference in favor of clopidogrel).

This was mainly due to a reduction in occlusion in the infarct-related coronary arteries.

This benefit remained constant across all predefined subgroups of patients by age and gender, infarct location, and type of fibrinolytic or heparin used.

The COMMIT study with a 2×2 factorial design included 45,852 patients admitted within 24 hours of the onset of symptoms of suspected MI, confirmed by ECG abnormalities (i.e., ST-segment elevation, ST-segment depression, or left bundle branch block).

Patients received Clopidogrel (75 mg/day, n=22961) or placebo (n=22891) in combination with ASA (162 mg/day) for 28 days or until hospital discharge.

The combined primary endpoints were death from any cause and the development of recurrent infarction, stroke or death.

The population included 27.8% women, 58.4% patients aged 60 years and older (26% ≥70 years) and 54.5% patients receiving fibrinolytics.

Clopidogrel significantly reduced the relative risk of death from any cause by 7% and the relative risk of the combination of recurrent infarction, stroke or death by 9%, representing an absolute reduction of 0.5 and 0.9%, respectively.

This benefit remained constant for patient groups of different ages, genders, receiving or not receiving fibrinolytics, and was observed as early as 24 hours.

De-escalation of P2Y12 receptor inhibitors in ACS therapy

The transition from therapy with a potent P2Y12 receptor inhibitor to treatment with clopidogrel in combination with ASA after the acute phase of acute MI was studied in 2 randomized investigator-initiated clinical trials (TOPIC and TROPICAL-ACS).

The randomized open-label clinical trial TOPIC involved patients who had an acute MI and underwent PCI.

Patients receiving ASA and one of the more potent P2Y12 receptor inhibitors who did not develop adverse events within one month were either switched to therapy with a fixed combination of ASA and clopidogrel (DAPT de-escalation) or continued to take the previously prescribed drugs (unchanged DAPT).

Events included in the combined primary endpoint (death from CVD complications, stroke, emergency revascularization and type 2 or more severe bleeding according to the BARC scale (Bleeding Academic Research Consortium)) at 1 year after acute MI were recorded in 43 of 322 patients (13.4%) in the DAPT de-escalation group and 85 patients out of 323 (26.3%) in the unchanged DAPT group (p< 0.01).

The statistically significant difference is mainly due to a reduction in the number of bleeding cases, including bleeding that was BARC ≥2 (4% in the de-escalation group and 14.9% in the group receiving unchanged DAPT), with no significant differences in the frequency of ischemic complications (p=0.36).

The randomized open-label clinical trial TROPICAL-ACS included 2610 patients with acute MI confirmed by biomarker analysis after PCI.

Patients were randomized to receive prasugrel (days 0-14) or prasugrel (days 0-7) and then clopidogrel (days 8-14) in combination with ASA.

Platelet function was assessed on day 14.

Patients from the first prasugrel-only therapy group continued to take prasugrel for 11.5 months.

In patients from the therapy switch group, an analysis for high platelet reactivity (HPR) was performed.

Patients with HPR ≥46 units were switched back to prasugrel therapy, which they received for 11.5 months.

Patients with HPR< 46 units continued treatment with clopidogrel at a dose of 75 mg/day for 11.5 months.

Thus, in the managed therapy switch group, patients received either prasugrel (40%) or Clopidogrel (60%).

All patients received ASA, follow-up continued for 1 year.

The primary endpoint included a combination of cardiovascular death, MI, stroke and type 2 or more severe bleeding according to the BARC scale.

The study demonstrated no differences between the groups in the primary endpoint according to the non-inferiority criterion.

Managed therapy switching did not lead to an increased risk of ischemic complications (2.5% in the de-escalation group and 3.2% in the control group), nor the frequency of type 2 or more bleeding according to the BARC scale.

DAPT for acute minor ischemic stroke or moderate or high risk TIA

The assessment of DAPT in combination with clopidogrel and ASA for the prevention of stroke after acute minor ischemic stroke or moderate or high risk TIA was conducted in 2 randomized studies: CHANCE and POINT – with data on clinical safety and efficacy outcomes.

CHANCE study (Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events)

This randomized double-blind multicenter placebo-controlled clinical trial involved 5170 patients from China with acute TIA (ABCD2 score ≥4) or acute minor stroke (NIHSS≤ 3).

Patients in both groups received an open-label dose of ASA on day 1 (dose varied in the range from 75 to 300 mg, the dose was set by the attending physician).

Patients randomized to the clopidogrel and ASA group received a loading dose of 300 mg on day 1, then received Clopidogrel at a dose of 75 mg once/day from day 2 to day 90 inclusive, and ASA at a dose of 75 mg once/day from day 2 to day 21 inclusive.

Patients randomized to the ASA group received a placebo version of clopidogrel from day 1 to day 90 inclusive, and ASA at a dose of 75 mg once/day from day 2 to day 90 inclusive.

The primary efficacy endpoint was a new stroke (ischemic or hemorrhagic) within the first 90 days after an acute minor ischemic stroke or high-risk TIA.

Such cases were recorded in 212 patients (8.2%) in the clopidogrel and ASA group compared with 303 patients (11.7%) in the ASA group.

Cases of ischemic stroke were observed in 204 patients (7.9%) in the clopidogrel and ASA group compared with 295 patients (11.4%) in the ASA group.

Hemorrhagic stroke occurred in 8 patients in each of the two study groups (0.3% in each group).

Moderate or severe hemorrhage was observed in 7 patients (0.3%) in the clopidogrel and ASA group and in 8 patients (0.3%) in the ASA group.

The incidence of bleeding was 2.3% in the clopidogrel and ASA group compared with 1.6% in the ASA group.

POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke)

This randomized double-blind multicenter placebo-controlled clinical trial involved 4881 patients from different countries with acute TIA (ABCD2 score ≥4) or acute minor stroke (NIHSS≤ 3).

All patients in both groups received an open-label dose of ASA from day 1 to day 90 (dose varied in the range from 50 to 325 mg, the dose was set by the attending physician).

Patients randomized to the clopidogrel group received a loading dose of clopidogrel 600 mg on day 1, then received Clopidogrel at a dose of 75 mg once/day from day 2 to day 90 inclusive.

Patients randomized to the placebo group received a placebo version of clopidogrel from day 1 to day 90 inclusive.

The primary efficacy endpoint was a combination of major ischemic complications (ischemic stroke, MI, or death from an ischemic vascular complication) by day 90.

Such cases were recorded in 121 patients (5.0%) in the clopidogrel and ASA group compared with 160 patients (6.5%) in the ASA-only group.

Ischemic stroke, a secondary endpoint, was observed in 112 patients (4.6%) receiving Clopidogrel and ASA, compared with 155 patients receiving ASA (6.3%).

Major bleeding, the primary safety endpoint, occurred in 23 of 2432 patients (0.9%) receiving Clopidogrel and ASA, and in 10 of 2449 patients receiving ASA (0.4%).

Minor hemorrhage occurred in 40 patients (1.6%) receiving Clopidogrel and ASA, and in 13 patients receiving ASA (0.5%).

Analysis of the drug action period within the CHANCE and POINT studies

There was no benefit in continuing DAPT beyond 21 days.

Clinical benefit from continuing DAPT beyond 3 weeks was not demonstrated.

The aim of distributing major ischemic complications and cases of major hemorrhage by treatment groups in the drug action period was to analyze the effect of the short-term DAPT action period.

Atrial fibrillation

The ACTIVE-A clinical study showed that in patients with atrial fibrillation who had at least one risk factor for vascular complications but were unable to take vitamin K antagonists, Clopidogrel in combination with ASA (compared with taking ASA alone) reduced the incidence of the combined outcome of stroke, MI, systemic embolism outside the CNS, or vascular death, largely due to a reduction in the risk of stroke.

The efficacy of clopidogrel in combination with ASA was detected early and persisted for up to 5 years.

The reduction in the risk of major vascular complications in the group of patients taking Clopidogrel in combination with ASA was observed mainly due to a greater reduction in the incidence of strokes.

The risk of stroke of any severity when taking clopidogrel in combination with ASA was reduced, and there was also a trend towards a reduction in the incidence of MI in the group receiving treatment with clopidogrel in combination with ASA, but no differences were observed in the frequency of embolisms outside the CNS or vascular death.

In addition, taking clopidogrel in combination with ASA reduced the total number of days of hospitalization for cardiovascular reasons.

Pharmacokinetics

Absorption

After single and repeated oral administration at a dose of 75 mg/day, Clopidogrel is rapidly absorbed.

The mean C_max of unchanged clopidogrel in plasma (approximately 2.2-2.5 ng/ml after a single oral dose of 75 mg) is reached approximately 45 minutes after administration.

According to the excretion of clopidogrel metabolites by the kidneys, its absorption is approximately 50%.

Distribution

In vitro, Clopidogrel and its main circulating inactive metabolite reversibly bind to plasma proteins (98% and 94%, respectively) and this binding is non-saturable up to a concentration of 100 mg/L.

Metabolism

Clopidogrel is extensively metabolized in the liver.

In vitro and in vivo, Clopidogrel is metabolized by two pathways: the first is carried out by esterases and leads to the hydrolysis of clopidogrel to form an inactive carboxylic acid derivative (85% of circulating metabolites); the second pathway is carried out by cytochrome P450 isoenzymes.

Initially, Clopidogrel is metabolized to 2-oxo-clopidogrel, which is an intermediate metabolite.

Subsequent metabolism of 2-oxo-clopidogrel leads to the formation of the active metabolite of clopidogrel – the thiol derivative of clopidogrel.

In vitro, this active metabolite is formed mainly by the CYP2C19 isoenzyme, but other isoenzymes, including CYP1A2, CYP2B6 and CYP3A4, are also involved in its formation.

The active thiol metabolite of clopidogrel, isolated in in vitro studies, rapidly and irreversibly binds to platelet receptors, thus blocking platelet aggregation.

The C_max of the active metabolite of clopidogrel after a single loading dose of 300 mg is twice that after 4 days of administration of clopidogrel at a maintenance dose of 75 mg.

C_max is reached within approximately 30-60 minutes.

Elimination

Within 120 hours after oral administration of ¹⁴C-labeled clopidogrel in humans, approximately 50% of the radioactivity is excreted by the kidneys and approximately 46% of the radioactivity is excreted via the intestine. After a single oral dose of 75 mg, the T_1/2 of clopidogrel is approximately 6 hours. After single and repeated doses, the T_1/2 of the main circulating inactive metabolite in the blood is 8 hours.

Pharmacogenetics

The active metabolite, as well as the intermediate metabolite 2-oxo-clopidogrel, are formed by the CYP2C19 isoenzyme. The pharmacokinetics and antiplatelet effect of the active metabolite of clopidogrel, when studying platelet aggregation ex vivo, vary depending on the CYP2C19 isoenzyme genotype. The CYP2C19*1 gene allele corresponds to fully functional metabolism, whereas the CYP2C19*2 and CYP2C19*3 gene alleles are non-functional. The CYP2C19*2 and CYP2C19*3 gene alleles are responsible for reduced metabolism in the majority of Caucasians (85%) and Mongoloids (99%). Other alleles associated with absent or reduced metabolism are less common and include, but are not limited to, the CYP2C19*4, *5, *6, *7, and *8 gene alleles. Patients with low CYP2C19 isoenzyme activity must possess two of the aforementioned loss-of-function gene alleles. Published frequencies of the poor metabolizer phenotype for the CYP2C19 isoenzyme are 2% in Caucasian patients, 4% in Black patients, and 14% in Mongoloid patients. There are specific tests to determine a patient’s CYP2C19 isoenzyme genotype.

According to a cross-over study (40 volunteers) involving volunteers with ultra-rapid, extensive, intermediate, and poor CYP2C19 metabolizer status, no significant differences in the exposure to the active metabolite and in the mean values of inhibition of ADP-induced platelet aggregation (IPA) were found in volunteers with ultra-rapid, extensive, and intermediate CYP2C19 metabolizer status. In volunteers with poor CYP2C19 metabolizer status, the exposure to the active metabolite was reduced by 63-71% compared to volunteers with extensive CYP2C19 metabolizer status. When using the 300 mg loading dose/75 mg maintenance dose (300 mg/75 mg) regimen in volunteers with poor CYP2C19 metabolizer status, the antiplatelet effect was reduced, with mean IPA values of 24% (at 24 hours) and 37% (on day 5 of the study) compared to IPA values of 39% (at 24 hours) and 58% (on day 5) in volunteers with extensive CYP2C19 metabolizer status, and 37% (at 24 hours) and 60% (on day 5) in volunteers with intermediate CYP2C19 metabolizer status.

When volunteers with poor CYP2C19 metabolizer status received the drug according to the 600 mg loading dose/150 mg maintenance dose (600 mg/150 mg) regimen, the exposure to the active metabolite was higher than with the 300 mg/75 mg regimen. Furthermore, the IPA was 32% (at 24 hours) and 61% (on day 5), which was greater than that in volunteers with poor CYP2C19 metabolizer status treated with the 300 mg/75 mg regimen and was similar to that in patient groups with higher CYP2C19 metabolic activity treated with the 300 mg/75 mg regimen. However, in outcome clinical trials, the dosing regimen of clopidogrel for this patient group (patients with poor CYP2C19 metabolizer status) has not yet been established.

Similarly to the results of this study, a meta-analysis of six studies, which included data from 335 volunteers receiving clopidogrel at steady state, showed that compared to volunteers with extensive CYP2C19 metabolizer status, the exposure to the active metabolite was reduced by 28% in volunteers with intermediate CYP2C19 metabolizer status and by 72% in volunteers with poor CYP2C19 metabolizer status, while the IPA was reduced with differences in IPA of 5.9% and 21.4%, respectively.

The influence of the CYP2C19 genotype on clinical outcomes in patients receiving clopidogrel has not been evaluated in prospective randomized controlled trials. However, several retrospective analyses are available to date. Genotyping results were obtained in the following clinical trials: CURE, CHARISMA, CLARITY-TIMI 28, TRITON-TIMI 38, and ACTIVE-A, as well as in several published cohort studies.

In the TRITON-TIMI 38 study and 3 cohort studies (Collet, Sibbing, Giusti), patients in the combined group with intermediate or poor CYP2C19 metabolizer status had a higher incidence of cardiovascular events (death, myocardial infarction, and stroke) or stent thrombosis compared to patients with extensive CYP2C19 metabolizer status.

In the CHARISMA study and one cohort study (Simon), an increase in the incidence of cardiovascular events was observed only in patients with poor CYP2C19 metabolizer status (when compared to patients with extensive CYP2C19 metabolizer status).

In the CURE, CLARITY, ACTIVE-A studies and one of the cohort studies (Trenk), no increase in the incidence of cardiovascular events was observed depending on CYP2C19 metabolizer status.

Pharmacokinetics in special patient groups

The pharmacokinetics of the active metabolite of clopidogrel have not been studied in special patient groups.

Patients over 75 years of age In volunteers over 75 years of age compared to young volunteers, no differences in platelet aggregation parameters and bleeding time were obtained. Dose adjustment is not required.

Children under 18 years of age Clinical data are lacking.

Patients with impaired renal function. After repeated doses of clopidogrel 75 mg/day in patients with severe renal impairment (CrCl from 5 ml/min to 15 ml/min), inhibition of ADP-induced platelet aggregation was lower (by 25%) compared to healthy volunteers, but the prolongation of bleeding time was similar to that in healthy volunteers receiving clopidogrel 75 mg/day.

Patients with impaired hepatic function. There were no significant differences in the degree of inhibition of ADP-induced platelet aggregation after daily administration of clopidogrel at a dose of 75 mg for 10 days in patients with severe hepatic impairment compared to healthy volunteers. The mean bleeding time was also comparable in both groups.

Race. The prevalence of CYP2C19 isoenzyme gene alleles causing intermediate and poor metabolizer status differs among various racial groups. There is limited literature data on their prevalence in Mongoloids, which does not allow for an assessment of the value of CYP2C19 isoenzyme genotyping for the development of ischemic complications in them.

Indications

Secondary prevention of atherothrombotic complications

• In adult patients after a recent myocardial infarction (from a few days to 35 days ago), a recent ischemic stroke (from 7 days to 6 months ago), or with diagnosed peripheral arterial disease (PAD);
• In adult patients with acute coronary syndrome (ACS):
  • Without ST-segment elevation (unstable angina or non-Q-wave myocardial infarction), including patients scheduled for medical treatment and patients scheduled for percutaneous coronary intervention (PCI) (with or without stenting) or coronary artery bypass grafting (CABG);
  • Acute myocardial infarction with ST-segment elevation, including patients receiving medical treatment, including thrombolytic therapy.

Prevention of atherothrombotic and thromboembolic complications in adult patients with atrial fibrillation

• In adult patients with atrial fibrillation, who have at least one risk factor for vascular complications, who cannot take vitamin K antagonists (VKA) and have a low risk of bleeding, Clopidogrel in combination with acetylsalicylic acid (ASA) is indicated for the prevention of atherothrombotic and thromboembolic events, including stroke.

In adult patients with transient ischemic attack (TIA) of moderate or high risk or with minor stroke (in combination with ASA)

Clopidogrel in combination with ASA is indicated

• In adult patients with moderate or high risk TIA (ABCD2* score ≥4) or with minor stroke (NIHSS** ≤ 3) within 24 hours of the TIA or stroke event.

*ABCD2 score for assessing the risk of early stroke after TIA, based on the following parameters: age, blood pressure, clinical symptoms, duration of TIA, and diabetes.

**National Institutes of Health Stroke Scale.

ICD codes

Dosage Regimen

Tablets

The drug is taken orally, regardless of meals.

Recent myocardial infarction, recent stroke, and diagnosed PAD

The recommended dose is 75 mg once daily.

Acute coronary syndrome without ST-segment elevation (unstable angina, non-Q-wave myocardial infarction)

Treatment with clopidogrel should be started with a single loading dose of 300 mg or 600 mg. A loading dose of 600 mg can be prescribed to patients aged <75 years when PCI is planned. Treatment with clopidogrel should be continued at a dose of 75 mg once daily in combination with ASA at a dose of 75 to 325 mg once daily. Since higher doses of ASA have been associated with a higher risk of bleeding, it is recommended that the ASA dose does not exceed 100 mg. The optimal duration of treatment has not been officially established. Clinical trial data support the possibility of treatment duration up to 12 months; the maximum efficacy of therapy was observed at 3 months of treatment.

Acute myocardial infarction with ST-segment elevation

Clopidogrel is prescribed at a dose of 75 mg once daily with or without a 300 mg loading dose in combination with ASA, and with or without thrombolytic drugs. In patients >75 years of age, treatment with clopidogrel should be started without a loading dose. Combination therapy should be started as early as possible after symptom onset and continued for at least 4 weeks.

Atrial fibrillation

Clopidogrel should be taken at a daily dose of 75 mg.

In combination with clopidogrel, it is necessary to take ASA at a dose of 75-100 mg daily (see the “Pharmacological action” section).

Adult patients with moderate or high risk TIA or with minor stroke

Adult patients with moderate or high risk TIA (ABCD2* score ≥4) or with minor stroke (NIHSS** ≤3) are prescribed a loading dose of clopidogrel 300 mg, after which Clopidogrel is prescribed at a dose of 75 mg once daily and ASA (75-100 mg once daily). Therapy with clopidogrel and ASA should be started within 24 hours of the event and continued for 21 days, after which therapy with a single antiplatelet agent is prescribed.

Pharmacogenetics (patients with genetically determined reduced CYP2C19 isoenzyme activity)

Poor CYP2C19 metabolizer status is associated with a reduced antiplatelet effect of clopidogrel. The use of higher dose regimens (600 mg loading dose, then 150 mg once daily) in patients with poor CYP2C19 metabolizer status increases the antiplatelet effect of clopidogrel (see the “Pharmacokinetics” section, subsection “Pharmacogenetics”). In patients with poor CYP2C19 metabolizer status, the use of higher doses of clopidogrel may be considered. The precise dosing regimen for this patient population in outcome clinical trials has not been established.

Missed dose

If a dose is missed within

• less than 12 hours after the scheduled time patients should take the dose immediately, and then take the next dose at the usual scheduled time;
• more than 12 hours after the scheduled time patients should take the next dose at the usual scheduled time and should not double the dose.

Special patient groups

Patients over 75 years of age. For information on the loading dose for patients >75 years, see the “Special Instructions” section.

Patients with impaired renal function. No dose adjustment is required (see the “Special Instructions” section).

Patients with impaired hepatic function. No dose adjustment is required (see the “Special Instructions” section).

Children under 18 years of age. The safety and efficacy of the drug in children under 18 years of age have not been established.

Adverse Reactions

Summary of the safety profile

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. Overall, the tolerability of clopidogrel 75 mg/day in the CAPRIE study was consistent with that of ASA 325 mg/day, regardless of patient age, gender, or race. Clinically significant adverse effects observed in five large clinical trials: CAPRIE, CURE, CLARITY, COMMIT, and ACTIVE-A are listed below.

Bleeding is the most frequently reported reaction, both in clinical trials and in post-marketing experience with clopidogrel. Bleedings were most frequently reported during the first month of treatment.

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

Overall, the incidence of gastrointestinal bleedings in patients taking Clopidogrel and in patients taking ASA was (2.0% and 2.7% respectively). The overall incidence of bleedings at other sites was higher with clopidogrel compared to ASA (7.3% vs. 6.5% respectively). However, the incidence of severe bleedings with clopidogrel and ASA was comparable (0.6% and 0.4% respectively). The most frequently reported bleedings were: purpura/bruising, epistaxis. Less frequently reported were hematomas, hematuria, and eye hemorrhages (mainly conjunctival).

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

In the CURE clinical trial, in patients taking Clopidogrel + ASA compared to patients taking placebo + ASA, there was an increase in the incidence of major bleedings (3.7% vs. 2.7%) and minor bleedings (5.1% vs. 2.4%). The main sources of major bleedings were the GI tract and arterial puncture sites.

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

The incidence of non-life-threatening major bleedings was significantly higher in patients taking Clopidogrel + ASA compared to patients taking placebo + ASA (1.6% and 1% respectively), but the incidence of intracranial hemorrhages was the same (0.1% with both therapies).

The incidence of major bleedings in the Clopidogrel + ASA group depended on the ASA dose (< 100 mg: 2.6%; 100-200 mg: 3.5%; > 200 mg: 4.9%), as did the incidence of major bleedings in the placebo + ASA group (<100 mg: 2.0%; 100-200 mg: 2.3%; > 200 mg: 4.0%).

In patients who discontinued antiplatelet therapy more than 5 days before CABG, there was no increase in the incidence of major bleedings 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 within the last 5 days before CABG, 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 bleedings (defined as intracranial bleeding or bleeding with a hemoglobin decrease >5 g/dL) in both groups (Clopidogrel + ASA and placebo + ASA) was comparable in both treatment groups (1.3% vs. 1.1% in the Clopidogrel + ASA group and the placebo + ASA group, respectively). It was the same in patient subgroups divided by baseline characteristics and by type of fibrinolytic therapy or heparin therapy.

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

In the COMMIT clinical trial, the overall incidence of non-cerebral major bleedings or cerebral bleedings was low and the same (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 bleedings in the Clopidogrel + ASA group was higher than in the placebo + ASA group (6.7% vs. 4.3% respectively). Major bleedings were mainly extracranial in both groups (5.3% vs. 3.5%), primarily from the GI tract (3.5% vs. 1.8%).

In the Clopidogrel + ASA group, there were more intracranial hemorrhages compared to 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 bleedings (1.1% vs. 0.7%) and hemorrhagic stroke (0.8% vs. 0.6%).

Tabulated summary of adverse reactions

Adverse reactions are listed by system organ class in order of decreasing severity with their frequency of occurrence according to the WHO classification: very common (≥1/10); common (≥1/100 and <1/10); uncommon (≥1/1000 and <1/100); rare (≥1/10000 and <1/1000); very rare (<1/10000), frequency not known (cannot be estimated from the available data).

Description of selected adverse reactions

Neutropenia

In the CAPRIE study, severe neutropenia (<0.45×10⁹/L) was observed 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 myelotoxic effects with clopidogrel is quite low, if a patient taking Clopidogrel develops fever or other signs of infection, they should be examined for possible neutropenia.

Aplastic anemia

One case of aplastic anemia was observed during treatment with clopidogrel.

Thrombocytopenia

The incidence of severe thrombocytopenia (<80×10⁹/L) was 0.2% in patients taking Clopidogrel and 0.1% in patients taking ASA; very rare cases of platelet count reduction ≤30×10⁹/L have been reported.

In the CURE and CLARIFY studies, a comparable number of patients with thrombocytopenia or neutropenia was observed in both treatment groups.

Contraindications

• Hypersensitivity to clopidogrel or any of the excipients of the drug;
• Severe hepatic impairment;
• Active bleeding, such as peptic ulcer bleeding or intracranial hemorrhage;
• Hereditary lactose intolerance, lactase deficiency and glucose-galactose malabsorption (see section "Special Precautions");
• Pregnancy;
• Breast-feeding period;
• Age under 18 years (safety and efficacy have not been established).

With caution

• In moderate hepatic impairment, where there may be a predisposition to bleeding (limited clinical experience);
• In renal impairment (limited clinical experience);
• In conditions with a predisposition to bleeding (in particular, gastrointestinal or intraocular) and especially with the concomitant use of drugs that can cause damage to the gastrointestinal mucosa (such as ASA and NSAIDs);
• In patients with an increased risk of bleeding: due to trauma, surgery or other pathological conditions, as well as in patients receiving therapy with ASA, heparin, warfarin, glycoprotein IIb/IIIa inhibitors, NSAIDs, including selective COX-2 inhibitors, and other drugs associated with a risk of bleeding, selective serotonin reuptake inhibitors (SSRIs) (see section "Drug Interactions");
• With concomitant use with drugs that are substrates of the CYP2C8 isoenzyme (repaglinide, paclitaxel) (see section "Drug Interactions");
• In patients with low activity of the CYP2C19 isoenzyme (see section "Pharmacological Properties" subsection "Pharmacogenetics");;
• With a history of allergic and hematological reactions to other thienopyridines (such as ticlopidine, prasugrel) (possibility of cross-allergic and hematological reactions);
• In patients with recently experienced transient ischemic attack or ischemic stroke (when combined with ASA).

Use in Pregnancy and Lactation

Pregnancy

Animal studies have not revealed any direct or indirect adverse effects on pregnancy, embryonic/fetal development, parturition or postnatal development. Since animal studies are not always predictive of human response, and due to the lack of controlled clinical studies on the use of clopidogrel in pregnant women, as a precautionary measure, the use of Clopidogrel-SZ during pregnancy is not recommended except in cases where, in the physician’s opinion, its use is strongly indicated.

Breast-feeding

Studies in rats have shown that Clopidogrel and/or its metabolites are excreted in breast milk. It is not known whether Clopidogrel is excreted in human breast milk. Since many drugs are excreted in human milk and there is a risk of potential adverse events for the breast-fed child, a decision should be made whether to discontinue breast-feeding or to discontinue the drug, taking into account the importance of the drug to the mother.

Fertility

Animal studies did not reveal any effect of Clopidogrel on fertility.

Use in Hepatic Impairment

The use of the drug is contraindicated in severe hepatic impairment.

The drug should be used with caution in moderate hepatic impairment, where there may be a predisposition to bleeding (limited clinical experience).

Use in Renal Impairment

The drug should be used with caution in renal impairment (limited clinical experience).

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

No dose adjustment is required for patients over 75 years of age.

Special Precautions

Bleeding and hematological disorders

Due to the risk of bleeding and blood disorders (see section "Adverse Reactions"), if clinical symptoms suspicious for bleeding occur during treatment, a complete blood count, APTT, platelet count, platelet function tests and other necessary investigations should be urgently performed.

Clopidogrel, like other antiplatelet agents, should be used with caution in patients with an 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, SSRIs and potent inducers of the CYP2C19 isoenzyme. Due to the increased risk of bleeding, triple antiplatelet therapy (Clopidogrel+ASA+dipyridamole) used for secondary prevention of stroke is not recommended for patients with acute non-cardioembolic ischemic stroke or TIA.

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 occult bleeding. Concomitant use of clopidogrel with oral anticoagulants is not recommended as it may increase the intensity of bleeding (see section "Drug Interactions"). Concomitant use of clopidogrel with warfarin may increase the risk of bleeding, so caution should be exercised when using clopidogrel and warfarin concomitantly (see section "Drug Interactions").

If a patient is to undergo elective surgery and the antiplatelet effect is not desired, clopidogrel should be discontinued 7 days prior to surgery.

Clopidogrel prolongs bleeding time and should be used with caution in patients with conditions predisposing to bleeding (especially gastrointestinal and intraocular).

Drugs that may cause lesions of the gastrointestinal mucosa (such as ASA, NSAIDs) in patients taking Clopidogrel should be used with caution.

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

A loading dose of clopidogrel 600 mg is not recommended for patients with non-ST-elevation ACS aged >75 years due to the increased risk of bleeding in this patient group.

Thrombotic thrombocytopenic purpura (TTP)

Very rarely, cases of thrombotic thrombocytopenic purpura (TTP) have been reported following the use of clopidogrel (sometimes even short-term), 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 requiring immediate treatment, including plasmapheresis.

Acquired hemophilia

Cases of acquired hemophilia have been reported with clopidogrel use. In case of confirmed isolated increase in APTT, with or without bleeding, the possibility of acquired hemophilia should be considered. Patients with a confirmed diagnosis of acquired hemophilia should be managed and treated by specialists for this condition and discontinue clopidogrel.

Recent stroke

Initiation of therapy

• In patients with acute minor ischemic stroke or with moderate or high-risk TIA, dual antiplatelet therapy (DAPT) including Clopidogrel and ASA should be initiated no later than 24 hours after the onset of event symptoms;
• Data on the benefit-risk ratio of short-term DAPT in patients with acute minor ischemic stroke or moderate or high-risk TIA with a history of (non-traumatic) intracranial hemorrhage are lacking;
• Clopidogrel monotherapy in patients with non-minor ischemic stroke should be initiated 7 days after the event onset.

Patients with non-minor ischemic stroke (NIHSS >4)

Due to the lack of data, DAPT is not recommended.

Patients with recent minor ischemic stroke or moderate or high-risk TIA who are indicated for or scheduled for intervention

Data supporting the use of DAPT in patients indicated for carotid endarterectomy or intravascular thrombectomy, or in patients scheduled for thrombolysis or anticoagulant therapy, are lacking. DAPT is not recommended in these situations.

CYP2C19 isoenzyme activity

In patients with low CYP2C19 isoenzyme activity, less of the active metabolite of clopidogrel is formed and its antiplatelet effect is weaker when clopidogrel is used at recommended doses; therefore, when taking the usual recommended doses of clopidogrel for acute coronary syndrome or percutaneous coronary intervention, a higher frequency of cardiovascular complications may occur than in patients with normal CYP2C19 isoenzyme activity.

The use of drugs that induce the activity of the CYP2C19 isoenzyme is expected to increase the concentration of the active metabolite of clopidogrel and increase the risk of bleeding. As a precaution, concomitant use of potent CYP2C19 inducers and Clopidogrel is not recommended.

Tests are available to determine the CYP2C19 genotype, which can be used to assist in the selection of therapeutic strategy. Consideration should be given to using higher doses of clopidogrel in patients with low CYP2C19 activity (see sections "Dosage and Administration", "Pharmacological Properties" subsection "Pharmacogenetics").

Cross-allergic and/or hematological reactions between thienopyridines

A history of previous allergic and/or hematological reactions to other thienopyridines (such as ticlopidine, prasugrel) should be sought in patients, as cross-allergic and/or hematological reactions between thienopyridines have been reported (see section "Adverse Reactions"). Thienopyridines can cause moderate and severe allergic reactions (such as skin rash, angioedema) or hematological reactions (such as thrombocytopenia and neutropenia). Patients who have previously experienced allergic and/or hematological reactions to one drug from the thienopyridine group may have an increased risk of developing similar reactions to another drug from the thienopyridine group. Monitoring for cross-allergic and/or hematological reactions is recommended.

Renal impairment

Experience with clopidogrel in patients with severe renal impairment is limited. Therefore, Clopidogrel should be used with caution in this group of patients.

Hepatic impairment

There is limited experience with clopidogrel in patients with severe liver disease who may be predisposed to hemorrhagic diathesis. Therefore, Clopidogrel should be used with caution in this group of patients.

Excipients

The drug Clopidogrel-SZ contains lactose anhydrous (lactopress anhydrous) (milk sugar). Patients with rare hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this medicine.

The drug Clopidogrel-SZ contains hydrogenated castor oil, which may cause stomach upset and diarrhea.

The drug Clopidogrel-SZ contains aluminum lacquer based on the dye azorubine (carmoisine) E 122, which may cause allergic reactions.

Effect on ability to drive and operate machinery

The drug Clopidogrel-SZ does not significantly affect the ability to drive vehicles and work with machinery requiring increased concentration and speed of psychomotor reactions.

Overdose

Symptoms

Overdose of clopidogrel may lead to prolonged bleeding time with subsequent complications in the form of bleeding development.

Treatment

If bleeding occurs, appropriate therapeutic measures are required. No antidote to clopidogrel has been established. If rapid correction of prolonged bleeding time is required, platelet transfusion is recommended.

Drug Interactions

Drugs associated with a risk of bleeding

There is an increased risk of bleeding due to their potential additive effect with clopidogrel. Treatment should be conducted with caution.

Oral anticoagulants (e.g., warfarin)

Although administration of clopidogrel 75 mg/day did not alter 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 coagulation. Therefore, caution should be exercised when warfarin and clopidogrel are used concomitantly.

Glycoprotein IIb/IIIa Receptor Blockers

Due to the possibility of a pharmacodynamic interaction between clopidogrel and glycoprotein IIb/IIIa receptor blockers, their concomitant use requires caution, especially in patients with an increased risk of bleeding (due to trauma, surgery, or other pathological conditions) (see the “Special Instructions” section).

Acetylsalicylic Acid (ASA)

ASA does not alter the inhibitory effect of clopidogrel on ADP-induced platelet aggregation, but clopidogrel potentiates the effect of ASA on collagen-induced platelet aggregation. However, concomitant administration of clopidogrel with ASA at 500 mg twice daily for one day did not cause a significant increase in the bleeding time induced by clopidogrel. Since a pharmacodynamic interaction between clopidogrel and ASA is possible, which may lead to an increased risk of bleeding, caution should be exercised when they are used concomitantly. Nevertheless, in clinical trials, patients received combination therapy with clopidogrel and ASA (75-325 mg once daily) for up to one year.

Heparin

According to a clinical study in healthy volunteers, clopidogrel administration did not necessitate a change in the heparin dose and did not alter its anticoagulant effect. Concomitant use of heparin did not change the antiplatelet effect of clopidogrel. A pharmacodynamic interaction between clopidogrel and heparin is possible, which may increase the risk of bleeding. Caution should be exercised during concomitant use.

Thrombolytics

The safety of the concomitant use of clopidogrel, fibrin-specific or fibrin-non-specific thrombolytic agents, and heparin was studied in patients with acute myocardial infarction. The incidence of clinically significant bleeding was similar to that observed with the concomitant use of thrombolytic agents and heparin with ASA.

NSAIDs

In a clinical study in healthy volunteers, concomitant use of clopidogrel and naproxen increased occult gastrointestinal blood loss. However, due to the lack of interaction studies between clopidogrel and other NSAIDs, it is currently unknown whether there is an increased risk of gastrointestinal bleeding when clopidogrel is taken with other NSAIDs. Therefore, caution should be exercised when NSAIDs, including COX-2 inhibitors, are used concomitantly with clopidogrel (see the “Special Instructions” section).

Selective Serotonin Reuptake Inhibitors (SSRIs)

Since SSRIs impair platelet activation and increase the risk of bleeding, caution should be exercised during concomitant use.

Inducers of the CYP2C19 Isoenzyme

Since clopidogrel is metabolized to its active metabolite partly via the CYP2C19 isoenzyme, it is expected that the use of drugs that induce the activity of this isoenzyme may lead to an increased concentration of the active metabolite of clopidogrel. Rifampicin, being a potent inducer of the CYP2C19 isoenzyme, when used concomitantly with clopidogrel, leads to both an increase in the concentration of the active metabolite of clopidogrel and inhibition of platelet aggregation, which may increase the risk of bleeding. As a precaution, the concomitant use of potent inducers of the CYP2C19 isoenzyme and clopidogrel is not recommended.

Inhibitors of the CYP2C19 Isoenzyme

Since clopidogrel is metabolized to its active metabolite partly via 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 precaution, the concomitant use of clopidogrel and potent or moderate inhibitors of the CYP2C19 isoenzyme should be avoided. Potent and moderate inhibitors of the CYP2C19 isoenzyme include omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine, chloramphenicol.

Proton Pump Inhibitors

Concomitant administration of clopidogrel with omeprazole at a dose of 80 mg (simultaneously or with a 12-hour interval between the two drugs) reduces the exposure of the active metabolite of clopidogrel by 45% when a loading dose is administered and by 40% when a maintenance dose is administered. This reduction was associated with a 39% decrease in platelet aggregation inhibition (PAI) with the loading dose and a 21% decrease with the maintenance dose. Esomeprazole is presumed to interact with clopidogrel in a similar manner.

Observational data and clinical studies on the consequences of these pharmacokinetic and pharmacodynamic interactions in terms of major cardiovascular events are conflicting. As a precaution, the concomitant use of clopidogrel with omeprazole or esomeprazole is not recommended.

A less pronounced reduction in metabolite exposure was observed when the drug was taken with pantoprazole and lansoprazole.

When pantoprazole was taken concomitantly at a dose of 80 mg once daily, the concentration of the active metabolite of clopidogrel decreased by 20% with the loading dose and by 14% with the maintenance dose. This was accompanied by a decrease in the mean PAI level by 15% and 11%, respectively. These results indicate the possibility of concomitant use of clopidogrel and pantoprazole.

A number of clinical studies have been conducted with clopidogrel and other concomitantly used drugs to investigate possible pharmacodynamic and pharmacokinetic interactions, which showed that

• No clinically significant pharmacodynamic interaction was observed when clopidogrel was used concomitantly with atenolol and/or nifedipine;
• Concomitant use of phenobarbital and estrogens did not significantly affect the pharmacodynamics of clopidogrel;
• The pharmacokinetic parameters of digoxin and theophylline were not altered when they were used concomitantly with clopidogrel;
• There is no evidence that other drugs that reduce gastric acidity, such as histamine H₂-receptor blockers or antacids, interfere with the antiplatelet activity of clopidogrel; antacids do not reduce the absorption of clopidogrel;
• phenytoin and tolbutamide can be safely used concomitantly with clopidogrel (CAPRIE study). It is unlikely that clopidogrel affects the metabolism of other drugs such as phenytoin and tolbutamide, as well as NSAIDs, which are metabolized by the cytochrome P450 CYP2C9 isoenzyme;
• No clinically significant adverse interaction was identified in clinical studies with ACE inhibitors, diuretics, beta-blockers, calcium channel blockers, lipid-lowering agents, coronary vasodilators, hypoglycemic agents (including insulin), antiepileptic drugs, hormone replacement therapy, and GPIIb/IIIa receptor blockers.

Drugs that are Substrates of the CYP2C8 Isoenzyme

Clopidogrel has been shown to increase the systemic exposure of repaglinide in healthy volunteers. In vitro studies have shown that the increase in systemic exposure of repaglinide is a result of inhibition of the CYP2C8 isoenzyme by the glucuronide metabolite of clopidogrel. Caution should be exercised when clopidogrel is used concomitantly with drugs metabolized by the CYP2C8 isoenzyme (e.g., repaglinide, paclitaxel) due to the risk of increased plasma concentrations.

Opioid Agonists

As with other oral P2Y12 inhibitors, concomitant use of opioid agonists may delay and reduce the absorption of clopidogrel, probably due to delayed gastric emptying. The clinical significance of this interaction is unknown. Consideration should be given to the administration of a parenteral antiplatelet agent in patients with acute coronary syndrome who require concomitant use of morphine or other opioid agonists.

Rosuvastatin

Clopidogrel has been shown to increase the exposure (AUC) of rosuvastatin by 2 times and C_max by 1.3 times after a single 300 mg dose of clopidogrel, and by 1.4 times for AUC without affecting C_max after repeated administration of clopidogrel at a dose of 75 mg.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.