Expiration date: 01/2026

The composition and form of issue:

Tablets, film-coated 1 tab.

active substances: 

clopidogrel hydrosulfate in the form II 97,875 mg

(in terms of clopidogrel — 75 mg) 

acetylsalicylic acid 100 mg

excipients 

core: mannitol — 68,925 mg macrogol 6000 — 34 mg MKC — 144,764 mg hyprolose nizkosoleva — 19,567 mg castor oil hydrogenated — 3.3 mg stearic acid — 1,161 mg silica colloidal anhydrous — 0,631 mg corn starch — 11,111 mg 

shell: Opadry pink 20 mg Carnauba wax traces 

*Opadry pink lactose monohydrate hypromellose titanium dioxide (E171) triacetin dye iron oxide red (E172) 

according to table 7. in PVC/aluminium blister packs in cardboard pack 1, 2 or 4 blisters.

Description pharmaceutical form:

Tablets, film-coated, oval, biconvex light pink color, engraved with C75 on one side and A100 on the other side.

Pharmacokinetics:

Clopidogrel

In exchange oral administration at a dose of 75 mg/day, clopidogrel is rapidly absorbed. Mean Cmax of unchanged clopidogrel in plasma (approximately 2.2–2.5 ng/ml after ingestion of a single dose of 75 mg) are achieved after about 45 min after ingestion. According excretion of clopidogrel metabolites with the urine, its absorption is approximately 50%.

In vitro clopidogrel and the main circulating inactive metabolite bind reversibly to plasma proteins (98% and 94%, respectively), and this relationship is an unsaturated up to a concentration of 100 mg/L.

Clopidogrel is extensively metabolized in the liver. In vitro and in vivo, clopidogrel is metabolized in two ways: one is via esterase with subsequent hydrolysis with the formation of the inactive carboxylic acid derivative (85% of circulating metabolites), and the second way is via the cytochrome P450 system. First, clopidogrel is metabolized to 2-oxo-clopidogrel, which is an intermediate metabolite. Subsequent metabolism of 2-oxo-clopidogrel leads to the formation of the active metabolite clopidogrel — Colnago derivative of clopidogrel. In vitro, this pathway occurs by means of P450 isoenzymes CYP2C19, CYP1A2 and CYP2B6. Carbothiolic active metabolite of clopidogrel, which has been highlighted in studies in vitro, rapidly and irreversibly binds to receptors on platelets, thus inhibiting platelet aggregation.

Within 120 h after ingestion by a human of 14C-labelled clopidogrel is about 50% of the radioactivity excreted by the kidneys and approximately 46% of the radioactivity in the intestine. After a single oral dose of 75 mg T1/2 of clopidogrel is approximately 6 h After a single dose and receiving repeated doses T1/2 of the main circulating inactive metabolite is 8 h.

Pharmacogenetics

Several polymorphic enzymes P450 system involved in the activation of clopidogrel. The isoenzyme CYP2C19 is involved in education as an active metabolite, and intermediate metabolites — 2-oxo-clopidogrel. Pharmacokinetics and antiplatelet effects of the active metabolite of clopidogrel, was investigated by platelet aggregation ex vivo, differ depending on the genotype of the CYP2C19 isoenzyme. The allele of CYP2C19*1 is responsible for the normal functioning of the metabolism, whereas alleles of the gene for the isoenzyme CYP2C19*2 and CYP2C19 isoenzyme*3 responsible for reduced metabolism. These alleles are responsible for the decrease in metabolism of approximately 85% of Caucasian and 99% of representatives of the Mongoloid race. Other alleles that cause reduced metabolism, represented by the isoenzymes CYP2C19*4, *5, *6, *7 and *8, but they are rare in the General population. Published data on the frequency of occurrence of the phenotype and genotype of the CYP2C19 isoenzyme in the table.

The frequency of phenotype and genotype of CYP2C19 isoenzyme

Kind of metabolism genotype CYP2C19	Frequency, %
	Caucasians (n=1356)	Negroid (n=966)	Mongoloids (n=573)
Intensive metabolism — CYP2C19*1/*1	74	66	38
Intermediate metabolism — CYP2C19*1/*2 ??? *1/*3	26	29	50
Reduced metabolism — CYP2C19*2/*2 ??? *2/*3 ??? *3/*3	2	4	14

The influence of genotype of CYP2C19 isoenzyme on the pharmacokinetics of the active metabolite of clopidogrel was studied in 227 people in 7 published studies. Individuals with reduced metabolism of isoenzyme CYP2C19 was found to decrease Cmax and AUC of the active metabolite by 30-50% after taking a loading dose 300 or 600 mg and subsequent maintenance doses to 75 mg. a Reduced activity of the metabolite of clopidogrel may lead to less inhibition of platelets or Hyper-reactivity. At the moment, attenuated antiplatelet response to clopidogrel have been described for individuals with intermediate and reduced metabolism in 21 study subjects 4520. The relative difference in antiplatelet response between groups with different genotype differed in the studies due to the use of different methods of assessment of response, but was more than 30%.

The relationship between the genotype of isozyme CYP2C19 and outcome with clopidogrel therapy were evaluated in two post-marketing clinical studies (study CLARITY-TIMI 28, n=465 and TRITON-TIMI 38, n=1477) and 5 cohort studies (n=6489). In CLARITY-TIMI 28 and one of the cohort studies (Trenk, n=765) frequency of cardiovascular events did not differ significantly depending on the genotype. In TRITON-TIMI 38 and three cohort studies (Collet, Sibbing, Giusti, n=3516) patients with intermediate and reduced metabolism had a greater frequency of cardiovascular events (death, myocardial infarction, stroke) or stent thrombosis compared to patients with intense metabolism. In the fifth cohort study (Simon, n=2208) increase in frequency of cardiovascular events was observed only in patients with reduced metabolism.

Pharmacogenetic testing allows us to determine the genotype with variability in the activity of isoenzyme CYP2C19.

It is also possible genetic variants of other enzymes of the P450 system with influence on the formation of active metabolites of clopidogrel.

Pharmacokinetics of clopidogrel in certain group of patients

The pharmacokinetics of the active metabolite of clopidogrel in certain group of patients has not been studied.

The elderly. The volunteers of advanced age (over 75 years) when compared with young volunteers has not been received differences in platelet aggregation and bleeding time. No dose adjustment is required for elderly.

Children and adolescents. Data are not available.

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

The liver dysfunction. After daily within 10 days of receiving clopidogrel at a daily dose of 75 mg in patients with severe liver damage (classes A and b on a scale child-Pugh) inhibition of ADP-induced platelet aggregation was similar to that in healthy volunteers. The average time of bleeding was also comparable in both groups.

Ethnicity.The prevalence of gene alleles of the CYP2C19 isoenzyme responsible for the intermediate and reduced metabolism, excellent representatives of various ethnic groups. There is very little published data on their prevalence among the representatives of the Mongoloid race, which does not allow to evaluate the impact of genotyping of CYP2C19 isoenzyme on the clinical outcome.

Acetylsalicylic acid

Contained in the product, Koplewicz® acetylsalicylic acid after intake and admission into the systemic circulation undergoes hydrolysis in plasma to salicylic acid, where Cmax in plasma achieved through 1-1. 5 h after administration of the drug. Due to the rapid hydrolysis of acetylsalicylic acid it is practically not detected in the plasma after 1.5–4 h after ingestion of the drug, Koplewicz®.

Aspirin is poorly bound to plasma proteins and has a small Vd (10 l). A metabolite of acetylsalicylic acid, salicylic acid, irrespective of its plasma concentration, is very well bound with plasma proteins. At low concentrations (<100 µg/ml) about 90% of salicylic acid is bound to plasma proteins. Salicylic acid is well distributed to all tissues and body fluids, including the CNS, breast milk and fetal tissue.

Acetylsalicylic acid at doses between 75 and 325 mg has T1/2, amounting to 0.3–0.4 hours (due to rapid hydrolysis in plasma to salicylic acid). Salicylic acid mainly undergoes conjugation in the liver with the formation comprise acid the phenolic and acyl glucuronides of salicylic acid, and several other minor metabolites. Plasma T1/2 of salicylic acid is approximately 2 h. The rate of excretion of salicylic acid is constant, not dependent on its plasma concentration, and high doses of acetylsalicylic acid T1/2 of salicylic acid is 6 hours or more. Salicylate metabolism is saturable, its total clearance at high concentrations of salicylic acid in the serum is reduced due to the limited ability of the liver to form comprise acid and phenolic glucuronide of salicylic acid. After the toxic doses of acetylsalicylic acid (10-20 g) plasma T1/2 of salicylate may increase to 20 h. Excretion through the kidneys unchanged salicylic acid depends on urinary pH. So when urine pH values above 6.5, the renal clearance of free salicylate increases from <5% to >80%. After administration of therapeutic doses in the urine is found in about 10% of salicylic acid, 75% comprise acid, 10% phenolic and 5% acyl glucuronides of salicylic acid.

On the basis of the pharmacokinetics and metabolic properties of both active drug substances, Koplewicz® between them is not expected to be clinically relevant pharmacokinetic interactions.

Description pharmacological action:

Clopidogrel (or rather its active metabolite) irreversibly binds to the platelet ADP-receptor and selectively inhibits binding of ADP to ADP receptors of platelets and subsequent activation of the complex GPIIb/IIIa by the action of ATP, thereby suppressed the ADP-induced platelet aggregation. Clopidogrel also inhibits platelet aggregation, caused by other agonists, due to the fact that blocks the activation of platelets released ADP. In connection with the irreversibility of communication with clopidogrel ADP-receptor of platelets, the platelets remain unresponsive to stimulation of the ADP for the remaining period of his life, and the restoration of normal platelet function occurs at a rate corresponding with the refresh rate of platelets.

The daily clopidogrel dose of 75 mg from the first day of admission showed a significant inhibition of ADP-induced platelet aggregation, which gradually increased over 3-7 days and then goes at a constant level (at equilibrium state). In steady state, platelet aggregation is inhibited on average by 40-60%. After stopping clopidogrel, platelet aggregation and bleeding time gradually return to baseline levels within an average of 5 days.

Acetylsalicylic acid inhibits platelet aggregation through irreversible inhibition of COX-1, thereby reducing the formation of thromboxane A2, which is the inducer of platelet aggregation and vasoconstriction. This effect persists for the entire lifetime of the platelets.

Acetylsalicylic acid does not alter the inhibitory effects of clopidogrel on ADP-induced platelet aggregation, as clopidogrel increases the effect of acetylsalicylic acid on collagen-induced platelet aggregation.

Both active ingredients are able to prevent the development of atherothrombosis in all localizations of atherosclerotic vascular lesions, in particular lesions in the cerebral, coronary or peripheral arteries.

Indications:

Prevention of atherothrombotic events in acute coronary syndrome:

• without ST-segment elevation (unstable angina or myocardial infarction without Q wave), including patients who was held stenting in percutaneous coronary intervention
  
• segment elevation ST (acute myocardial infarction) treatment is medication and the possibility of thrombolysis.
  

Contraindications:

hypersensitivity to any of the active or the excipients of the drug

severe liver failure

severe renal insufficiency

acute pathological bleeding, such as bleeding peptic ulcer or intracranial hemorrhage

allergic to NSAIDs and syndrome Fernand-Vidal (intolerance to aspirin, asthma and nasal polyposis, and paranasal sinuses)

rare hereditary disorders of galactose tolerance, lactase deficiency or malabsorption syndrome glucose-galactose

pregnancy and lactation (see "pregnancy and breastfeeding")

children up to age 18 years (safety and efficacy not established)

the concomitant use of methotrexate in a dose of 15 mg per week.

Caution: moderate hepatic impairment, where a possible predisposition to bleeding (limited clinical experience) renal failure mild and moderate severity (limited clinical experience) trauma, surgery (see "Special instructions") disease in which there is a predisposition to the development of bleeding (especially gastrointestinal or intra-ocular) the simultaneous use of other NSAIDs, including and selective COX-2 inhibitors the simultaneous use of warfarin, heparin, inhibitors of the glycoprotein IIb/IIIa, and thrombolytic drugs (see "Interactions" and "Special instructions") asthma and allergic disease (increased risk of allergic reactions to acetylsalicylic acid) gout, hyperuricemia (acetylsalicylic acid, including in low doses, increases the concentration of uric acid in the blood) in patients with genetically determined reduced function of the CYP2C19 isoenzyme (there are published data indicating that patients with genetically determined reduced function of the CYP2C19 isoenzyme are exposed to lower systemic exposure of the active metabolite of clopidogrel and they have less pronounced antiaggregatory action of the drug, in addition they may experience increased frequency of cardiovascular complications after myocardial infarction compared with patients with normal function of the isoenzyme CYP2C19) concomitant use of methotrexate at a dose less than 15 mg per week.

Application of pregnancy and breast-feeding:

As a precaution the drug, Koplewicz during pregnancy is contraindicated.

Animal studies have revealed no clopidogrel have no direct or indirect adverse effects on pregnancy, embryonic development, childbirth and postnatal development, but acetylsalicylic acid was found to have teratogenic effects. Clinical data for clopidogrel and drug Koplewicz pregnant women do not exist.

Breastfeeding in the case of drug treatment, Koplewicz should stop, because it is established that acetylsalicylic acid is excreted in human milk, and studies in rats have shown that clopidogrel and/or its metabolites also are excreted in breast milk. Penetrates or not clopidogrel in human breast milk is unknown.

Side effects:

Bleeding

- In the clinical trial CAPRIE

The overall incidence of all bleeding in patients treated with or clopidogrel, or acetylsalicylic acid, was 9.3%. The frequency of severe bleeding with the use of clopidogrel was 1.4%, and in the application of atsetilsalitsilovoj acid is 1.6%.

Patients treated with clopidogrel and patients treated with acetylsalicylic acid gastrointestinal bleeding were found respectively in 2% and 2.7% of cases and hospitalization was required in 0.7 and 1.1% of cases.

The frequency of other bleeding was higher in patients treated with clopidogrel than in patients receiving aspirin (compared to 6.5 and 7.3%, respectively). However, the frequency of serious bleeding in both groups was the same (0,6 versus 0.4%). Most frequently in both groups was observed purpura/bruising and epistaxis. Rarely met hematomas, hematuria, eye bleeding (mainly conjunctival).

The frequency of intracranial hemorrhage was 0.4% in patients receiving clopidogrel and 0.5% — in patients receiving acetylsalicylic acid.

- In a clinical study CURE

The combination of clopidogrel with acetylsalicylic acid in comparison with the combination of placebo with acetylsalicylic acid did not lead to statistically reliable increase in the frequency of life-threatening bleeding (2.2 and 1.8% respectively) and fatal bleeding (0.2 and 0.2 percent, respectively). However, with the combination of clopidogrel + acetylsalicylic acid, the risk of large, small and other bleeding was significantly higher: not dangerous for the life of major bleeding primarily gastrointestinal and at puncture location (1,6% — clopidogrel + acetylsalicylic acid vs. 1% placebo + aspirin) and minor bleeding (5.1%, or clopidogrel + aspirin vs. 2.4% placebo + aspirin). The frequency of intracranial hemorrhage in both groups was 0.1%.

Frequency of major bleeding with the combination of clopidogrel + acetylsalicylic acid was dependent on the dose of the latter (<100 mg and 2.6 % for 100-200 mg and 3.5%, >200 mg to 4.9%) as well as their frequency in the use of one aspirin (<100 mg — 2%, 100-200 mg of 2.3%, >200 mg — 4%).

In the study, risk of bleeding is increased (representing a danger to life, major, small, other) decreased as when taking the combination of clopidogrel and acetylsalicylic acid, and by only taking one of acetylsalicylic acid, accounting respectively for 9.6% (599/6259) and 6.6% (413/6303) (0-1 months of treatment), 4,5% (276/6123) and 2.3% (144/6168) (1-3 months of treatment) to 3.8% (228/6037) and 1.6% (99/6048) (3-6 months of treatment) and 3.2% (162/5005) and 1.5% (74/4972) (6-9 months of treatment), 1,9% (73/3841) and 1.0% (40/3844) (9-12 months of treatment).

Patients ceased taking the drug more than 5 days before CABG, there has been no increase in cases of major bleeding within 7 days after the intervention (4,4% — clopidogrel + acetylsalicylic acid vs. 5.3% — when receiving one acetylsalicylic acid). Patients remain on antiplatelet therapy in the last five days before coronary artery bypass grafting, the frequency of these events after the intervention was 9.6% (clopidogrel + acetylsalicylic acid) and 6.3% (one acetylsalicylic acid).

- In a clinical study CLARITY

Observed a General increase in the frequency of bleeding in the group of clopidogrel + acetylsalicylic acid (17,4%) compared with placebo + acetylsalicylic acid (12.9 per cent). Frequency of major bleeding was in both groups similar (1.3 and 1.1% in groups of clopidogrel + acetylsalicylic acid and placebo + acetylsalicylic acid, respectively) and practically did not depend on the baseline characteristics of patients and type of fibrinolytic or heparin therapy. The frequency of fatal bleeding (0.8% and 0.6% in groups of clopidogrel + acetylsalicylic acid and placebo + acetylsalicylic acid, respectively) and intracranial hemorrhage (0.5 and 0.7% in groups of clopidogrel + acetylsalicylic acid and placebo + acetylsalicylic acid, respectively) was low and was not significantly different in both treatment groups.

- In a clinical trial COMMIT

Acerebral the overall frequency of major bleeding or cerebral bleeding was low and was not significantly different in both groups (0.6 and 0.5% in groups of clopidogrel + acetylsalicylic acid and placebo + acetylsalicylic acid, respectively).

Hematological disorders

- In the clinical trial CAPRIE

Severe neutropenia (<0,45·109/l) was observed in 4 patients (0,04%) that received clopidogrel and 2 patients (0.02 per cent) treated with acetylsalicylic acid. Two of the 9599 patients who received clopidogrel, the number of neutrophils was zero, and none of the 9586 patients who received aspirin, the extent of reduction in the number of neutrophils were noted. In the course of treatment with clopidogrel was observed one case of aplastic anemia.

The frequency of severe thrombocytopenia (<80·109/l) was 0.2% in the clopidogrel group and 0.1% in the group of acetylsalicylic acid.

- In clinical studies, CURE and CLARITY

The number of patients with thrombocytopenia or neutropenia in both groups was the same.

Other clinically significant side effects

Side effects observed in clinical trials CAPRIE, CURE, CLARITY and COMMIT with a frequency of <0.1% and all severe side effects are listed below in accordance with the classification of side effects who. Their frequency is defined as follows: common (>1/100, <1/10) uncommon (>1/1000, <1/100) rare (>1/10000, <1/1000).

Violations of the Central and peripheral nervous system: rare — headache, dizziness paresthesia, and rarely vertigo.

Violations by the gastrointestinal tract: common — diarrhea, abdominal pain, dyspepsia rare — nausea, gastritis, flatulence, constipation, vomiting, gastric ulcer and duodenal ulcer.

Violations of hemostasis: rare — prolonged bleeding time.

Violations of the blood: rare — thrombocytopenia, leukopenia, neutropenia, and eosinophilia.

Violations of the skin and subcutaneous tissue: uncommon — rash and itching.

Undesirable effects observed during post-marketing period, the use of clopidogrel monotherapy and in combination with acetylsalicylic acid

Bleeding

The most frequent reports of adverse effects have been reports on the development of bleeding, which are often observed in the first month of treatment. There have been several cases of bleeding/hemorrhage with fatal outcome, mainly intracranial, gastrointestinal and retroperitoneal. There are reports of severe cases of hemorrhage in the tissue of the skin (purpura), bleeding into muscles and joints (hemarthrosis, hematoma), eye bleeding (conjunctival, tissue and the retina of the eye), nasal bleeding, bleeding from the respiratory organs (hemoptysis, pulmonary hemorrhage), hematuria and hemorrhage of operative wound. In patients, taking clopidogrel simultaneously with acetylsalicylic acid or simultaneously with acetylsalicylic acid and heparin have also been cases of severe bleeding (see "Interactions" and "Special instructions").

Other side effects

In addition to the side effects identified during clinical trials and listed above, the results of spontaneous messages were registered is presented below side effects, divided into groups according to the classification of adverse reactions in accordance with the defeat of organs and systems of organs, represented in the medical dictionary for regulatory activities MedDRA. The frequency of all spontaneous reports of adverse effects observed when clopidogrel was very low (they are classified as very rare <1/10000). For acetylsalicylic acid the data on the frequency of occurrence of side effects. In each frequency group, adverse effects are presented in order of decreasing of their severity.

Violations of the blood: anemia (due to clopidogrel or acetylsalicylic acid) tromboliticescoe thrombocytopenic purpura (TTP) (1:200000 of treated patients), severe thrombocytopenia (platelet count <30·109/l), agranulocytosis, granulocytopenia, aplastic anemia (pancytopenia) (caused by clopidogrel).

Violations by the immune system: angioedema, urticaria, anaphylactoid reactions, serum sickness (caused by clopidogrel), anaphylactic shock, aggravation of symptoms of food allergies (caused by acetylsalicylic acid).

Psychiatric disorders: confusion, hallucinations (caused by clopidogrel).

Violations of the nervous system: changes in taste (caused by clopidogrel).

Violations of the organ of hearing and labyrinth disorders: tinnitus, hearing loss (due to acetylsalicylic acid and is usually occur when the overdose).

Violations of the cardiovascular system: vasculitis, decrease in blood pressure (caused by clopidogrel).

Disorders from the respiratory: bronchospasm (due to clopidogrel or acetylsalicylic acid), interstitial pneumonitis (caused by clopidogrel).

Disorders gastrointestinal: pancreatitis, colitis (including ulcerative or lymphocytic), stomatitis (caused by clopidogrel) ulcer or ulcerative perforation of the stomach or duodenum, symptoms of lesions of the upper gastrointestinal tract, such as gastralgia (caused by acetylsalicylic acid).

Violations of the hepatobiliary system: acute hepatic failure, hepatitis (caused by clopidogrel).

Violations of the skin and subcutaneous tissue: maculopapular or erythematous rash, pruritus, bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), eczema and oral lichen planus (caused by clopidogrel).

Violations of the musculoskeletal system: arthralgia, arthritis, myalgia (caused by clopidogrel).

Violations of the kidney and urinary tract diseases: glomerular disease (caused by clopidogrel), acute renal failure (especially in patients with already existing renal insufficiency, cardiac insufficiency, nephritic syndrome, or concurrent use of diuretics) (caused by acetylsalicylic acid).

Violations of metabolism: hypoglycemia, gout (caused by acetylsalicylic acid).

General disorders: fever (caused by clopidogrel).

Changes in laboratory values: abnormal biochemical indicators of liver function, the increase in creatinine concentration in the blood (caused by clopidogrel).

Drug interactions:

Warfarin: concomitant use of the drug, Koplewicz with warfarin is not recommended because this combination can increase the intensity of bleedings (see section "Special instructions").

Inhibitors of glycoprotein IIb/IIIA: inhibitors of glycoprotein IIb/IIIA in conjunction with the drug Koplewicz requires caution in patients with an increased risk of bleeding (trauma and surgical interventions or other pathological conditions) (see "Special instructions").

Heparin: in clinical studies conducted in healthy individuals, while clopidogrel did not require changing the dose of heparin and did not change its anticoagulant effects. Coadministration of heparin did not change the inhibitory effect of clopidogrel on platelet aggregation. Between the drug, Koplewicz and heparin is possible pharmacodynamic interaction, which may increase the risk of bleeding, therefore the simultaneous use of these drugs requires caution (see section "Special instructions").

Thrombolytics: the safety of joint use of clopidogrel, fibrinoliticeski or not fibrinoliticeski thrombolytic drugs and heparin was studied in patients with acute myocardial infarction. The frequency of clinically significant bleeding was similar to that observed in the case of a joint application means of the thrombolytic and heparin with acetylsalicylic acid. In connection with insufficiency of clinical data on the combined use of the drug, Koplewicz and thrombolytic means in combination with caution (see "Special instructions").

NSAIDs: in a clinical study involving healthy volunteers, the combined use of clopidogrel and naproxen increased the hidden blood loss through the gastrointestinal tract. Therefore, the use of NSAIDs, including COX-2 inhibitors, in combination with the drug, Koplewicz is not recommended (see "Special instructions").

Other combination therapy with clopidogrel

Since clopidogrel is metabolized to its active metabolite partly by using isozyme CYP2C19, it is anticipated that the use of drugs that inhibit the activity of this isoenzyme, may result in decreased concentrations of the active metabolite of clopidogrel. The clinical significance of this interaction is unknown. Simultaneous with clopidogrel, the use of strong or moderate inhibitors of the isoenzyme CYP2C19 (e.g., omeprazole) is not recommended. If the patient still requires the assignment of proton pump inhibitors concurrently with the drug, Koplewicz, you should use the drug with little effect on the activity ???2?19, such as pantoprazole.

Conducted a series of clinical trials with clopidogrel and other simultaneously used drugs to study the possible pharmacodynamic and pharmacokinetic interactions, which showed that:

• the use of clopidogrel in conjunction with atenolol, nifedipine, or both drugs simultaneously clinically significant pharmacodynamic interactions were observed
  
• concurrent use of phenobarbital, cimetidine or estrogen had no significant effect on the pharmacodynamics of clopidogrel
  
• the pharmacokinetic parameters of digoxin or theophylline was not altered in a joint application their with clopidogrel
  
• antacids did not reduce the absorption of clopidogrel
  
• phenytoin and tolbutamide can be safely used in conjunction with clopidogrel (CAPRIE study), despite the fact that data obtained in studies with human liver microsomes, indicate that the carboxyl metabolite of clopidogrel can inhibit the activity of CYP2C9 isoenzyme of the cytochrome P450 family that can lead to increased plasma concentrations of certain drugs, such as phenytoin, tolbutamide, and some NSAIDs, which metaboli