Coplavix^® (Tablets) Instructions for Use

Marketing Authorization Holder

Sanofi Winthrop Industrie (France)

Manufactured By

Sanofi Winthrop Industrie (France)

Contact Information

SANOFI

ATC Code

B01AC30 (Platelet aggregation inhibitors in combination)

Active Substances

Acetylsalicylic acid (Ph.Eur.)

Clopidogrel (Rec.INN)

Dosage Form

Coplavix®

Film-coated tablets, 100 mg+75 mg: 7, 14, 28, or 100 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets light pink in color, oval, biconvex, with an engraving “C75” on one side and “A100” on the other side.

Excipients : mannitol, macrogol 6000, microcrystalline cellulose (90 μm), low-substituted hydroxypropyl cellulose, hydrogenated castor oil, stearic acid, colloidal silicon dioxide, corn starch.

Film coating composition pink dye*, carnauba wax.

* the ready-made pink dye contains lactose monohydrate, hypromellose, titanium dioxide (E171), triacetin, iron oxide red dye (E172). Opadry^® II pink 32K24375 of identical composition may be used.

7 pcs. – PA/Al/PVC//Aluminum blisters (1) – cardboard packs.
7 pcs. – PA/Al/PVC//Aluminum blisters (2) – cardboard packs.
7 pcs. – PA/Al/PVC//Aluminum blisters (4) – cardboard packs.
10 pcs. – PA/Al/PVC//Aluminum blisters (10) – cardboard packs.

Clinical-Pharmacological Group

Antiplatelet agent

Pharmacotherapeutic Group

Antiaggregant agent

Pharmacological Action

Pharmacodynamics

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 ADP to the platelet P2Y₁₂ receptor and the subsequent ADP-mediated activation of the glycoprotein IIb/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 rate of platelet renewal.

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 involves 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, 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.

Acetylsalicylic acid (ASA) has an antiplatelet action mechanism that differs from and complements that of clopidogrel. ASA inhibits platelet aggregation by irreversibly inhibiting prostaglandin COX-1 and consequently reducing the formation of thromboxane A₂, which is an inducer of platelet aggregation and vasoconstriction. This effect lasts for the entire lifespan of the platelets.

ASA does not alter the inhibitory effect of clopidogrel on ADP-induced platelet aggregation, while clopidogrel enhances the effect of ASA on collagen-induced platelet aggregation.

Both active substances, in monotherapy and when used concomitantly, are capable of preventing the development of atherothrombosis in any location of atherosclerotic vascular lesions, particularly in lesions of cerebral, coronary, or peripheral arteries.

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 indirect anticoagulants, clopidogrel in combination with ASA (compared with taking ASA alone) reduced the incidence of the combined endpoint of stroke, myocardial infarction, systemic embolism outside the CNS vessels, or vascular death, largely due to a reduction in the risk of stroke.

The benefit of taking clopidogrel in combination with ASA compared with taking ASA in combination with placebo was detected early and persisted throughout the study period (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 mainly due to a greater reduction in the incidence of strokes.

The risk of stroke of any severity was reduced with clopidogrel in combination with ASA, and there was also a trend towards a reduction in the incidence of myocardial infarction in the group receiving clopidogrel in combination with ASA, but no differences were observed in the frequency of embolism outside the CNS vessels or death from vascular causes. Furthermore, the use of clopidogrel in combination with ASA reduced the total number of days of hospitalization for cardiovascular pathology.

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

The randomized open-label clinical trial TOPIC involved patients who had undergone AMI and had percutaneous coronary intervention (PCI). Patients receiving ASA and one of the more potent P2Y12 receptor inhibitors were switched within one month to therapy with a fixed combination of ASA and clopidogrel (de-escalation of dual antiplatelet therapy (DAPT)) or continued to take the previously prescribed drugs (unchanged DAPT).

Death from cardiovascular complications, stroke, emergency revascularization, and BARC type 2 or more severe bleeding one year after AMI were registered in 13.4% of patients in the DAPT de-escalation group and in 26.3% of patients in the unchanged DAPT group (p<0.01).

The statistically significant difference is mainly due to a reduction in the number of bleeding cases in the DAPT de-escalation group.

The randomized open-label clinical trial TROPICAL-ACS included 2610 patients with biomarker-confirmed AMI after PCI. Patients were randomized to groups to receive prasugrel (days 0-14) or prasugrel (days 0-7) and then clopidogrel (days 8-14) in combination with ASA. Patients in the switching group were tested for high platelet reactivity.

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

Guided switching of therapy from prasugrel to clopidogrel did not lead to an increased risk of cardiovascular death, AMI, and stroke (2.5% in the DAPT de-escalation group and 3.2% in the control group), nor in the frequency of BARC type 2 or more severe bleeding.

Pharmacokinetics

Absorption

Clopidogrel

After single and repeated oral administration at a dose of 75 mg/day, clopidogrel is rapidly absorbed from the intestine. 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 min after its single administration. According to the excretion of clopidogrel metabolites by the kidneys, its absorption is approximately 50%.

ASA

After absorption, ASA undergoes hydrolysis to form salicylic acid, the C_max of which in plasma is reached 1 hour after ASA administration. Due to rapid hydrolysis, 1.5-3 hours after oral administration of the drug Coplavix^®, ASA is practically undetectable in plasma.

Distribution

Clopidogrel

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

ASA

ASA is weakly bound to plasma proteins and has a small V_d(10 L). Its metabolite, salicylic acid, is highly bound to plasma proteins, but its binding to plasma proteins depends on its plasma concentration (non-linear binding). At low concentrations (<100 µg/ml), about 90% of salicylic acid is bound to plasma albumin. Salicylic acid is well distributed in tissues and body fluids, including the CNS, breast milk, and fetal tissues.

Metabolism

Clopidogrel

Clopidogrel is extensively metabolized in the liver. In vitro and in vivo, clopidogrel is metabolized via two metabolic pathways. The first pathway: metabolism is carried out by enzymes (esterases), leading to hydrolysis with the formation of an inactive metabolite – a carboxylic acid derivative (accounts for 85% of the metabolites circulating in the systemic bloodstream). The second pathway: metabolism by several cytochrome P450 system isoenzymes. In this case, clopidogrel is first 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 – a thiol derivative of clopidogrel. The active metabolite is formed mainly by CYP2C19 with the participation of some other isoenzymes, including CYP1A2, CYP2B6, and CYP3A4. The active thiol metabolite of clopidogrel, which was isolated in in vitro studies, rapidly and irreversibly binds to platelet receptors, inhibiting platelet aggregation.

After administration of a clopidogrel loading dose of 300 mg, the C_max of the active metabolite is 2 times higher than that after administration of a clopidogrel maintenance dose of 75 mg for 4 days, and its C_max is reached approximately 30-60 minutes after clopidogrel administration.

ASA

ASA, when taken in combination with clopidogrel, is rapidly hydrolyzed in plasma to salicylic acid with a T_1/2 of 0.3-0.4 hours for ASA doses of 75-100 mg. Salicylic acid is mainly conjugated in the liver to form salicyluric acid, phenolic glucuronide, and acyl glucuronide, as well as a large number of minor metabolites.

Excretion

Clopidogrel

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

ASA

When taking the drug Coplavix^®, salicylic acid has a T_1/2 from plasma of approximately 2 hours. The metabolism of salicylate is saturable, and the total clearance decreases at higher serum concentrations due to the limited ability of the liver to form salicyluric acid and phenolic glucuronide. After taking toxic doses of ASA (10-20 g), the plasma T_1/2 can increase to 20 hours. At high doses of ASA, the elimination of salicylic acid follows zero-order kinetics (i.e., the elimination rate depends on plasma concentration) with a T_1/2 of 6 hours or more.

Renal excretion of the unchanged active substance depends on urine pH. When the pH increases above 6.5, the renal clearance of free salicylate increases from <5% to >80%. After taking therapeutic doses, approximately the following is found in the urine: 10% of the administered dose as salicylic acid, 75% of the administered dose as salicyluric acid, 10% of the administered dose as phenolic glucuronides, and 5% of the administered dose as acyl glucuronides.

Pharmacogenetics

The isoenzyme CYP2C19 is involved in the formation of both the active metabolite and the intermediate metabolite, 2-oxo-clopidogrel. The pharmacokinetics and antiplatelet effect of the active metabolite of clopidogrel, when studying platelet aggregation ex vivo (in vitro study of platelet aggregation in blood taken from a patient taking clopidogrel orally, i.e., after metabolism of clopidogrel in the body), vary depending on the CYP2C19 isoenzyme genotype. The CYP2C19*1 gene allele corresponds to fully functional metabolism, while the CYP2C19*2 and CYP2C19*3 gene alleles are non-functional. The CYP2C19*2 and CYP2C19*3 gene alleles are the cause of 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 have two of the aforementioned loss-of-function gene alleles. The published frequency of the phenotype of individuals with low CYP2C19 isoenzyme activity is 2% in Caucasians, 4% in Negroids, and 14% in Mongoloids. Appropriate tests exist to determine a patient’s CYP2C19 isoenzyme genotype.

According to a crossover study (40 healthy volunteers) and a meta-analysis of 6 studies (335 volunteers taking clopidogrel), which included individuals with very high, high, intermediate, and low CYP2C19 isoenzyme activity, no significant differences in the exposure of the active metabolite and in the mean values of inhibition of platelet aggregation (IPA) (ADP-induced) were found in healthy volunteers with very high, high, and intermediate CYP2C19 isoenzyme activity. In healthy volunteers with low CYP2C19 isoenzyme activity compared to healthy volunteers with high CYP2C19 isoenzyme activity, the exposure of the active metabolite was reduced.

When volunteers with low CYP2C19 isoenzyme activity took clopidogrel according to the regimen: 600 mg loading dose/150 mg maintenance dose (600 mg/150 mg), the exposure of the active metabolite was higher than when taking the 300 mg/75 mg regimen. Furthermore, the IPA was similar to that in the groups of patients with higher CYP2C19 isoenzyme metabolic intensity taking clopidogrel according to the 300 mg/75 mg regimen. However, in studies considering clinical outcomes, the clopidogrel dosage regimen for this group of patients (patients with low CYP2C19 isoenzyme activity) has not yet been established. This is because the clinical studies conducted to date have not had a sufficient sample size to detect differences in clinical outcomes in patients with low CYP2C19 isoenzyme activity.

Special Patient Groups

The pharmacokinetics of the active metabolite of clopidogrel in individual patient groups has not been studied.

Patients over 75 years old. In volunteers over 75 years old compared with young volunteers, no differences were obtained in platelet aggregation parameters and bleeding time. No dose adjustment is required for elderly persons.

Children under 18 years of age. Data are absent.

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

Patients with impaired liver function. After daily administration for 10 days of clopidogrel at a daily dose of 75 mg in patients with severe liver impairment (more than 9 points on the Child-Pugh scale), inhibition of ADP-induced platelet aggregation was similar to that in healthy volunteers. The mean bleeding time was also comparable in both groups.

Ethnicity. The prevalence of CYP2C19 isoenzyme gene alleles responsible for intermediate and reduced metabolism differs among representatives of various ethnic groups. There are limited literature data on their prevalence among Mongoloids, which does not allow assessing the clinical significance of the influence of CYP2C19 isoenzyme genotypes on clinical outcomes.

Based on the pharmacokinetics and metabolism characteristics of both active substances of the drug Coplavix^®, no clinically significant pharmacokinetic interaction between them is expected.

Indications

The combination drug is indicated for use in patients who are already receiving clopidogrel and acetylsalicylic acid simultaneously.

Secondary prevention of atherothrombotic complications

In adult patients with acute coronary syndrome

• Without ST-segment elevation (unstable angina or myocardial infarction without Q-wave), including patients who underwent stenting during percutaneous coronary intervention;
• With ST-segment elevation (acute myocardial infarction) during drug treatment and the possibility of thrombolysis.

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

It has been shown that in patients with atrial fibrillation at increased risk of vascular complications, therapy with indirect anticoagulants, which are vitamin K antagonists (VKA), is associated with greater clinical benefit compared with the use of ASA alone or the combination of clopidogrel with ASA in reducing the risk of stroke.

For patients with atrial fibrillation who have at least one risk factor for vascular complications and who cannot take VKAs (for example, due to a particular risk of bleeding, the patient’s inability, in the opinion of the treating physician, to adequately control INR, or in case of patient refusal of VKA treatment), to prevent atherothrombotic and thromboembolic complications, including stroke, the administration of clopidogrel in combination with ASA is indicated.

It has been shown that clopidogrel in combination with ASA reduced the incidence of the combined endpoint, which included stroke, myocardial infarction, systemic embolism outside the CNS, or cardiovascular death, mainly due to a reduction in the incidence of stroke.

ICD codes

Dosage Regimen

Orally, regardless of food intake, once daily.

The drug Coplavix^® is used after the initiation of treatment with clopidogrel and acetylsalicylic acid (ASA) as separate drugs in appropriate doses and replaces the intake of separate clopidogrel and ASA drugs.

Adults and patients over 75 years of age with normal CYP2C19 isoenzyme activity

Acute coronary syndrome (ACS)

Treatment should be started as early as possible after the onset of symptoms.

Coplavix^® should be taken as 1 tablet once daily. The intake of Coplavix^® is started after taking a single loading dose of clopidogrel in combination with ASA as separate drugs, namely – clopidogrel at a dose of 300 mg and ASA at doses of 75-325 mg/day, and in acute ST-segment elevation myocardial infarction – in combination with or without thrombolytics. Since the use of higher doses of ASA is associated with an increased risk of bleeding, the recommended dose of ASA for this indication should not exceed 100 mg. In acute ST-segment elevation myocardial infarction in patients over 75 years of age, treatment with clopidogrel should be started without a loading dose.

In patients with non-ST-segment elevation ACS (unstable angina or non-Q-wave myocardial infarction), the maximum beneficial effect is observed by the 3rd month of treatment.

The optimal duration of treatment has not been officially established. Clinical trial data support taking the drug for up to 12 months.

In patients with acute ST-segment elevation myocardial infarction, treatment should be continued for at least 4 weeks.

Atrial fibrillation

Coplavix^® should be taken as 1 tablet once daily, after initiation of treatment with clopidogrel 75 mg and ASA 100 mg as separate drugs.

Patients with genetically determined reduced CYP2C19 isoenzyme activity

Low CYP2C19 isoenzyme activity is associated with a reduction in the antiplatelet effect of clopidogrel. The use of higher doses of clopidogrel (600 mg – loading dose, then – 150 mg once daily) in patients with low CYP2C19 isoenzyme activity increases the antiplatelet effect of clopidogrel. However, currently, clinical trials considering clinical outcomes have not established the optimal dosing regimen of clopidogrel for patients with its reduced metabolism due to genetically determined low CYP2C19 isoenzyme activity.

Special patient groups

Safety and efficacy in children have not been established to date.

In elderly patients, no dose adjustment is required.

Patients with hepatic impairment. Therapeutic experience with the drug is limited to its use in patients with moderate liver disease, who may be prone to developing hemorrhagic diathesis. Therefore, caution should be exercised when using Coplavix^® in such patients.

Patients with renal impairment. There is limited therapeutic experience with the drug in patients with mild to moderate renal impairment. Therefore, caution should be exercised when using Coplavix^® in such patients.

Adverse Reactions

The safety of clopidogrel in clinical trials has been studied in more than 44,000 patients, including more than 12,000 patients who took it for a year or more, and 30,000 patients who took clopidogrel and ASA simultaneously; in the CURE clinical trial, the safety of clopidogrel in combination with ASA was assessed in more than 6,200 patients who took them for 1 year or more.

Clinically significant adverse effects observed in five large clinical trials: CAPRIE, CURE, CLARITY, COMMIT, and ACTIVE A, and during post-marketing use of the clopidogrel+ASA combination, clopidogrel as monotherapy, and ASA as monotherapy are listed below.

Bleeding and hemorrhages were the most frequently observed adverse events in clinical trials and post-marketing use of the drug, mainly occurring during the first month of treatment.

The frequency of major bleeding with the clopidogrel+ASA combination depended on the ASA dose (<100 mg – 2.6%; 100-200 mg – 3.5%, >200 mg – 4.9%), as did their frequency with ASA alone (<100 mg – 2%, 100-200 mg – 2.3%, >200 mg – 4%).

In patients who discontinued treatment more than 5 days before coronary artery bypass grafting, there was no increase in the incidence of major bleeding within 7 days after this intervention (4.4% – with the clopidogrel + ASA combination versus 5.3% – with ASA alone). In patients who remained on antiplatelet therapy within the last 5 days before coronary artery bypass grafting, the frequency of these bleedings after the intervention was 9.6% (clopidogrel + ASA combination) and 6.3% (ASA monotherapy).

Although the risk of myelotoxic effects with clopidogrel is quite low, its possibility should be considered when a patient taking clopidogrel develops fever and other infectious manifestations; fatal bleedings¹.

The frequency of occurrence of side effects was determined 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 unknown (cannot be calculated from the available data).

Blood and lymphatic system disorders common – major bleedings¹ [life-threatening bleedings requiring transfusion of 4 or more units of blood; other major bleedings requiring transfusion of 2-3 units of blood; non-life-threatening major bleedings (according to the COMMIT study, the frequency of major non-cerebral bleedings and intracranial hemorrhages was “uncommon”)¹; minor bleedings (according to the ACTIVE-A study, the frequency of minor bleedings was “very common”)¹]; bleeding at the site of vascular puncture^1,2; bruising²; hematomas², leukopenia¹; uncommon – decrease in platelet count in peripheral blood¹, severe thrombocytopenia with platelet count in peripheral blood ≤80×10⁹/L, but >30×10⁹/L¹, decrease in neutrophil count in peripheral blood¹, eosinophilia¹, prolonged bleeding time¹; rare – neutropenia¹, including severe neutropenia (<0.45×10⁹/L)¹, life-threatening bleedings [bleedings with a decrease in blood hemoglobin of more than 5 g/dL (according to the CLARITY clinical trial, their frequency of development was “common”)¹; bleedings requiring surgical intervention¹; intracranial hemorrhages (hemorrhagic strokes) (according to the CLARITY clinical trial, their frequency of development was “common”)¹; bleedings requiring the administration of inotropic drugs]¹; severe bleedings (most commonly observed were purpura, nosebleeds; less commonly hematuria and intraocular hemorrhages, mainly conjunctival²), intraocular hemorrhages with significant visual impairment¹, retroperitoneal hemorrhages¹; very rare – aplastic anemia¹, severe thrombocytopenia with platelet count in peripheral blood ≤30×10⁹/L¹; frequency unknown (post-marketing experience) – thrombocytopenia³, hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency³, agranulocytosis^2,3; aplastic anemia^2,3/pancytopenia^2,3, bicytopenia³, bone marrow hematopoiesis disorders³, neutropenia³, leukopenia³, granulocytopenia³, anemia¹, acquired hemophilia A², thrombotic thrombocytopenic purpura (TTP)², serious cases of bleeding², mainly hemorrhages into skin tissues², into bones, muscles and joint cavity (hemarthrosis)², into eye tissues (conjunctival, into internal media and retina)², bleeding from the respiratory tract², hemoptysis², epistaxis², hematuria², bleeding from the surgical wound²; intracranial hemorrhages³, including fatal cases³, especially in elderly patients; other cases of fatal bleeding (in particular, gastrointestinal bleeding and retroperitoneal hemorrhages)².

Central and peripheral nervous system disorders uncommon – headache¹, dizziness¹ and paresthesia¹; rare – vertigo¹; frequency unknown (post-marketing experience) – taste perversion², ageusia.

Gastrointestinal system disorders common – gastrointestinal bleeding¹, dyspepsia¹, abdominal pain¹, diarrhea¹; uncommon – nausea¹, gastritis¹, flatulence¹, constipation¹, vomiting¹, gastric ulcer¹ and duodenal ulcer¹; frequency unknown (post-marketing experience) – colitis^2,3 (including ulcerative or lymphocytic colitis)², pancreatitis², stomatitis², esophagitis³, esophageal ulceration/perforation³, erosive gastritis³, erosive duodenitis³, gastric and/or duodenal ulcer or ulcer perforation³, symptoms of upper gastrointestinal tract lesions such as gastralgia³, small intestine ulcers (jejunum and ileum)³ and large intestine ulcers (colon and rectum)³, intestinal perforation³ (these reactions may or may not be accompanied by bleeding and can occur with any dose of ASA, as well as in patients both with and without warning symptoms and a history of serious gastrointestinal complications); acute pancreatitis, as a manifestation of a hypersensitivity reaction to acetylsalicylic acid³.

Hepatobiliary disorders: frequency unknown (post-marketing experience) – hepatitis (non-infectious)², acute liver failure², increased activity of liver enzymes³, liver damage, mainly hepatocellular³, chronic hepatitis³.

Skin and subcutaneous tissue disorders: uncommon – skin rash¹, pruritus¹; frequency unknown (post-marketing experience) – maculopapular, erythematous or exfoliative skin rash², urticaria², pruritus², angioedema², bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis)², acute generalized exanthematous pustulosis², drug hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS syndrome)², eczema², lichen planus², fixed skin rash (single or multiple skin changes, usually in the form of erythematous plaques of round or oval shape, appearing in the same place upon repeated administration of the drug)³.

Immune system disorders: frequency unknown (post-marketing experience) – anaphylactoid reactions², serum sickness², cross-hypersensitivity reactions with other thienopyridines (such as ticlopidine, prasugrel)², anaphylactic shock³, exacerbation of food allergy symptoms³, autoimmune insulin syndrome (may lead to serious hypoglycemia, especially in patients with HLA DRA4 serotype)².

Psychiatric disorders: frequency unknown (post-marketing experience) – confusion², hallucinations².

Vascular disorders frequency unknown (post-marketing experience) – vasculitis^2,3, including Henoch-Schönlein purpura³, decreased blood pressure².

Cardiac disorders: frequency unknown (post-marketing experience) – Kounis syndrome (vasospastic allergic angina/allergic myocardial infarction), caused by a hypersensitivity reaction to acetylsalicylic acid and clopidogrel ^2,3.

Respiratory system disorders: frequency unknown (post-marketing experience) – bronchospasm², interstitial pneumonitis², eosinophilic pneumonia², non-cardiogenic pulmonary edema with long-term use of the drug, associated with a hypersensitivity reaction³.

Musculoskeletal and connective tissue disorders: frequency unknown (post-marketing experience) – arthralgia², arthritis², myalgia².

Renal and urinary disorders: frequency unknown (post-marketing experience) – glomerulopathy, including glomerulonephritis², renal failure³, acute renal impairment (especially in patients with pre-existing renal failure, decompensated chronic heart failure, nephrotic syndrome, or in patients simultaneously taking diuretics)³.

Reproductive system and breast disorders: frequency unknown (post-marketing experience) – gynecomastia².

General disorders and administration site conditions: frequency unknown (post-marketing experience) – fever².

Ear and labyrinth disorders: frequency unknown (post-marketing experience) – hearing loss³, tinnitus³.

Metabolism and nutrition disorders: frequency unknown (post-marketing experience) – hypoglycemia³, gout³.

Investigations: frequency unknown (post-marketing experience) – abnormal liver function tests², increased blood creatinine concentration².

General disorders and administration site conditions edema, reported with high (anti-inflammatory) doses of ASA (≥1.5 g/day).

¹ Adverse effects observed with the use of the clopidogrel and ASA combination.

² Adverse effects observed with the use of clopidogrel.

³ Adverse effects observed with the use of ASA.

Contraindications

• Hypersensitivity to any of the active or auxiliary substances of the drug;
• Severe hepatic impairment (more than 9 points on the Child-Pugh scale);
• Severe renal failure (CrCl <30 ml/min) – due to the content of acetylsalicylic acid in the drug;
• Acute bleeding, for example, bleeding from a peptic ulcer or intracranial hemorrhage;
• Bronchial asthma induced by the intake of salicylates and other NSAIDs, syndrome of bronchial asthma, rhinitis and recurrent polyposis of the nose and paranasal sinuses, hypersensitivity to NSAIDs (due to the content of ASA in the drug);
• Mastocytosis, in which the use of ASA can cause severe hypersensitivity reactions, including the development of shock with skin hyperemia, decreased blood pressure, tachycardia and vomiting (due to the content of ASA in the drug);
• Rare hereditary conditions: galactose intolerance, lactose intolerance due to lactase deficiency, glucose-galactose malabsorption syndrome (due to the lactose content in the drug);
• Pregnancy;
• Breastfeeding period;
• Children under 18 years of age (safety and efficacy of use have not been established).

With caution

• In moderate hepatic impairment (7-9 points on the Child-Pugh scale), in which there may be a predisposition to bleeding (limited clinical experience of use).
• In mild to moderate renal impairment with CrCl 60-30 ml/min (limited clinical experience of use).
• In trauma, surgical interventions, including invasive cardiological procedures or surgical interventions (see section “Special Instructions”).
• In diseases where there is a predisposition to the development of bleeding, especially intraocular or gastrointestinal (with peptic ulcer of the stomach and duodenum or a history of gastrointestinal bleeding, with symptoms of upper gastrointestinal tract disorders).
• In recently suffered transient ischemic attack or ischemic stroke (see section “Special Instructions”).
• With simultaneous use of NSAIDs, including selective COX-2 inhibitors (see section “Drug Interactions”).
• With simultaneous use of warfarin, heparin, glycoprotein IIb/IIIa inhibitors, selective serotonin reuptake inhibitors and thrombolytic drugs (see sections “Drug Interactions” and “Special Instructions”).
• In bronchial asthma and a history of allergies (increased risk of developing allergic reactions to ASA).
• In gout, hyperuricemia (ASA, including in low doses, increases the concentration of uric acid in the blood).
• In patients with genetically determined reduced activity of the CYP2C19 isoenzyme (see section “Pharmacokinetics” subsection “Pharmacogenetics”, sections “Dosage Regimen” and “Special Instructions”).
• In case of a history indicating allergic and hematological reactions to other thienopyridines (such as ticlopidine, prasugrel) due to the possibility of cross-allergic and hematological reactions (see section “Special Precautions”).
• With concurrent use of methotrexate at a dose of more than 20 mg per week (see section “Drug Interactions”).
• With concurrent use of medicinal products associated with a risk of bleeding and medicinal products that are substrates of the CYP2C8 isoenzyme (such as repaglinide, paclitaxel) due to identified drug interactions.
• In patients with glucose-6-phosphate dehydrogenase deficiency (due to the risk of hemolysis) (see sections “Adverse Reactions” and “Special Precautions”).
• With concurrent intake of alcohol (ethanol) (due to the presence of ASA in the preparation) (see sections “Drug Interactions” and “Special Precautions”).

Use in Pregnancy and Lactation

Pregnancy

As a precaution, Coplavix^® should not be used during the first and second trimesters of pregnancy, except in cases where the woman’s clinical condition requires treatment with clopidogrel in combination with ASA. Due to the presence of ASA in the preparation, it is contraindicated in the third trimester of pregnancy.

Animal studies have not revealed any direct or indirect adverse effects of clopidogrel on pregnancy, embryonic development, childbirth, or postnatal development. However, sufficient and controlled studies in pregnant women have not been conducted. ASA has been established to have a teratogenic effect, although clinical studies have established that doses of ASA up to 100 mg/day, used limitedly in obstetrics and requiring specialized monitoring, have been shown to be safe.

Breastfeeding period

Breastfeeding should be discontinued during treatment with Coplavix^®, as it has been established that ASA is excreted in breast milk. 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 in the breastfed child, a decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the necessity of the drug for the mother.

Use in Hepatic Impairment

Contraindicated in severe hepatic impairment (more than 9 points on the Child-Pugh scale).

The drug should be used with caution in moderate hepatic impairment (7-9 points on the Child-Pugh scale), in which a predisposition to bleeding is possible.

Use in Renal Impairment

Contraindicated in severe renal failure (CrCl <30 ml/min).

The drug should be used with caution in mild to moderate renal failure with CrCl 60-30 ml/min.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

No dose adjustment is required in elderly patients.

Special Precautions

Bleeding and hematological disorders

Due to the risk of bleeding and hematological adverse effects, if clinical symptoms suspicious for bleeding occur during treatment, a clinical blood test, determination of aPTT (activated partial thromboplastin time), platelet count in peripheral blood, indicators of platelet functional activity, and other necessary tests should be urgently performed.

Concomitant use of Coplavix^® with warfarin is not recommended, as it may increase the intensity of bleeding (see section “Drug Interactions”).

Due to the presence of two antiplatelet agents in Coplavix^®, it should be used with caution in patients at increased risk of bleeding due to trauma, surgery, or other pathological conditions, as well as in patients receiving NSAIDs (including COX-2 inhibitors), heparin, glycoprotein IIb/IIIa inhibitors, SSRIs, and thrombolytic drugs. Patients should be carefully monitored for signs of bleeding, including occult bleeding, especially during the first weeks of treatment and/or after invasive cardiac procedures/surgery.

If a patient is scheduled for elective surgery and there is no need for continuous antiplatelet therapy, clopidogrel should be discontinued 5-7 days before surgery.

Coplavix^® increases bleeding time and should be used with caution in patients with diseases and conditions predisposing to bleeding (especially gastrointestinal bleeding and intraocular hemorrhages).

Patients should be warned that when taking Coplavix^®, it may take longer than usual to stop bleeding, and that they should report any unusual bleeding (in location or duration) to their doctor.

Before any upcoming surgery and before starting any new medication, patients should inform their physician (including dentist) about treatment with Coplavix^®.

Recently experienced ischemic stroke

It has been shown that in patients with a recent transient ischemic attack or stroke, who have an increased risk of recurrent ischemic complications, the combination of ASA and clopidogrel increases the possibility of major bleeding. Therefore, the use of Coplavix^® in such patients should be done with caution and only in cases of proven clinical benefit.

Thrombotic thrombocytopenic purpura

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 the use of clopidogrel. In case of a confirmed isolated increase in aPTT, with or without bleeding development, 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 should discontinue clopidogrel.

Atrial fibrillation

In patients with atrial fibrillation who have an increased risk of cardiovascular complications and who could take indirect anticoagulants, indirect anticoagulants have been shown to be superior compared to ASA monotherapy or the combination of clopidogrel + ASA in reducing the risk of stroke.

CYP2C19 isoenzyme functional activity

In patients with low metabolic activity of the CYP2C19 isoenzyme, less of the active metabolite of clopidogrel is formed when using clopidogrel at recommended doses, and its effect on platelet function is reduced. Therefore, such patients with acute coronary syndrome or undergoing percutaneous coronary intervention and taking clopidogrel may have a higher frequency of cardiovascular events than patients with normal CYP2C19 isoenzyme activity.

The use of drugs that induce the activity of the CYP2C19 isoenzyme is expected to lead to an increase in the concentration of the active metabolite of clopidogrel and increase the risk of bleeding. As a precaution, the concomitant use of strong inducers of the CYP2C19 isoenzyme and clopidogrel should be avoided.

There are tests to determine the CYP2C19 genotype that can be used in choosing a therapeutic strategy. The use of clopidogrel in higher doses in patients with low CYP2C19 activity is being considered (see section “Pharmacokinetics”, subsection “Pharmacogenetics”, section “Dosage and Administration”), however, the efficacy and safety of using clopidogrel at increased doses in patients with low CYP2C19 isoenzyme activity have not been established to date.

Cross-allergic reactions and/or hematological reactions between thienopyridines

A history should be taken from patients regarding previous allergic and/or hematological reactions to other thienopyridines (such as ticlopidine, prasugrel), as cross-allergic and/or hematological reactions between thienopyridines have been reported (see section “Adverse Reactions”). Thienopyridines can cause moderate and severe allergic reactions (such as skin rash, angioedema) or hematological reactions (such as thrombocytopenia, 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

The combination of clopidogrel + ASA should not be used in patients with severe renal impairment (see section “Contraindications”). Experience with clopidogrel in patients with mild to moderate renal impairment is limited. Therefore, in this group of patients, the combination of clopidogrel + ASA should be used with caution.

Hepatic impairment

The combination of clopidogrel + ASA should not be used in patients with severe hepatic impairment (see section “Contraindications”). Experience with clopidogrel in patients with moderate liver disease, who may have a predisposition to bleeding, is limited. Therefore, in this group of patients, the combination of clopidogrel + ASA should be used with caution.

Precautions required due to the presence of ASA in the preparation

• In patients with a history of bronchial asthma or other allergic diseases, as they have an increased risk of hypersensitivity reactions.
• In patients with gout, as low-dose ASA increases blood urate levels.
• There may be a relationship between ASA intake and the development of Reye’s syndrome, a rare and life-threatening disease, usually observed in the prodromal period of infections in children, characterized by encephalopathy and acute fatty liver degeneration and rapid development of liver failure, which can be fatal.
• Ethanol may increase the risk of gastrointestinal damage when taken during treatment with ASA. Therefore, caution should be exercised when consuming alcohol (ethanol) during treatment with ASA (see section “Drug Interactions”). In addition, patients should be warned about the risk of bleeding due to chronic consumption of large amounts of alcohol (ethanol) while taking the combination of clopidogrel + ASA.
• Coplavix^® should be used under close medical supervision in patients with glucose-6-phosphate dehydrogenase deficiency due to the risk of hemolysis.
• Concomitant intake of levothyroxine and salicylates should be avoided, especially in doses above 2 g/day (see section “Drug Interactions”).

Effect on the gastrointestinal tract

Coplavix^® should be used with caution in patients with a history of gastric and duodenal ulcers or gastrointestinal bleeding, or in patients with even minor symptoms from the upper gastrointestinal tract, which may be manifestations of gastric ulcerative lesions that can lead to gastric bleeding.

During treatment with Coplavix^®, symptoms from the upper gastrointestinal tract, such as gastralgia, heartburn, nausea, vomiting, and gastrointestinal bleeding, may occur at any time. Although minor gastrointestinal side effects, such as dyspeptic disorders, are common during treatment with Coplavix^®, the attending physician should always rule out gastrointestinal mucosal ulceration and bleeding in these cases, even in the absence of a history of gastrointestinal pathology.

Patients should be informed about the symptoms of gastrointestinal adverse reactions and instructed to seek immediate medical attention if they occur.

Patients concurrently taking nicorandil and NSAIDs, including ASA and lysine acetylsalicylate, have an increased risk of severe complications, such as ulcer formation and perforations in the gastrointestinal tract and gastrointestinal bleeding (see section “Drug Interactions”).

Excipients

Coplavix^® contains lactose monohydrate. Patients with rare hereditary conditions such as galactose intolerance, lactose intolerance due to lactase deficiency, or glucose-galactose malabsorption syndrome should not take this medicine.

Coplavix^® contains hydrogenated castor oil, which may cause diarrhea.

Effect on ability to drive and use machines

Usually, Coplavix^® does not significantly affect the ability to drive vehicles and engage in other potentially hazardous activities requiring increased concentration and speed of psychomotor reactions. However, if the patient experiences adverse reactions from the nervous system and psyche (see section “Adverse Reactions”), a decrease in concentration and speed of psychomotor reactions is possible, which may impede engagement in such activities. In such cases, the attending physician should decide on the possibility of engaging in potentially hazardous activities.

Overdose

Clopidogrel

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

Treatment: If bleeding occurs, appropriate treatment is required. An antidote for clopidogrel has not been established. If rapid correction of prolonged bleeding time is necessary, platelet transfusion is recommended.

Acetylsalicylic acid

Moderate overdose: Dizziness, tinnitus, headache, confusion, and gastrointestinal symptoms (nausea, vomiting, and stomach pain).

Severe overdose: Severe disturbances of acid-base balance occur. Initial hyperventilation leads to the development of respiratory alkalosis, then respiratory acidosis develops as a consequence of the inhibitory effect of respiratory alkalosis on the respiratory center. Metabolic acidosis also develops due to the presence of salicylates in the blood. Additionally, the following symptoms appear: hyperthermia and profuse sweating leading to dehydration, motor restlessness, convulsions, hallucinations, and the development of hypoglycemia. Depression of the nervous system can lead to coma, collapse, and respiratory arrest. The lethal dose of ASA is 25-30 g. A plasma salicylate concentration above 300 mg/l (1.67 mmol/l) confirms intoxication. Overdose of salicylates, especially in young children, can lead to severe hypoglycemia and potentially fatal poisoning. Acute and chronic overdose of ASA can lead to non-cardiogenic pulmonary edema (see section “Adverse Reactions”).

Treatment: If symptoms of severe overdose are detected, hospitalization is required. In case of moderate intoxication, an attempt can be made to induce vomiting artificially; if unsuccessful, gastric lavage is indicated. After this, activated charcoal (adsorbent) and a saline laxative should be taken orally (if the patient can swallow) or, otherwise, introduced into the stomach through a tube. For forced alkalinization of urine to accelerate the excretion of salicylates, intravenous drip infusion of 250 mmol of sodium bicarbonate over 3 hours under the control of urine pH and acid-base balance is indicated. The preferred treatment for severe overdose is hemodialysis or peritoneal dialysis. If necessary, symptomatic treatment of other manifestations of intoxication is applied.

Drug Interactions

Medicinal products 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.

Nicorandil

Patients concurrently taking nicorandil and NSAIDs, including ASA and lysine acetylsalicylate, have an increased risk of severe complications, such as ulcer formation and perforations in the gastrointestinal tract and gastrointestinal bleeding (see section “Special Precautions”).

Thrombolytics

The safety of the concomitant use of clopidogrel, fibrin-specific or non-fibrin-specific thrombolytic agents, and heparin was analyzed in patients with acute myocardial infarction. The frequency of clinically significant bleeding was similar to that observed with the concomitant use of thrombolytic agents and heparin with ASA. Due to insufficient clinical data on the concomitant use of clopidogrel and thrombolytic agents, caution should be exercised during their concurrent use (see section “Special Precautions”).

Glycoprotein IIb/IIIa inhibitors

A pharmacodynamic interaction between glycoprotein IIb/IIIa inhibitors and clopidogrel is possible, requiring caution during their concurrent use.

Heparin

According to a clinical study involving healthy volunteers, no change in the dose of heparin was required when taking clopidogrel, and its anticoagulant effect was not altered. Concomitant use of heparin did not alter the inhibitory effect of clopidogrel on platelet aggregation. A pharmacodynamic interaction between clopidogrel and heparin is possible, which may increase the risk of bleeding, therefore the concomitant use of these drugs requires caution (see section “Special Precautions”).

Indirect anticoagulants

Concomitant administration of clopidogrel and oral anticoagulants (warfarin) may increase the intensity of bleeding, therefore the use of this combination is not recommended. Clopidogrel at a dose of 75 mg does not affect the pharmacokinetics of warfarin and does not change INR values in patients taking warfarin long-term. Nevertheless, the concomitant use of warfarin with clopidogrel may increase the risk of bleeding due to the independent effects of these drugs on hemostasis.

NSAIDs

In a clinical study involving healthy volunteers, the concomitant use of clopidogrel and naproxen increased occult gastrointestinal blood loss. Therefore, the use of NSAIDs, including COX-2 inhibitors, in combination with clopidogrel is not recommended. Experimental data suggest that ibuprofen (when taken as a single 400 mg dose between 8 hours before or within 30 minutes after the immediate intake of 81 mg ASA in immediate-release form) may inhibit the effect of low-dose ASA on platelet aggregation. However, with irregular intake of ibuprofen, no clinically significant effects on the antiplatelet action of ASA are expected.

Selective serotonin reuptake inhibitors (SSRIs)

Since SSRIs impair platelet activation and increase the risk of bleeding, concomitant use of SSRIs with clopidogrel should be undertaken with caution.

Other combination therapy with clopidogrel

Inducers of the CYP2C19 isoenzyme

Since clopidogrel is metabolized to its active metabolite partly by the CYP2C19 isoenzyme, the use of drugs that induce the activity of this isoenzyme is expected to 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 to platelet inhibition, 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.

Potent and moderate inhibitors of the CYP2C19 isoenzyme

Since clopidogrel is metabolized to its active metabolite partly by the CYP2C19 isoenzyme, the use of drugs that inhibit the activity of this isoenzyme is expected to lead to a decrease in the concentration of the active metabolite of clopidogrel. The clinical significance of this interaction is unknown. 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.

Concomitant use of proton pump inhibitors that are potent or moderate inhibitors of the CYP2C19 isoenzyme (e.g., omeprazole, esomeprazole) with clopidogrel is not recommended. If a patient nevertheless requires the use of a proton pump inhibitor concomitantly with clopidogrel, a proton pump inhibitor with minimal influence on CYP2C19 activity, such as pantoprazole or lansoprazole, should be used.

Drugs that are substrates of the CYP2C8 isoenzyme

Clopidogrel increased the systemic exposure of repaglinide in healthy volunteers. In vitro studies have shown that the increase in systemic exposure of repaglinide is a consequence of inhibition of the CYP2C8 isoenzyme by the glucuronide metabolite of clopidogrel. Caution should be exercised when clopidogrel is used concomitantly with drugs that are eliminated from the body primarily via metabolism by the CYP2C8 isoenzyme (e.g., repaglinide, paclitaxel).

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

• When clopidogrel was used concomitantly with atenolol, nifedipine or with both of these drugs simultaneously, no clinically significant pharmacodynamic interaction was observed;
• Concomitant use of phenobarbital, cimetidine and estrogens did not have a significant effect on the pharmacodynamics of clopidogrel;
• The pharmacokinetic parameters of digoxin and theophylline did not change when they were used concomitantly with clopidogrel;
• antacid drugs did not reduce the absorption of clopidogrel;
• phenytoin and tolbutamide can be safely used concomitantly with clopidogrel (CAPRIE study), despite the fact that data obtained from human liver microsome studies indicate that the carboxylic acid metabolite of clopidogrel may inhibit the activity of the CYP2C9 isoenzyme, which may lead to increased plasma concentrations of some drugs, for example, phenytoin, tolbutamide and some NSAIDs, which are metabolized by the CYP2C9 isoenzyme.

Other combination therapy with ASA

Interactions of ASA with the following drugs have been reported

• Uricosuric drugs (drugs that promote the excretion of uric acid) (benzbromarone, probenecid, sulfinpyrazone) – caution is required, as ASA may suppress their uricosuric effect due to competition with uric acid at the level of excretion;
• Methotrexate – methotrexate, taken in doses greater than 20 mg/week, should be used with caution when combined with clopidogrel (due to the presence of ASA in the Coplavix^® preparation), as ASA may reduce the renal clearance of methotrexate, which, in turn, may increase its myelotoxic effect;
• Metamizole – metamizole, when used concomitantly with ASA, may reduce the effect of ASA on platelet aggregation. Therefore, this combination should be used with caution in patients taking low doses of ASA for cardioprotective action;
• Acetazolamide – caution is recommended when salicylates and acetazolamide are used concomitantly due to an increased risk of metabolic acidosis;
• Varicella vaccine – it is recommended that patients do not take salicylates for 6 months after vaccination against varicella, as cases of Reye’s syndrome have been observed during chickenpox disease after taking salicylates (see section “Special Instructions”);
• Levothyroxine sodium – salicylates, especially in doses greater than 2 g/day, may inhibit the binding of thyroid hormones to carrier proteins and therefore lead to an initial transient increase in free thyroid hormone concentrations followed by a decrease in their concentrations. Thyroid hormone concentrations should be monitored (see section “Special Instructions”);
• Valproic acid – concomitant use of valproic acid and salicylates may lead to a decrease in the binding of valproic acid to blood proteins and inhibition of the metabolism of valproic acid, leading to an increase in the total serum concentration of valproic acid and the serum concentration of its free fraction;
• Tenofovir – concomitant use of tenofovir disoproxil fumarate and NSAIDs may increase the risk of renal failure;
• ACE inhibitors, anticonvulsants (phenytoin and valproic acid), beta-blockers, diuretics and oral hypoglycemic agents – interaction of these drugs with ASA used in high (anti-inflammatory) doses is possible;
• Ethanol – when used concomitantly with ASA, the risk of bleeding increases with chronic consumption of large amounts of alcohol (ethanol). In addition, ethanol may increase the risk of gastrointestinal damage when using ASA. Therefore, patients taking ASA should consume alcohol (ethanol) with caution (see section “Special Instructions”).

Other interactions with clopidogrel and ASA

• Diuretics, beta-blockers, ACE inhibitors, slow calcium channel blockers, hypolipidemic agents, coronary vasodilators, hypoglycemic agents (including insulin), antiepileptic drugs, hormone replacement therapy and glycoprotein IIb/IIIa receptor blockers – in clinical studies on the use of clopidogrel in combination with ASA in maintenance doses ≤325 mg, involving more than 30,000 patients, no clinically significant adverse interaction with these drugs was identified.
• Opioid receptor agonists – as with other oral P2Y12 inhibitors, concomitant use of opioid receptor agonists may reduce the absorption of clopidogrel, probably due to delayed gastric emptying. The clinical significance of this interaction is unknown. Consideration should be given to prescribing a parenteral antiplatelet agent in patients with acute coronary syndrome requiring concomitant use of morphine or other opioid agonists.

Storage Conditions

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

Shelf Life

The shelf life is 2 years. Do not use after the expiration date stated 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.