Clopigrant^® A (Capsules) Instructions for Use

Marketing Authorization Holder

Micro Labs Limited (India)

ATC Code

B01AC30 (Platelet aggregation inhibitors in combination)

Active Substances

Acetylsalicylic acid (Ph.Eur.)

Clopidogrel (Rec.INN)

Dosage Form

Clopigrant® A

Modified-release capsules: 7, 10, 14, 28, 30, 84, or 90 pcs.

Dosage Form, Packaging, and Composition

Modified-release capsules are hard gelatin capsules size 0, with a white body and a green cap, printed with black ink ” MICRO ” on the body and ” MICRO ” on the cap; the capsule contents are a mixture of white or almost white and orange colored granules (pellets).

Excipients (acetylsalicylic acid granules) sucrose (as microspheres) – 57.777 mg, sucrose – 11.378 mg, povidone K-30 – 1.378 mg, hypromellose – 8.889 mg, methacrylic acid and ethyl acrylate copolymer 1:1 (type A, eudragit L 30 D ) – 40.555 mg, sodium hydroxide – 0.111 mg, talc – 0.953 mg, titanium dioxide – 0.78 mg, macrogol 6000 – 0.4 mg.
Excipients (clopidogrel granules) sucrose (as microspheres) – 70.35 mg, colloidal anhydrous silicon dioxide – 1.875 mg, crospovidone – 3.75 mg, sucrose – 3.75 mg, hypromellose – 7.5 mg, macrogol 6000 – 0.5625 mg, talc – 1.40625 mg, titanium dioxide – 0.46875 mg.
Capsule shell (body) titanium dioxide – 2.1118%, purified water – 14-15%, gelatin – up to 100%; capsule shell (cap) yellow iron oxide – 0.15%, patent blue V dye – 0.0065%, titanium dioxide – 1.74%, purified water – 14-15%, gelatin – up to 100%.
Composition of the capsule printing ink ethanol – 29-33%, isopropyl alcohol – 9-12%, butanol – 4-7%, shellac – 24-28%, black iron oxide – 24-28%, aqueous ammonia – 1-3%, propylene glycol – 0.5-2%.

7 pcs. – aluminum strips (1) – cardboard packs.
7 pcs. – aluminum strips (2) – cardboard packs.
7 pcs. – aluminum strips (4) – cardboard packs.
7 pcs. – aluminum strips (12) – cardboard packs.
10 pcs. – aluminum strips (1) – cardboard packs.
10 pcs. – aluminum strips (3) – cardboard packs.
10 pcs. – aluminum strips (9) – cardboard packs.

Clinical-Pharmacological Group

Antiplatelet agent

Pharmacotherapeutic Group

Antiaggregant agent

Pharmacological Action

Combined antiplatelet drug.

Acetylsalicylic acid (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 persists for the entire lifespan of 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.

Clopidogrel is a prodrug, one of whose active metabolites is a platelet aggregation inhibitor. Its active metabolite irreversibly binds to platelet ADP receptors (adenosine diphosphate receptors) and selectively inhibits the binding of ADP to platelet ADP receptors and the subsequent ADP-induced activation of the GPIIb/IIIa complex, thereby suppressing ADP-induced platelet aggregation. Clopidogrel also inhibits platelet aggregation induced by other agonists by blocking the activation of platelets by released ADP. Due to the irreversibility of the binding of clopidogrel to platelet ADP receptors, platelets remain unresponsive to ADP stimulation for the rest of their lifespan (approximately 7-10 days), and the restoration of normal platelet function occurs at a rate corresponding to the rate of platelet renewal.

Since the formation of the active metabolite is mediated by cytochrome P450 system isoenzymes, some of which may be polymorphic or inhibited by other drugs, not all patients may achieve sufficient platelet aggregation inhibition.

With daily administration of clopidogrel at a dose of 75 mg, significant inhibition of ADP-induced platelet aggregation is observed from the first day of administration, gradually increasing over 3-7 days and then reaching a constant level (upon reaching steady state). At steady state, platelet aggregation is inhibited by an average of 40-60%. After discontinuation of clopidogrel, platelet aggregation and bleeding time gradually return to baseline levels within an average of 5 days.

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 cerebral, coronary, or peripheral arteries.

The ACTIVE-A clinical trial 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 ASA alone) reduced the combined incidence of stroke, myocardial infarction, systemic embolism outside the CNS, 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 or vascular death. Furthermore, the use of clopidogrel in combination with ASA reduced the total number of days of hospitalization for cardiovascular pathology.

Pharmacokinetics

ASA

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

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 mcg/mL), about 90% of salicylic acid is bound to plasma albumin. Salicylic acid is well distributed in body tissues and fluids, including the CNS, breast milk, and fetal tissues.

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.

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 capacity of the liver to form salicyluric acid and phenolic glucuronide. After ingestion of 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 pH increases above 6.5, the renal clearance of free salicylate increases from <5% to >80%. After therapeutic doses, approximately the following is found in 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.

Clopidogrel

After single and repeated oral administration at a dose of 75 mg/day, clopidogrel is rapidly absorbed. Mean C_max of unchanged clopidogrel in plasma (approximately 2.2-2.5 ng/mL after a single oral dose of 75 mg) is achieved approximately 45 minutes after a single dose. Based on the excretion of clopidogrel metabolites in urine, its absorption is approximately 50%.

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

Clopidogrel is extensively metabolized in the liver. In vitro and in vivo, clopidogrel is metabolized via two metabolic pathways. The first pathway: metabolism by esterases, leading to hydrolysis to form an inactive metabolite, a carboxylic acid derivative (constitutes 85% of the metabolites circulating in the systemic bloodstream). The second pathway: metabolism by several cytochrome P450 system isoenzymes. In this process, 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 primarily 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 a loading dose of clopidogrel 300 mg, the C_max of the active metabolite is twice that after 4 days of maintenance dose of clopidogrel 75 mg, and its C_max is reached approximately 30-60 minutes after clopidogrel administration.

Within 120 hours after oral administration of ¹⁴C-labeled clopidogrel, 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 is 8 hours.

Pharmacogenetics

The isoenzyme CYP2C19 produces 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, 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 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 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 Blacks, and 14% in Chinese. Appropriate tests are available to determine a patient’s CYP2C19 isoenzyme genotype.

According to a cross-over study (40 volunteers) and a meta-analysis of 6 studies (335 volunteers taking clopidogrel), which included individuals 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 platelet aggregation (IPA) (induced by ADP) were found in healthy 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 compared to volunteers with extensive CYP2C19 metabolizer status.

When volunteers with poor CYP2C19 metabolizer status took clopidogrel according to the regimen: 600 mg loading dose/150 mg maintenance dose (600 mg/150 mg), the exposure to the active metabolite was higher than with the 300 mg/75 mg treatment regimen. Furthermore, the IPA was similar to that in the groups of patients with higher CYP2C19-mediated metabolic intensity taking clopidogrel according to the 300 mg/75 mg regimen. However, in outcome studies, the dosing regimen of clopidogrel for this group of patients (patients with poor CYP2C19 metabolizer status) 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 poor CYP2C19 metabolizer status.

Pharmacokinetics in special clinical situations

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

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

After daily administration for 10 days of clopidogrel at a daily dose of 75 mg in patients with severe hepatic impairment (Child-Pugh class A and B), the inhibition of ADP-induced platelet aggregation was similar to that in healthy volunteers. The mean bleeding time was also comparable in both groups.

The prevalence of CYP2C19 isoenzyme gene alleles responsible for intermediate and poor metabolism differs among different ethnic groups. There are limited published data on their prevalence among Mongoloids, which does not allow for an assessment of 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, no clinically significant pharmacokinetic interaction between them is expected.

Indications

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

Prevention of atherothrombotic complications

In adult patients with acute coronary syndrome

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

Prevention of atherothrombotic and thromboembolic complications, including stroke, in atrial fibrillation

In adult patients with atrial fibrillation who have at least one risk factor for vascular complications, cannot take vitamin K antagonists, and have a low risk of bleeding.

ICD codes

Dosage Regimen

The drug should be taken once a day, regardless of meals.

Adults and elderly patients with normal CYP2C19 isoenzyme activity

Acute coronary syndrome (ACS)

Treatment should be started as early as possible after symptom onset. Administration of the drug begins 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 myocardial infarction with ST-segment elevation – in combination with thrombolytics or without them. 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 myocardial infarction with ST-segment elevation in patients over 75 years of age, treatment with clopidogrel should be started without a loading dose.

In patients with ACS without ST-segment elevation (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 defined. Clinical trial data support taking the drug for up to 12 months.

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

Atrial fibrillation

The drug should be taken once daily, after starting treatment with clopidogrel 75 mg and ASA 100 mg as separate preparations.

Patients with genetically determined reduced activity of the CYP2C19 isoenzyme

Low activity of the CYP2C19 isoenzyme 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, at present, 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 activity of the CYP2C19 isoenzyme.

Special patient groups

The safety and efficacy in children have not been established to date.

In elderly patients, no dose adjustment is required.

Therapeutic experience with the drug is limited to use in patients with moderate hepatic impairment, who may be prone to developing a hemorrhagic diathesis. Therefore, caution should be exercised when using the drug in such patients.

There is limited therapeutic experience with the drug in patients with mild to moderate renal impairment. Therefore, caution should be exercised when using the drug 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 concomitantly; 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 one 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.

The frequency of adverse effects was determined according to the WHO classification: very common (≥10%), common (≥1% and <10%), uncommon (≥0.1% and <1%), rare (≥0.01% and <0.1%), very rare (<0.01%), frequency unknown (cannot be estimated from the available data).

Hemorrhagic adverse events

Hemorrhagic adverse events, including purpura/ecchymosis; epistaxis; hematuria; hemorrhages into skin tissue, bone and muscle; hematomas; hemorrhages into the joint cavity (hemarthrosis), into the conjunctiva, into the intraocular media and retina; respiratory tract bleeding, hemoptysis; surgical wound bleeding; intracranial hemorrhages (hemorrhagic strokes); gastrointestinal bleeding, retroperitoneal hemorrhages.

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

Common major bleeding¹ – life-threatening bleeding requiring transfusion of 4 or more units of blood; other major bleeding requiring transfusion of 2-3 units of blood; non-life-threatening major bleeding (according to the COMMIT study, the frequency of major non-cerebral bleeding and intracranial hemorrhages was “uncommon”)¹; minor bleeding (according to the ACTIVE-A study, the frequency of minor bleeding was “very common”)¹; bleeding at the vascular puncture site^1,2; bruising²; hematomas².

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, no increase in the incidence of major bleeding was observed within 7 days after this intervention (4.4% – with clopidogrel+ASA 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) and 6.3% (ASA alone).

Uncommon fatal bleeding¹; life-threatening bleeding [bleeding with a decrease in blood hemoglobin of more than 5 g/dL (according to the CLARITY clinical trial, their frequency was “common”)¹; bleeding requiring surgical intervention¹; intracranial hemorrhages (hemorrhagic strokes) (according to the CLARITY clinical trial, their frequency was “common”)¹; bleeding requiring inotropic drug administration]¹; severe bleeding (most commonly purpura, epistaxis; less commonly hematuria and intraocular hemorrhages, mainly conjunctival²).

Rare intraocular hemorrhages with significant visual impairment¹, retroperitoneal hemorrhages¹.

Frequency unknown ( post-marketing experience) – serious cases of bleeding², mainly hemorrhages into skin tissue², bone, muscle and joint cavity (hemarthrosis)², eye tissues (conjunctival, into the intraocular media and retina)², respiratory tract bleeding², hemoptysis², epistaxis², hematuria², surgical wound bleeding²; intracranial hemorrhages³, including fatal cases³, especially in elderly patients; other fatal bleeding cases (in particular, gastrointestinal bleeding and retroperitoneal hemorrhages².

Hematologic system disorders

Uncommon – decreased platelet count in peripheral blood¹, severe thrombocytopenia with platelet count in peripheral blood ≤80×10⁹/L, but >30×10⁹/L¹, leukopenia¹, decreased neutrophil count in peripheral blood¹, eosinophilia¹, prolonged bleeding time¹; rare – neutropenia¹, including severe neutropenia (<0.45×10⁹/L)¹ (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); very rare – aplastic anemia¹, severe thrombocytopenia with platelet count in peripheral blood ≤30×10⁹/L¹; frequency unknown (post-marketing experience) – agranulocytosis^2,3; aplastic anemia^2,3/pancytopenia^2,3, thrombocytopenia, hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency, neutropenia³, bicytopenia³, bone marrow depression³, leukopenia³, granulocytopenia³, anemia¹, acquired hemophilia A², thrombotic thrombocytopenic purpura (TTP)².

Nervous system disorders

Uncommon – headache¹, dizziness¹ and paresthesia¹; rare – vertigo¹; frequency unknown (post-marketing experience) – taste perversion².

Digestive 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 (including ulcerative or lymphocytic colitis)^2,3, pancreatitis², stomatitis², esophagitis³, esophageal ulceration/perforation³, erosive gastritis³, erosive duodenitis³, gastric and/or duodenal ulcer or ulcer perforation³, symptoms of upper GI 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 may occur with any dose of ASA, as well as in patients with or without warning symptoms and a history of serious gastrointestinal complications), acute pancreatitis as a manifestation of hypersensitivity reaction to ASA³.

Hepatobiliary disorders

Frequency unknown (post-marketing experience) – hepatitis (non-infectious etiology)², acute liver failure², increased liver enzyme activity³, liver damage, mainly hepatocellular³, chronic hepatitis³.

Skin and subcutaneous tissue disorders

Uncommon – skin rash¹, pruritus¹; frequency unknown (post-marketing experience) – maculopapular, erythematous or exfoliative 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 lesions, usually in the form of round or oval erythematous plaques, 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.

Psychiatric disorders

Frequency unknown (post-marketing experience) – confusion², hallucinations².

Cardiovascular disorders

Frequency unknown (post-marketing experience) – vasculitis², including Henoch-Schönlein purpura³, decreased BP², Kounis syndrome (allergic coronary syndrome), caused by a hypersensitivity reaction to acetylsalicylic acid³.

Respiratory disorders

Frequency unknown (post-marketing experience) – bronchospasm², interstitial pneumonitis², eosinophilic pneumonia², non-cardiogenic pulmonary edema with continuous 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, acute renal impairment (especially in patients with pre-existing renal failure, decompensated chronic heart failure, nephrotic syndrome, or in patients concomitantly taking diuretics)³.

Reproductive system and breast disorders

Frequency unknown (post-marketing experience) – gynecomastia².

Ear and labyrinth disorders

Frequency unknown (post-marketing experience) – hearing loss³, tinnitus³.

Metabolism and nutrition disorders

Frequency unknown (post-marketing experience) – hypoglycemia³, gout³.

General disorders and administration site conditions

Frequency unknown (post-marketing experience) – fever²; edema reported with high (anti-inflammatory) doses of ASA.

Investigations

Frequency unknown (post-marketing experience) – abnormal liver function tests², increased blood creatinine².

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

² Adverse effects observed with clopidogrel.

³ Adverse effects observed with ASA.

Contraindications

Severe hepatic impairment (more than 9 points on the Child-Pugh scale); severe renal impairment (CrCl <30 mL/min) due to the acetylsalicylic acid content in the drug; active bleeding, e.g., peptic ulcer bleeding or intracranial hemorrhage; bronchial asthma induced by salicylates and other NSAIDs, combination of bronchial asthma, rhinitis and recurrent nasal and paranasal sinus polyposis and intolerance to NSAIDs (due to the ASA content in the drug); mastocytosis, in which the use of ASA may cause severe allergic reactions, including the development of shock with skin hyperemia, decreased BP, tachycardia and vomiting (due to the ASA content in the drug); rare hereditary conditions such as galactose intolerance, lactose intolerance due to lactase deficiency, glucose-galactose malabsorption syndrome (due to the lactose content in the drug); pregnancy; lactation period (breastfeeding); children and adolescents under 18 years of age (safety and efficacy of use have not been established); hypersensitivity to any of the active or auxiliary substances of the drug.

With caution in moderate hepatic impairment (7-9 points on the Child-Pugh scale), in which a predisposition to bleeding is possible (limited clinical experience); mild to moderate renal impairment with CrCl 30-60 mL/min (limited clinical experience); trauma, surgical interventions, including invasive cardiac procedures or surgery; diseases with a predisposition to bleeding, especially intraocular or gastrointestinal (with a history of peptic ulcer disease or gastrointestinal bleeding, with symptoms of upper GI tract disorders); recently experienced transient ischemic attack or ischemic stroke; concomitant use of NSAIDs, including selective COX-2 inhibitors; gout, hyperuricemia (ASA, including in low doses, increases blood uric acid concentration); history of bronchial asthma and allergies (increased risk of developing allergic reactions to ASA); in patients with genetically determined reduced activity of the CYP2C19 isoenzyme; in patients with glucose-6-phosphate dehydrogenase deficiency (due to the risk of hemolysis); concomitant use of warfarin, heparin, glycoprotein IIb/IIIa inhibitors, selective serotonin reuptake inhibitors and thrombolytic agents; concomitant use of methotrexate at a dose of more than 20 mg per week; concomitant use of drugs associated with a risk of bleeding and drugs that are substrates of the CYP2C8 isoenzyme (such as repaglinide, paclitaxel) due to identified drug interactions; concomitant intake of alcohol (ethanol) (due to the ASA content in the drug); with a history of allergic and hematological reactions to other thienopyridines (such as ticlopidine, prasugrel) due to the possibility of cross-allergic and hematological reactions.

Use in Pregnancy and Lactation

As a precaution, the drug should not be taken in 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 ASA content, the drug is contraindicated in the third trimester of pregnancy.

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

Breastfeeding should be discontinued during treatment with the drug, as it has been established that ASA is excreted in breast milk, and studies in rats have shown that clopidogrel and/or its metabolites are also excreted in the milk of lactating rats. It is not known whether clopidogrel is excreted in human breast milk.

Use in Hepatic Impairment

The use of the drug is 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 (limited clinical experience).

Use in Renal Impairment

The use of the drug is contraindicated in severe renal impairment (CrCl <30 mL/min) due to the acetylsalicylic acid content in the drug.

The drug should be used with caution in mild to moderate renal impairment with CrCl 30-60 mL/min (limited clinical experience).

Pediatric Use

The use of the drug is contraindicated in children and adolescents under 18 years of age (safety and efficacy of use have not been established).

Geriatric Use

In elderly patients, no dose adjustment is required.

Special Precautions

Bleeding and hematological disorders

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

Concomitant use of the drug with warfarin is not recommended, as it may increase the intensity of bleeding.

Due to the presence of two antiplatelet agents in the drug, 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, then clopidogrel should be discontinued 5-7 days before the surgery.

The drug increases bleeding time; therefore, it 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 it may take longer than usual to stop bleeding while taking the drug and that they should inform their doctor if any unusual bleeding (in location or duration) occurs.

Before any scheduled surgery and before starting any new medication, patients should inform their physician (including a dentist) about treatment with the drug.

Recently experienced ischemic stroke

In patients with a recently experienced ischemic transient ischemic attack or stroke who are at increased risk of ischemic complications, the combination of acetylsalicylic acid (ASA) and clopidogrel has been shown to increase the possibility of major bleeding. Therefore, the use of the drug in such patients should be carried out with caution and only in case of proven clinical benefit from its use.

Thrombotic thrombocytopenic purpura

Very rarely, cases of thrombotic thrombocytopenic purpura (TTP) have been reported following the use of clopidogrel (sometimes even short-term). TTP 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. If a confirmed isolated increase in aPTT is observed, with or without bleeding development, the possibility of acquired hemophilia should be considered. Patients with a confirmed diagnosis of acquired hemophilia should discontinue clopidogrel and be monitored and treated by specialists in this disease.

Atrial fibrillation

In patients with atrial fibrillation who are at increased risk of cardiovascular complications and who could have taken vitamin K antagonists (VKAs), VKAs have been shown to be superior compared to ASA monotherapy or 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 at recommended doses, and its effect on platelet function is reduced. Therefore, 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. Tests are available to determine the CYP2C19 genotype, which can be used when choosing a therapeutic strategy. The use of clopidogrel in higher doses in patients with low CYP2C19 activity is being considered; however, the efficacy and safety of using clopidogrel in increased doses in patients with low CYP2C19 isoenzyme activity have not been established to date.

Cross-allergic reactions and/or hematological reactions between thienopyridines

Patient history should be taken for previous allergic and/or hematological reactions to other thienopyridines (such as ticlopidine, prasugrel), as cross-allergic reactions between thienopyridines have been reported. Thienopyridines can cause moderate and severe allergic reactions (such as 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

Clopidogrel+ASA should not be used in patients with severe renal impairment. Experience with clopidogrel in patients with mild to moderate renal impairment is limited. Therefore, the clopidogrel+ASA combination should be used with caution in this group of patients.

Hepatic impairment

Clopidogrel+ASA should not be used in patients with severe hepatic impairment. Experience with clopidogrel in patients with moderate liver disease, who may be predisposed to bleeding, is limited. Therefore, clopidogrel+ASA should be used with caution in this group of patients.

Precautions required due to the presence of ASA in the drug

In patients with a history of bronchial asthma or other allergic diseases, as they have an increased risk of developing hypersensitivity reactions.

In patients with gout, as low-dose ASA increases blood urate concentrations.

There may be a connection between taking ASA and the development of Reye’s syndrome, a rare and life-threatening disease usually observed in the prodromal period of infections in children, presenting with 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 ASA treatment. Furthermore, patients should be warned about the risk of bleeding due to chronic consumption of large amounts of alcohol (ethanol) while taking the clopidogrel+ASA combination.

The drug should be used under close medical supervision in patients with glucose-6-phosphate dehydrogenase deficiency due to the risk of hemolysis.

Concomitant use of levothyroxine and salicylates should be avoided, especially in doses above 2 g/day.

Effect on the gastrointestinal tract

The drug should be used with caution in patients with a history of gastric and duodenal ulcers or gastrointestinal bleeding, or in patients even with minor upper gastrointestinal symptoms that may be manifestations of gastric ulcerations that could lead to gastric bleeding.

During treatment with the drug, upper gastrointestinal symptoms 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 the drug, the attending physician should always rule out gastrointestinal mucosal ulcerations 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.

Other

The drug contains hydrogenated castor oil, which may cause stomach upset or diarrhea.

Effect on ability to drive vehicles and operate machinery

The drug 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, a decrease in concentration and speed of psychomotor reactions is possible, which may impede engaging in such activities. In such cases, the attending physician should decide on the possibility of engaging in potentially hazardous activities.

Drug Interactions

The safety of the concomitant use of clopidogrel, fibrin-specific or non-fibrin-specific thrombolytic drugs, and heparin has been 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 the Acetylsalicylic acid+clopidogrel combination and thrombolytic agents, caution should be exercised during their simultaneous use.

A pharmacodynamic interaction between glycoprotein IIb/IIIa inhibitors and the drug is possible, which requires caution during their concomitant use.

According to a clinical study involving healthy volunteers, no dose adjustment of heparin was required when taking clopidogrel, and its anticoagulant effect was not altered. Concomitant use of heparin did not change the inhibitory effect of clopidogrel on platelet aggregation. A pharmacodynamic interaction between the Acetylsalicylic acid+clopidogrel combination and heparin is possible, which may increase the risk of bleeding, and therefore the concomitant use of these drugs requires caution.

Concomitant use of the drug and vitamin K antagonists (warfarin) may increase the intensity of bleeding, and 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, concomitant use of warfarin with clopidogrel may increase the risk of bleeding due to the independent effects of these drugs on hemostasis.

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

Since selective serotonin reuptake inhibitors (SSRIs) impair platelet activation and increase the risk of bleeding, concomitant use of SSRIs with clopidogrel should be done with caution.

Since clopidogrel is metabolized to its active metabolite partly via the CYP2C19 isoenzyme, it is expected that the use of drugs that inhibit the activity of this isoenzyme may lead to a decrease in the concentration of the active metabolite of clopidogrel. The clinical significance of this interaction is unknown. As a precaution, concomitant use of clopidogrel and strong or moderate inhibitors of the CYP2C19 isoenzyme should be avoided. Strong 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 strong or moderate inhibitors of the CYP2C19 isoenzyme (e.g., omeprazole, esomeprazole) with clopidogrel is not recommended. If a patient nevertheless requires the use of proton pump inhibitors simultaneously with the drug, then a proton pump inhibitor with minimal influence on CYP2C19 activity, such as pantoprazole or lansoprazole, should be used.

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 result of inhibition of the CYP2C8 isoenzyme by the glucuronide metabolite of clopidogrel. Caution should be exercised when using clopidogrel 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 together with atenolol, nifedipine, or both drugs simultaneously, no clinically significant pharmacodynamic interaction was observed;
• Concomitant use of phenobarbital, cimetidine, and estrogens did not significantly affect the pharmacodynamics of clopidogrel;
• The pharmacokinetic parameters of digoxin and theophylline were not changed when used concomitantly with clopidogrel;
• antacids did not reduce the absorption of clopidogrel;
• phenytoin and tolbutamide can be safely used concomitantly with clopidogrel (CAPRIE study), despite data from human liver microsome studies indicating that the carboxylic acid metabolite of clopidogrel may inhibit the activity of the CYP2C9 isoenzyme, which could lead to increased plasma concentrations of some drugs, for example, phenytoin, tolbutamide, and some NSAIDs, which are metabolized via the CYP2C9 isoenzyme.

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, taken in doses greater than 20 mg per week, should be used with caution when combined with the drug (due to the presence of ASA in the drug), as ASA may reduce the renal clearance of methotrexate, which, in turn, may increase its myelotoxic effect;
• 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 using salicylates and acetazolamide 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;
• Levothyroxine – 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;
• Valproic acid – concomitant use of valproic acid and salicylates may lead to reduced binding of valproic acid to blood proteins and inhibition of valproic acid metabolism, leading to an increase in the total serum concentration of valproic acid and the serum concentration of its free fraction;
• 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;
• When ethanol is used concomitantly with ASA, the risk of bleeding increases with chronic consumption of large amounts of alcohol (ethanol). Furthermore, ethanol may increase the risk of gastrointestinal damage when using ASA. Therefore, patients taking ASA should consume alcohol (ethanol) with caution.
• Diuretics, beta-blockers, ACE inhibitors, calcium channel blockers, lipid-lowering 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.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.