Lopirel (Tablets) Instructions for Use

Marketing Authorization Holder

Actavis Group hf. (Iceland)

Manufactured By

Actavis, Ltd. (Malta)

Contact Information

TEVA (Israel)

ATC Code

B01AC04 (Clopidogrel)

Active Substance

Clopidogrel (Rec.INN registered by WHO)

Dosage Form

Lopirel

Film-coated tablets, 75 mg: 7, 10, 14, 20, 28, 30, 50, 56, 60, 90, or 100 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets pink, round, biconvex, engraved with “I” on one side.

Excipients: lactose anhydrous – 78.13 mg, microcrystalline cellulose – 68.75 mg, crospovidone (type A) – 13.75 mg, glyceryl dibehenate – 8.25 mg, talc – 8.25 mg, opadry II 85G34669 pink – about 8.25 mg (polyvinyl alcohol – 3.63 mg, talc – 1.65 mg, titanium dioxide (E171) – 1.63 mg, macrogol 3350 – 1.02 mg, lecithin (E322) – 0.29 mg, iron oxide red dye (E172) – 0.03 mg).

7 pcs. – blisters (1) – carton packs.
7 pcs. – blisters (2) – carton packs.
7 pcs. – blisters (4) – carton packs.
7 pcs. – blisters (8) – carton packs.
10 pcs. – blisters (1) – carton packs.
10 pcs. – blisters (2) – carton packs.
10 pcs. – blisters (3) – carton packs.
10 pcs. – blisters (5) – carton packs.
10 pcs. – blisters (6) – carton packs.
10 pcs. – blisters (9) – carton packs.
10 pcs. – blisters (10) – carton packs.

Clinical-Pharmacological Group

Antiplatelet agent

Pharmacotherapeutic Group

Antithrombotic agents; antiplatelet agents, other than heparin

Pharmacological Action

Mechanism of action

Clopidogrel is a prodrug, one of whose metabolites is active and inhibits platelet aggregation.

The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to the P2Y₁₂ platelet receptor and the subsequent ADP-mediated activation of the 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 induced by agonists other than ADP is also inhibited due to the blockade of enhanced platelet activation by released ADP.

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

Pharmacodynamic properties

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

At steady state with a dose of 75 mg/day, platelet aggregation is suppressed 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.

Clinical efficacy and safety

Clopidogrel is capable of preventing the development of atherothrombosis in any localization of atherosclerotic vascular lesions, in particular, in lesions of 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 able to take vitamin K antagonists, clopidogrel in combination with acetylsalicylic acid (compared with acetylsalicylic acid alone) reduced the incidence of the combined endpoint of stroke, myocardial infarction, systemic thromboembolism outside the CNS, or vascular death, largely due to a reduction in the risk of stroke.

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

The reduction in the risk of major vascular complications in the group of patients taking clopidogrel in combination with acetylsalicylic acid was mainly due to a greater reduction in the frequency of strokes.

The risk of stroke of any severity when taking clopidogrel in combination with acetylsalicylic acid was reduced, and there was also a tendency to reduce the frequency of myocardial infarction in the group receiving clopidogrel in combination with acetylsalicylic acid, but no differences were observed in the frequency of thromboembolism outside the CNS or vascular death.

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

Pharmacokinetics

Absorption

After a single dose and during a course of oral administration at a dose of 75 mg/day, clopidogrel is rapidly absorbed.

The mean C_max values of unchanged clopidogrel in plasma are about 2.2-2.5 ng/ml and are reached approximately 45 minutes after administration.

Based on the excretion of clopidogrel metabolites by the kidneys, its absorption is at least 50%.

Distribution

In vitro, clopidogrel and its main circulating inactive metabolite are reversibly bound to plasma proteins by 98% and 94%, respectively.

In vitro, this binding is non-saturable over a wide range of concentrations.

Metabolism

Clopidogrel is extensively metabolized in the liver.

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

Clopidogrel is initially 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.

In vitro, metabolism via this pathway occurs with the participation of isoenzymes CYP3A4, CYP2C19, CYP1A2 and CYP2B6.

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

After a single dose of clopidogrel at a loading dose of 300 mg, the C_max of the active metabolite is 2 times higher than the C_max after taking clopidogrel at a maintenance dose of 75 mg for 4 days.

The C_max of the active metabolite is reached 30-60 minutes after taking clopidogrel.

Excretion

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 through the intestines.

After a single oral dose of 75 mg, the T_1/2 of clopidogrel is about 6 hours.

After a single dose and repeated doses, 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 who are poor metabolizers must possess two of the aforementioned loss-of-function gene alleles.

Published frequencies of the CYP2C19 poor metabolizer phenotype are 2% in Caucasians, 4% in Blacks, and 14% in Chinese.

In a crossover study conducted on 40 volunteers, 10 people in each group with 4 CYP2C19 isoenzyme subtypes (ultrarapid metabolizers, extensive metabolizers, intermediate metabolizers, poor metabolizers), the pharmacokinetics and antiplatelet effect were evaluated when taking clopidogrel at a dose of 300 mg followed by 75 mg/day and when taking clopidogrel at a dose of 600 mg followed by 150 mg/day for 5 days (achieving steady state).

No significant differences in the exposure of the active metabolite and the mean values of inhibition of platelet aggregation (IPA) (ADP-induced) were found in ultrarapid, extensive and intermediate metabolizers.

In poor metabolizers, the exposure of the active metabolite was reduced by 63-71% compared to extensive metabolizers.

When using the 300 mg/75 mg treatment regimen in poor metabolizers, the antiplatelet effect was reduced with mean IPA values of 24% (at 24 hours) and 37% (on day 5 of treatment) compared to IPA values of 39% (at 24 hours) and 58% (on day 5 of treatment) in extensive metabolizers and 37% (at 24 hours) and 60% (on day 5 of treatment) in intermediate metabolizers.

If poor metabolizers received the 600 mg/150 mg treatment regimen, the exposure of the active metabolite was higher than when taking the 300 mg/75 mg treatment regimen.

In addition, the IPA was 32% (at 24 hours) and 61% (on day 5 of treatment), which was greater than that in poor metabolizers receiving the 300 mg/75 mg treatment regimen and was similar to that in patient groups with higher CYP2C19 metabolism intensity receiving the 300 mg/75 mg treatment regimen.

However, in studies taking into account clinical outcomes, the clopidogrel dosage regimen for patients in this group has not yet been established.

In accordance with the results of this study, a meta-analysis of six studies, which included data from 335 volunteers taking clopidogrel and in a state of achieving C_ss, showed that in intermediate metabolizers the exposure of the active metabolite was reduced by 28%, and in poor metabolizers by 72%, although the IPA was reduced compared to extensive metabolizers with differences in IPA of 5.9% and 21.4%, respectively.

The effect of the CYP2C19 genotype on clinical outcomes in patients taking clopidogrel has not been evaluated in prospective, randomized, controlled trials.

However, there are currently several retrospective analyses.

Genotyping results are available in the following clinical trials: CURE (n=2721), CHARISMA (n=2428), CLARITY-TIMI 28 (n=227), TRITON-TIMI 38 (n=1477) and ACTIVE-A (n=601), as well as in several published cohort studies.

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

In the CHARISMA study and one cohort study (Simon), an increase in the frequency of cardiovascular complications was observed only in poor metabolizers (when comparing them with extensive metabolizers).

In the CURE, CLARITY, ACTIVE-A studies and one of the cohort studies (Trenk), no increase in the frequency of cardiovascular complications was observed depending on the intensity of CYP2C19 metabolism.

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.

Pharmacokinetics in special clinical cases

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

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 of the drug is required in elderly patients.

The pharmacokinetics of clopidogrel in children has not been studied.

In patients with severe renal impairment (CC 5-15 ml/min) after repeated doses of clopidogrel at a dose of 75 mg/day, the initiation of ADP-induced platelet aggregation was lower (25%) compared to healthy volunteers, but the prolongation of bleeding time was similar to that in healthy volunteers taking clopidogrel at a dose of 75 mg/day.

Clopidogrel was well tolerated in all patients.

In patients with severe liver damage after daily administration of clopidogrel at a dose of 75 mg/day for 10 days, 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 CYP2C9 isoenzyme gene alleles responsible for intermediate and reduced metabolism is different in different racial groups.

There is very little literature data among Mongoloids, which does not allow assessing the significance of CYP2C19 isoenzyme genotyping for the development of ischemic complications.

Indications

Prevention of atherothrombotic complications

In adult patients with myocardial infarction (from several days to 35 days old), ischemic stroke (from 7 days to 6 months old) or with diagnosed occlusive peripheral arterial disease.

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 (in combination with acetylsalicylic acid);
• With ST-segment elevation (acute myocardial infarction) during drug therapy and the possibility of thrombolysis (in combination with acetylsalicylic acid).

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

In 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 (in combination with acetylsalicylic acid).

ICD codes

Dosage Regimen

Lopirel is taken orally, regardless of meals.

Adults and elderly patients with normal CYP2C19 isoenzyme activity

Myocardial infarction, ischemic stroke and diagnosed occlusive peripheral arterial disease

The drug is taken 75 mg once a day.

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

Treatment with clopidogrel should be started with a single loading dose of 300 mg, then continued with a dose of 75 mg once a day (in combination with acetylsalicylic acid at doses of 75-325 mg/day).

Since the use of acetylsalicylic acid in higher doses is associated with an increased risk of bleeding, the recommended dose of acetylsalicylic acid for this indication should not exceed 100 mg.

The optimal duration of treatment has not been officially determined.

Clinical trial data support taking the drug for up to 12 months, with the maximum beneficial effect observed by the third month of treatment.

Acute coronary syndrome with ST-segment elevation (acute myocardial infarction with ST-segment elevation)

Clopidogrel should be taken once at 75 mg/day with an initial single loading dose of clopidogrel 300 mg in combination with acetylsalicylic acid with or without thrombolytics.

In elderly patients over 75 years of age, treatment with clopidogrel should be started without a loading dose.

Combination therapy is started as early as possible after the onset of symptoms and continued for at least 4 weeks.

The efficacy of the combination of clopidogrel and acetylsalicylic acid for this indication beyond 4 weeks has not been studied.

Atrial fibrillation

Clopidogrel should be taken at a dose of 75 mg once a day.

In combination with clopidogrel, acetylsalicylic acid (75-100 mg/day) should be started and then continued.

Missed dose

1. If less than 12 hours have passed since missing the next dose, the missed dose of the drug should be taken immediately, and then the next doses should be taken at the usual time.
2. If more than 12 hours have passed since missing the next dose, the patient should take the next dose at the usual time (a double dose should not be taken).

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. A higher dose regimen (loading dose – 600 mg, 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 activity of the CYP2C19 isoenzyme.

Special patient groups

In elderly volunteers over 75 years of age compared to young volunteers, no differences were found in platelet aggregation parameters and bleeding time. For elderly patients, dose adjustment is not required.

Lopirel should not be used in children, as there is no experience with its use in this patient group.

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

After daily administration of clopidogrel for 10 days at a daily dose of 75 mg in patients with severe hepatic impairment, 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 reduced metabolism of clopidogrel to its active metabolite differs among representatives of various ethnic groups. There are only limited data for individuals of Mongoloid race regarding the influence of the CYP2C19 isoenzyme genotype on clinical outcome events.

In a small study comparing the pharmacodynamic properties of clopidogrel in men and women, less inhibition of ADP-induced platelet aggregation was observed in women, but there were no differences in the prolongation of bleeding time. In the large controlled CAPRIE trial (Clopidogrel versus Acetylsalicylic Acid in Patients at Risk of Ischaemic Events), the incidence of clinical outcomes, other adverse events, and deviations from normal clinical laboratory parameters was the same in both men and women.

Adverse Reactions

The safety of clopidogrel has been studied in more than 44,000 patients, including more than 12,000 patients treated for one year or longer. The overall tolerability of clopidogrel was similar to that of acetylsalicylic acid, regardless of patient age, sex, or race. Clinically significant adverse effects observed in clinical trials: CAPRIE, CURE, CLARITY, COMMIT, and ACTIVE-A are listed below. The tolerability of clopidogrel 75 mg/day in the CAPRIE trial was consistent with the tolerability of acetylsalicylic acid 325 mg/day. This includes reports of adverse reactions in spontaneous reports.

Most frequently, bleeding was reported in clinical trials and during the post-marketing use of clopidogrel, with the majority of bleeding occurring during the first month of treatment.

In the CAPRIE clinical trial, the overall incidence of bleeding in patients receiving Clopidogrel or acetylsalicylic acid was 9.3%. The incidence of severe bleeding with clopidogrel use was similar to that with acetylsalicylic acid use.

In the CURE clinical trial, no increase in the incidence of major bleeding was observed with the use of clopidogrel plus acetylsalicylic acid for up to 7 days after coronary artery bypass graft surgery in patients who discontinued therapy more than 5 days prior to surgery. In patients who continued therapy within 5 days before coronary artery bypass graft surgery, the incidence of this event was 9.6% for the combination of Clopidogrel with acetylsalicylic acid and 6.3% for placebo in combination with acetylsalicylic acid.

In the CLARITY clinical trial, an overall increase in the incidence of bleeding was observed in the Clopidogrel + acetylsalicylic acid group compared to the placebo + acetylsalicylic acid group. The incidence of major bleeding was similar in both groups and was largely independent of baseline patient characteristics and the type of fibrinolytic or heparin therapy.

In the COMMIT clinical trial, the overall incidence of non-cerebral major bleeding or cerebral hemorrhage was low and did not differ significantly between the two groups.

In the ACTIVE-A clinical trial, the incidence of major bleeding in the Clopidogrel + acetylsalicylic acid group was higher than in the placebo + acetylsalicylic acid group (6.7% vs. 4.3%). Major bleeding was predominantly extracranial in both groups (5.3% vs. 3.5%), mainly gastrointestinal bleeding (3.5% vs. 1.8%). There were more intracranial hemorrhages in the Clopidogrel + acetylsalicylic acid group compared to the placebo + acetylsalicylic acid group (1.4% vs. 0.8%, respectively). There were no statistically significant differences between these treatment groups in the incidence of fatal bleeding (1.1% vs. 0.7%) and hemorrhagic stroke (0.8% vs. 0.6%).

The following are adverse reactions that have been observed in clinical trials or reported as spontaneous reports. The frequency of reactions is presented according to the following classification: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data). Within each organ system class, adverse reactions are presented in order of decreasing severity.

Blood and lymphatic system disorders: uncommon – thrombocytopenia, leukopenia, eosinophilia; rare – neutropenia, including severe neutropenia; very rare – thrombotic thrombocytopenic purpura (TTP), aplastic anemia, pancytopenia, agranulocytosis, severe thrombocytopenia, acquired hemophilia A, granulocytopenia, anemia.

Immune system disorders: very rare – serum sickness, anaphylactoid reactions; frequency not known – cross-reactive hypersensitivity with thienopyridines (such as ticlopidine, prasugrel).

Psychiatric disorders: very rare – hallucinations, confusion.

Nervous system disorders: uncommon – intracranial hemorrhage (some cases were fatal), headache, paresthesia, dizziness; very rare – taste disorder.

Eye disorders: uncommon – eye hemorrhages (conjunctival, ocular tissue, retinal).

Ear and labyrinth disorders: rare – vertigo.

Vascular disorders: common – hematomas, very rare – severe bleeding, bleeding from surgical wounds, vasculitis, decreased blood pressure.

Respiratory, thoracic and mediastinal disorders: common – epistaxis; very rare – respiratory tract bleeding (hemoptysis, pulmonary hemorrhage), bronchospasm, interstitial pneumonitis, eosinophilic pneumonia.

Gastrointestinal disorders: common – gastrointestinal bleeding, diarrhea, abdominal pain, dyspepsia; uncommon – gastric and duodenal ulcer, gastritis, vomiting, nausea, constipation, flatulence; rare – retroperitoneal bleeding; very rare – fatal gastrointestinal and retroperitoneal bleeding, pancreatitis, colitis (including ulcerative or lymphocytic), stomatitis.

Hepatobiliary disorders: very rare – acute liver failure, hepatitis, abnormalities in liver function tests.

Skin and subcutaneous tissue disorders: common – bruising; uncommon – rash, pruritus, purpura; very rare – bullous dermatitis (toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme), angioedema, drug hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS syndrome), erythematous or exfoliative rash, urticaria, eczema, lichen planus.

Musculoskeletal and connective tissue disorders: very rare – hemorrhage in the musculoskeletal system (hemarthrosis), arthritis, arthralgia, myalgia.

Renal and urinary disorders: uncommon – hematuria; very rare – glomerulonephritis, increased blood creatinine.

General disorders and administration site conditions: common – bleeding at puncture site; very rare – fever.

Investigations: uncommon – prolonged bleeding time, decreased neutrophil count, decreased platelet count.

Contraindications

• Hypersensitivity to clopidogrel or any excipient of the drug;
• Severe hepatic impairment;
• Active bleeding (including bleeding from a peptic ulcer or intracranial hemorrhage);
• Pregnancy and breastfeeding;
• Children under 18 years of age (efficacy and safety have not been established);
• Rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

With caution

• In moderate hepatic impairment, where there may be a predisposition to bleeding (limited clinical experience);
• In renal impairment (limited clinical experience);
• In trauma, surgical interventions (risk of increased bleeding);
• In conditions with a predisposition to bleeding (especially gastrointestinal or intraocular);
• With concurrent use of selective serotonin reuptake inhibitors (SSRIs);
• With concurrent use of NSAIDs, including selective COX-2 inhibitors;
• With concurrent use of warfarin, heparin, glycoprotein IIb/IIIa inhibitors;
• 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;
• In patients with genetically reduced function of the CYP2C19 isoenzyme (in patients who are poor CYP2C19 metabolizers, less of the active metabolite of clopidogrel is formed at recommended doses and its antiplatelet effect is weaker; poor metabolizers receiving Clopidogrel at recommended doses for acute coronary syndrome or percutaneous coronary intervention may have a higher rate of cardiovascular events than patients with normal CYP2C19 isoenzyme function).

Use in Pregnancy and Lactation

As a precaution, the use of Lopirel is contraindicated during pregnancy due to the lack of clinical data on its use in pregnant women, although studies of clopidogrel in animals did not reveal any direct or indirect adverse effects on pregnancy, embryonic development, childbirth, or postnatal development.

Breastfeeding should be discontinued during treatment with Lopirel, as studies in rats have shown that Clopidogrel and/or its metabolites are excreted in breast milk. It is not known whether Clopidogrel passes into human breast milk.

Use in Hepatic Impairment

The drug should be used with caution in patients with moderate hepatic impairment.

The drug is contraindicated in severe hepatic impairment.

Use in Renal Impairment

The drug should be used with caution in patients with moderate renal impairment.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

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, APTT, platelet count, platelet function indicators, and other necessary tests should be performed urgently.

Clopidogrel, like other antiplatelet agents, should be used with caution in patients with an increased risk of bleeding associated with trauma, surgery, or other pathological conditions, as well as in patients receiving acetylsalicylic acid, other NSAIDs, including COX-2 inhibitors, heparin, SSRIs, or glycoprotein IIb/IIIa inhibitors.

During treatment with clopidogrel, especially during the first weeks of treatment and/or after invasive cardiac procedures/surgery, patients should be carefully monitored for signs of bleeding, including occult bleeding.

Concomitant use of clopidogrel with warfarin may increase the intensity of bleeding; therefore, except for specific rare clinical situations (such as the presence of a left ventricular floating thrombus, stenting in patients with atrial fibrillation), concomitant use of clopidogrel and warfarin is not recommended.

If a patient is scheduled for elective surgery and the antiplatelet effect is not required, clopidogrel should be discontinued 7 days before surgery.

Before any scheduled surgery and before starting any new medication, patients should inform their physician (including dentist) about taking clopidogrel.

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

Patients should be warned that when taking clopidogrel (alone or in combination with acetylsalicylic acid) it may take longer to stop bleeding, and that they should report any unusual bleeding (in location or duration) to their physician.

Thrombotic thrombocytopenic purpura

Very rarely, cases of 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, renal dysfunction, and fever. TTP is a potentially life-threatening condition requiring immediate treatment, including plasmapheresis.

Acquired hemophilia

Acquired hemophilia has been reported with the use of clopidogrel. In case of confirmed APTT prolongation with or without bleeding, the possibility of acquired hemophilia should be considered. If a diagnosis of acquired hemophilia is established, appropriate treatment should be initiated and clopidogrel should be discontinued.

Recent ischemic stroke

The use of Lopirel is not recommended in acute ischemic stroke of less than 7 days duration (as there are no data on its use in this condition).

In patients with a recent ischemic stroke or transient ischemic attack and a high risk of recurrent atherothrombotic events, combination therapy with clopidogrel and acetylsalicylic acid did not demonstrate higher efficacy compared to clopidogrel monotherapy but may increase the risk of major bleeding.

Cytochrome P450 isoenzyme CYP2C19

Pharmacogenetics: In patients with slow CYP2C19-mediated metabolism, at recommended doses of clopidogrel, less of the active metabolite of clopidogrel is formed and a weaker effect on platelet aggregation is observed. Tests are available to determine the CYP2C19 isoenzyme genotype in patients.

Since Clopidogrel is metabolized to active metabolites partly by the CYP2C19 isoenzyme, the use of drugs that inhibit the activity of this enzyme will 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 strong and moderate inhibitors of the CYP2C19 isoenzyme is not recommended.

Cross-reactions with thienopyridines

Since cross-hypersensitivity reactions have been reported during treatment with thienopyridines, before starting treatment, the patient should be asked about a history of hypersensitivity reactions to thienopyridines (Clopidogrel, ticlopidine, prasugrel).

Thienopyridines can cause allergic reactions of varying severity, such as rash, angioedema, or hematological cross-reactions (thrombocytopenia and neutropenia). In patients who have experienced allergic reactions and/or hematological reactions during previous treatment with one thienopyridine, the risk of developing similar reactions or reactions of a different kind when taking another thienopyridine may be increased. Monitoring for symptoms of hypersensitivity is recommended in patients with a history of allergic reactions to thienopyridines.

Renal impairment

Experience with clopidogrel in patients with renal impairment is limited, so it should be used with caution in this patient group.

Hepatic impairment

Experience in patients with moderate hepatic impairment, who are at risk of hemorrhagic diathesis, is limited. Lopirel should be used with caution in this patient group.

Lactose content in the drug

Lopirel should not be prescribed to patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Effect on ability to drive and use machines

Clopidogrel does not significantly affect the ability to drive or operate machinery.

Overdose

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

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

Drug Interactions

Indirect anticoagulants: Concomitant use of clopidogrel and indirect anticoagulants is not recommended due to a possible increase in bleeding intensity. Although the administration of clopidogrel 75 mg/day did not affect the pharmacokinetics of S-warfarin or INR in patients receiving long-term warfarin therapy, concomitant use of clopidogrel with warfarin increases the risk of bleeding due to independent effects on hemostasis.

IIb/IIIa receptor blockers: the administration of IIb/IIIa receptor blockers together with clopidogrel requires caution.

Acetylsalicylic acid does not alter the effect of clopidogrel inhibiting ADP-induced platelet aggregation, but Clopidogrel potentiates the effect of acetylsalicylic acid on collagen-induced platelet aggregation. However, the simultaneous administration of acetylsalicylic acid at a dose of 500 mg twice a day for 1 day with clopidogrel did not cause a significant increase in the bleeding time induced by clopidogrel. A pharmacodynamic interaction between clopidogrel and acetylsalicylic acid is possible, which leads to an increased risk of bleeding. Therefore, caution should be exercised when they are used concomitantly, although in clinical studies, patients received combination therapy with clopidogrel and acetylsalicylic acid for up to one year.

Heparin: according to a clinical study involving healthy individuals, the use of clopidogrel did not require a change in the heparin dose and did not alter its anticoagulant effect. The concomitant use of heparin did not change the antiplatelet effect of clopidogrel. A pharmacodynamic interaction between clopidogrel and heparin is possible, which may increase the risk of bleeding, so the concomitant use of these drugs requires caution.

Thrombolytics: the safety of the combined use of clopidogrel, fibrin-specific or fibrin-non-specific thrombolytic drugs and heparin was studied in patients with acute myocardial infarction. The incidence of clinically significant bleeding was similar to that observed with the combined use of thrombolytics and heparin with acetylsalicylic acid.

NSAIDs: in a clinical study involving healthy volunteers, the concomitant use of clopidogrel and naproxen increased occult gastrointestinal blood loss. However, due to the lack of studies on the interaction of clopidogrel with other NSAIDs, it is currently unknown whether there is an increased risk of gastrointestinal bleeding when taking clopidogrel together with other NSAIDs. Therefore, NSAIDs, including COX-2 inhibitors, should be prescribed in combination with clopidogrel with caution.

Selective serotonin reuptake inhibitors (SSRIs): since SSRIs affect platelet activation and increase the risk of bleeding, their simultaneous use with clopidogrel requires caution.

Other combination therapy. Since Clopidogrel is metabolized to form an active metabolite partially with the participation of the CYP2C19 isoenzyme, the use of drugs that inhibit this isoenzyme may lead to a decrease in the plasma concentration of the active metabolite of clopidogrel and a reduction in its clinical efficacy. The clinical significance of this interaction is unknown. As a precautionary measure, the simultaneous use of strong and moderate inhibitors of the CYP2C19 isoenzyme should be avoided.

Drugs that inhibit the CYP2C19 isoenzyme include omeprazole and esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine, and chloramphenicol.

Proton pump inhibitors

When omeprazole was taken at a dose of 80 mg once a day together with clopidogrel or when they were taken together with an interval of less than 12 hours, the exposure of the active metabolite decreased by 45% (loading dose) and by 40% when taking the maintenance dose. This change in values was associated with a reduction in platelet aggregation inhibition by 39% when taking the loading dose and by 21% when taking the maintenance dose. Esomeprazole is expected to have a similar interaction effect with clopidogrel. Clinical and observational studies have yielded a number of conflicting data on the clinical significance of this pharmacodynamic and pharmacokinetic interaction regarding the development of serious cardiovascular complications. As a precautionary measure, it is recommended to avoid the simultaneous use of omeprazole or esomeprazole with clopidogrel.

A less pronounced reduction in metabolite exposure was observed with the use of pantoprazole or lansoprazole.

The concentration of the active metabolite was reduced by 20% when taking the loading dose and by 14% when taking the maintenance dose during the simultaneous administration of pantoprazole at a dose of 80 mg once a day. This was also accompanied by a decrease in the mean value of platelet aggregation inhibition by 15% and 11%, respectively. These data indicate that Clopidogrel can be used concomitantly with pantoprazole. There are no data indicating that other drugs that reduce gastric acidity, such as histamine H₂-receptor blockers (except for cimetidine, which is a CYP2C19 isoenzyme inhibitor) or antacids, affect the antiplatelet properties of clopidogrel.

Other drugs: a number of clinical studies were conducted with clopidogrel and other concomitantly prescribed drugs to investigate possible pharmacodynamic and pharmacokinetic interactions. No clinically significant pharmacodynamic interaction was observed when clopidogrel was used together with atenolol, nifedipine, or both drugs simultaneously. Furthermore, the simultaneous administration of phenobarbital or estrogens had a minor effect on the pharmacodynamic activity of clopidogrel.

The pharmacokinetic parameters of digoxin and theophylline did not change when they were 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 the fact that data obtained from studies with human liver microsomes indicate that the carboxylic acid metabolite of clopidogrel may inhibit the activity of the cytochrome P450 family 2C9 isoenzyme, which may lead to increased plasma concentrations of some drugs (phenytoin, tolbutamide, and some NSAIDs) that are metabolized by the cytochrome P450 family 2C9 isoenzyme.

No other clinical studies of the interaction of clopidogrel with drugs frequently used in patients with atherothrombotic complications have been conducted. Clinical studies have not revealed any clinically significant adverse interactions with ACE inhibitors, diuretics, beta-blockers, slow calcium channel blockers, lipid-lowering agents, coronary vasodilators, hypoglycemic agents (including insulin), antiepileptic drugs, hormone replacement therapy, and IIb/IIIa receptor blockers.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 3 years.

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.