Instructions Trombonet film-coated tablets 0.075 g blister No. 30
Composition
active ingredient: clopidogrel bisulfate (clopidogrel hydrosulfate);
1 tablet contains clopidogrel bisulfate (clopidogrel hydrosulfate) 97.875 mg, equivalent to clopidogrel – 75 mg;
excipients: mannitol (E 421), microcrystalline cellulose, low-substituted hydroxypropylcellulose, hydrogenated castor oil, polyethylene glycol, Opadry II 85F 240069 Pink (polyvinyl alcohol, titanium dioxide (E 171), talc, red iron oxide (E 172), yellow iron oxide (E 172), polyethylene glycol).
Dosage form
Film-coated tablets.
Main physicochemical properties: round tablets with a biconvex surface, coated with a film coating from pink to dark pink.
Pharmacotherapeutic group
Platelet aggregation inhibitors, except heparin.
ATX code B01A C04.
Pharmacological properties
Pharmacodynamics.
Mechanism of action. Clopidogrel is a prodrug. One of the metabolites of clopidogrel is an inhibitor of platelet aggregation. To form the active metabolite, which inhibits platelet aggregation, clopidogrel must be biotransformed by cytochrome CYP 450 enzymes. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its P2Y12 receptors on the platelet surface and the subsequent ADP-induced activation of the glycoprotein IIb/IIIa complex, thereby inhibiting platelet aggregation. Since the binding is irreversible, platelets that have interacted with clopidogrel remain altered throughout their lifespan (which is approximately 7–10 days), and the restoration of normal platelet function occurs at a rate that corresponds to the rate of platelet turnover. Platelet aggregation induced by agonists other than ADP is also inhibited by the drug blocking platelet activation by released ADP.
Since the active metabolite is formed by cytochrome CYP 450 enzymes, some of which are polymorphic or inhibited by other drugs, not all patients experience sufficient inhibition of platelet aggregation.
Pharmacodynamic effects. From the first day of use, repeated daily doses of 75 mg of the drug show a significant inhibition of ADP-induced platelet aggregation. This effect progressively increases and stabilizes between 3 and 7 days. At steady state, the average level of inhibition of aggregation under the influence of a daily dose of 75 mg is from 40% to 60%. Platelet aggregation and bleeding time return to baseline on average 5 days after discontinuation of treatment.
Clinical efficacy and safety: The safety and efficacy of clopidogrel have been evaluated in seven double-blind studies involving over 100,000 patients: the CAPRIE study, comparing clopidogrel with acetylsalicylic acid (ASA), and the CURE, CLARITY, COMMIT, CHANCE, POINT, and ACTIVE-A studies, comparing clopidogrel with placebo, both in combination with ASA and other standard therapy.
Recent myocardial infarction (MI), stroke, or established peripheral arterial disease. CAPRIE enrolled patients with atherothrombosis as manifested by recent MI (<35 days ago), recent ischemic stroke (7 days to 6 months ago), or established peripheral arterial disease (PAD). Patients were randomized to receive clopidogrel 75 mg/day or ASA 325 mg/day and were followed for 1 to 3 years. In the MI subgroup, most patients received ASA within the first few days of their MI.
Clopidogrel significantly reduced the incidence of new ischemic events (a composite endpoint of MI, ischemic stroke, and death) compared with ASA. Analysis of all-cause mortality as a secondary endpoint revealed no significant differences between clopidogrel (5.8%) and ASA (6%).
Subgroup analysis by relevant diseases (MI, ischemic stroke and PAD) showed that the greatest effect was observed in patients with PAD, especially in those who had suffered a MI, and a smaller effect (which was not significantly different from the effect of ASA) was observed in patients with stroke. In patients included in the study who had recently suffered a MI, the effect of clopidogrel was numerically smaller, but it was not statistically significantly different from the effect of ASA. In addition, subgroup analysis of patients of different ages showed that the beneficial effect of clopidogrel in patients aged 75 years and older was lower than in patients ≤ 75 years.
Acute coronary syndrome. The CURE study enrolled patients with non-ST-segment elevation acute coronary syndrome (unstable angina or non-Q-wave MI) who had experienced chest pain or symptoms of ischemia within the previous 24 hours. Patients had ECG changes suggestive of new ischemia or elevations in cardiac enzymes or troponin I or T to at least twice the upper limit of normal. Patients were randomized to receive clopidogrel (300 mg loading dose, then 75 mg/day) or placebo, both in combination with ASA (75-325 mg once daily) and other standard therapy. Treatment duration was up to 1 year. In the CURE study, 6.6% of patients also received concomitant therapy with a GPIIb/IIIa receptor antagonist. More than 90% of patients received heparin. This concomitant therapy did not statistically significantly affect the relative incidence of bleeding between clopidogrel and placebo. The number of patients who reached the primary endpoint [cardiovascular death (CVD), MI, or stroke] was 9.3% in the clopidogrel group and 11.4% in the placebo group. The relative risk reduction was 20% for the clopidogrel group (17% for conservative management, 29% for patients undergoing percutaneous transluminal coronary angioplasty with or without stenting, and 10% for patients undergoing coronary artery bypass grafting). Prevention of new cardiovascular events (primary endpoint) occurred with relative risk reductions of 22%, 32%, 4%, 6% and 14% in the 0-1, 1-3, 3-6, 6-9 and 9-12 months of the study, respectively. That is, after more than 3 months of treatment, the beneficial effect observed in the clopidogrel + ASA group no longer increased, and the risk of bleeding remained (see section "Special instructions").
The use of clopidogrel in the CURE study reduced the need for thrombolytic therapy and GPIIb/IIIa glycoprotein receptor inhibitors.
The number of patients who reached the combined primary endpoint (CHD, MI, stroke, or refractory ischemia) was 16.5% in the clopidogrel group and 18.8% in the placebo group. The relative risk reduction was 14% in the clopidogrel group. This effect was mainly due to a statistically significant reduction in the incidence of MI (4.6% in the clopidogrel group and 5.8% in the placebo group). There was no change in the incidence of readmissions for unstable angina.
The results obtained in groups of patients with different characteristics (e.g. unstable angina or non-Q-wave MI, low- to high-risk status, diabetes, need for revascularization, age, gender) were consistent with the results of the primary analysis. In particular, an additional analysis of patients (17% of the total CURE patient group) who underwent stenting (PCI-CURE) showed that clopidogrel treatment, compared with placebo, had a significant relative risk reduction (RR) (26.2%), indicating a benefit of clopidogrel in preventing the primary endpoint (CHD, MI, stroke), as well as a significant RRR (23.9%) for the second combined primary endpoint (CHD, MI, stroke, or refractory ischemia). Moreover, the safety profile of clopidogrel in this subgroup of patients does not raise any special concerns. Thus, the results of the additional analysis of the patient group coincide with the results of the entire study.
The beneficial effect of clopidogrel was demonstrated regardless of the receipt of immediate and long-term treatment with other cardiovascular agents (such as heparin/low molecular weight heparin, GPIIb/IIIa glycoprotein receptor inhibitors, lipid-lowering drugs, beta-blockers and ACE inhibitors). The efficacy of clopidogrel was independent of the dose of ASA (75-325 mg once daily).
In patients with acute ST-segment elevation MI, the safety and efficacy of clopidogrel were evaluated in two randomized, placebo-controlled, double-blind studies, CLARITY and COMMIT.
The primary endpoint was achieved by 15% of patients in the clopidogrel group and 21.7% in the placebo group. This represented an absolute reduction of 6.7% and a 36% advantage in favor of clopidogrel, mainly due to a reduction in the incidence of occlusion of an infarct-related artery. This advantage was observed in all pre-specified subgroups of patients stratified by age, sex, infarct location, and type of fibrinolytic or heparin therapy.
The two-factor design of the COMMIT trial enrolled patients who had symptoms suggestive of MI within the previous 24 hours, as confirmed by ECG abnormalities (e.g., ST-segment elevation or depression, or left bundle branch block). Patients received clopidogrel (75 mg/day) or placebo in combination with ASA (162 mg/day) for 28 days or until discharge from the hospital. The combined primary endpoints were death from any cause and first recurrent MI, stroke, or death. The patient population consisted of 27.8% women, 58.4% ≥ 60 years (26% ≥ 70 years), and 54.5% receiving fibrinolytics.
Clopidogrel statistically significantly reduced the relative risk of all-cause mortality by 7% and the relative risk of the combination of recurrent infarction, stroke, or death by 9%, with a relative and absolute reduction of 0.5% and 0.9%, respectively. This effect was observed in patients of all ages and sexes, regardless of fibrinolytic therapy, and was observed within the first 24 hours.
Atrial fibrillation. ACTIVE-W and ACTIVE-A, which were separate studies within the ACTIVE program, enrolled patients with atrial fibrillation (AF) who had at least one risk factor for vascular events. Based on the study’s inclusion criteria, physicians enrolled patients in ACTIVE-W if they were candidates for vitamin K antagonist (VKA) therapy (e.g., warfarin). ACTIVE-A enrolled patients who were unable to receive VKA therapy due to contraindications or unwillingness to receive this treatment.
The ACTIVE-W study demonstrated that anticoagulant therapy with vitamin K antagonists was more effective than treatment with clopidogrel and ASA.
The ACTIVE-A study was a multicenter, randomized, double-blind, placebo-controlled trial comparing clopidogrel 75 mg/day + ASA to placebo + ASA. The recommended dose of ASA was 75 to 100 mg/day. Patients were treated for up to 5 years.
Patients randomized to ACTIVE had documented AF, i.e., persistent AF or at least 2 episodes of paroxysmal AF in the past 6 months, and at least one of the following risk factors: age ≥75 years or age ≥55–74 years and/or diabetes requiring medical treatment, or documented prior MI, or documented ischemic heart disease; prior treatment for systemic hypertension; prior stroke, transient ischemic attack (TIA), systemic embolism without CNS involvement; left ventricular dysfunction with left ventricular ejection fraction <45% or documented peripheral vascular disease. The median CHADS2 score was 2 (range 0–6).
The main exclusion criteria for patients from the study included documented peptic ulcer disease within the last 6 months; history of intracerebral hemorrhage, severe thrombocytopenia (platelet count <50×109/L); need for clopidogrel or oral anticoagulants (OCs), or intolerance to either of these two agents.
73% of patients enrolled in the ACTIVE-A study were unable to receive VKA due to physician judgment, inability to monitor international normalized ratio (INR), susceptibility to falls or head injury, or specific bleeding risk factors; for 26% of patients, the physician's decision was based on the patient's unwillingness to receive VKA.
41.8% of patients were female. The median age was 71 years, and 41.6% of patients were 75 years or older. Overall, 23% of patients were receiving antiarrhythmics, 52.1% were receiving beta-blockers, 54.6% were receiving angiotensin-converting enzyme inhibitors, and 25.4% were receiving statins.
Children: In a dose-escalation study in neonates or infants up to 24 months of age at risk of thrombosis (PICOLO), clopidogrel was administered at sequential doses of 0.01, 0.1, and 0.2 mg/kg to neonates and infants and at 0.15 mg/kg to neonates only. At 0.2 mg/kg, the mean inhibition of platelet aggregation was 49.3% (5 μM ADP-induced platelet aggregation), which was comparable to that in adults receiving clopidogrel 75 mg/day.
In a randomized, double-blind, parallel-group study (CLARINET), children (neonates and infants) with cyanotic congenital heart disease undergoing palliative surgery for systemic-pulmonary arterial shunting were randomized to receive clopidogrel 0.2 mg/kg or placebo with concomitant background therapy until the second stage of surgery. The median time between palliative surgery for shunting and the first administration of study drug was 20 days. Approximately 88% of patients received concomitant ASA (1 to 23 mg/kg/day). There were no significant differences between groups in the primary composite endpoint of death, shunt thrombosis, or cardiac surgery up to 120 days of life after the thrombotic event, with rates of 19.1% in the clopidogrel group and 20.5% in the placebo group (see Dosage and Administration). The most common adverse reaction in both the clopidogrel and placebo groups was bleeding, but there were no significant differences between groups in the incidence of bleeding. During the long-term follow-up period, 26 patients who still had a shunt at one year of age were treated with clopidogrel until 18 months of age. The safety profile of the drug was unchanged during this follow-up period.
The CLARINET and PICOLO studies used reconstituted clopidogrel solution. In a relative bioavailability study in adults, reconstituted clopidogrel solution demonstrated a similar extent and slightly higher rate of absorption of the major circulating (inactive) metabolite compared to the licensed tablet formulation.
Pharmacokinetics.
Absorption: Clopidogrel is rapidly absorbed after single and multiple oral doses of 75 mg/day. Mean peak plasma concentrations of unchanged clopidogrel (approximately 2.2-2.5 ng/ml after a single 75 mg oral dose) were reached approximately 45 minutes after dosing. Absorption is at least 50% based on urinary excretion of clopidogrel metabolites.
Distribution: Clopidogrel and the major (inactive) circulating metabolite are reversibly bound to human plasma proteins in vitro (98% and 94%, respectively). This binding remains unsaturated in vitro over a wide concentration range.
Metabolism: Clopidogrel is extensively metabolized in the liver. In vitro and in vivo, there are two main pathways of its metabolism: one involving esterases, which leads to hydrolysis with the formation of an inactive carboxylic acid derivative (which accounts for 85% of all metabolites circulating in blood plasma), and the other involving enzymes of the cytochrome P450 system. Clopidogrel is first converted to the intermediate metabolite 2-oxo-clopidogrel. As a result of further metabolism of 2-oxo-clopidogrel, a thiol derivative is formed - the active metabolite. This active metabolite is formed mainly by the enzyme CYP2C19, with the participation of several other enzymes of the CYP system, such as CYP1A2, CYP2B6 and CYP3A4. The active metabolite of clopidogrel (a thiol derivative), which was isolated in vitro, binds rapidly and irreversibly to receptors on platelets, thereby inhibiting platelet aggregation.
The Cmax for the active metabolite is twice as high after a single 300 mg loading dose of clopidogrel compared to that observed after four days of 75 mg maintenance dose. Cmax is reached approximately 30-60 minutes after administration.
Elimination: After 120 hours of oral administration of 14C-labeled clopidogrel in humans, approximately 50% of the dose was excreted in the urine and approximately 46% in the feces. After a single oral dose of 75 mg, the elimination half-life of clopidogrel is approximately 6 hours. The elimination half-life of the main (inactive) circulating metabolite is 8 hours after single and multiple administration.
The CYP2C19*1 allele corresponds to a fully functional metabolism, while the CYP2C19*2 and CYP2C19*3 alleles correspond to a non-functional metabolism. The CYP2C19*2 and CYP2C19*3 alleles constitute the majority of alleles in Caucasian (85%) and Mongoloid (99%) patients with reduced metabolism. Other alleles associated with absent or impaired metabolism are much less common. These include CYP2C19*4, *5, *6, *7, and *8. A patient with reduced metabolism has two non-functional alleles, as noted above. According to published data, CYP2C19 genotypes corresponding to reduced metabolism are found in 2% of Caucasians, 4% of Negroid patients, and 14% of Chinese patients. There are now tests that can determine the CYP2C19 genotype.
In a crossover study involving 40 healthy volunteers, 10 in each of four groups corresponding to a specific CYP2C19 metabolizer type (ultra-rapid, extensive, intermediate, and poor), the pharmacokinetics and antiplatelet effects of a 300 mg dose followed by 75 mg daily and a 600 mg dose followed by 150 mg daily were evaluated. Each of these treatments was administered for a total of 5 days (until steady state was achieved). There were no significant differences in blood concentrations of the active metabolite and mean platelet aggregation inhibition (PAI) between ultra-rapid, extensive, and intermediate metabolizers. In poor metabolizers, blood concentrations of the active metabolite were reduced by 63-71% compared with extensive metabolizers. After the 300 mg/75 mg regimen, the antiplatelet effects in poor metabolizers were less pronounced, with mean PAO (5 μM ADP) of 24% (24 hours) and 37% (day 5) compared with PAO of 39% (24 hours) and 58% (day 5) in extensive metabolizers and 37% (24 hours) and 60% (day 5) in intermediate metabolizers. When poor metabolizers were given the 600 mg/150 mg regimen, the blood concentration of the active metabolite was higher than with the 300 mg/75 mg regimen. In addition, the PBMC values were 32% (24 hours) and 61% (day 5), which were higher than those in poor metabolizers receiving the 300 mg/75 mg dose and similar to those obtained in other CYP2C19 metabolizer groups using the 300 mg/75 mg dose regimen. The appropriate dose regimen for this patient population has not been determined from clinical efficacy studies.
Similar to the results above, a meta-analysis of 6 studies using steady-state data in patients treated with clopidogrel demonstrated that the concentration of the active metabolite in the blood was reduced by 28% in intermediate metabolisers and 72% in poor metabolisers; inhibition of platelet aggregation (5 μM ADP) was also reduced, with a difference in PBMC of 5.9% and 21.4%, respectively, compared with extensive metabolisers.
The effect of CYP2C19 genotype on clinical outcomes in patients treated with clopidogrel has not been studied in prospective randomized controlled trials. However, a number of retrospective analyses have been conducted to assess this effect in patients treated with clopidogrel for whom genotyping results are available: CURE, CLARITY-TIMI 28, TRITON-T1MI 38, and ACTIVE-A. In addition, there are results from several published cohort studies.
In the TRITON TIMI 38 and 3 cohort studies (Collet, Sibbing, Giusti), the combined group of intermediate and poor metabolizers had a significantly higher incidence of cardiovascular events (fatal, MI, and stroke) or stent thrombosis than extensive metabolizers.
In the CHARISMA analysis and one cohort study (Simon), poor metabolizers had an increased event rate compared with extensive metabolizers.
In the analyses of CURE, CLARITY, ACTIVE-A and one of the cohort studies (Trenk), the incidence of cardiovascular events was not significantly dependent on metabolic characteristics.
None of these analyses included sufficient numbers of patients to detect a difference in clinical outcomes in patients with reduced metabolism.
Special patient populations: The pharmacokinetics of the active metabolite of clopidogrel have not been studied in the following special patient populations.
Renal impairment: Following regular administration of 75 mg clopidogrel daily to patients with severe renal impairment (creatinine clearance 5-15 ml/min), inhibition of ADP-induced platelet aggregation was less pronounced (25%) compared with the same effect in healthy volunteers, and bleeding time was prolonged to almost the same extent as in healthy volunteers receiving 75 mg clopidogrel daily. Clinical tolerability was good in all patients.
Race: The prevalence of CYP2C19 alleles that confer intermediate and poor CYP2C19 metabolic activity varies by race/ethnicity (see Pharmacogenetics). There are limited data in patients of Mongoloid race to assess the clinical relevance of genotyping for this CYP.
Preclinical safety data. The most common adverse reactions observed in preclinical animal studies were hepatic changes. These occurred at doses approximately 25 times the human therapeutic dose of 75 mg clopidogrel per day and were due to an effect on hepatic metabolism enzymes. No effect on hepatic metabolism enzymes was observed at therapeutic doses of clopidogrel in humans.
When high doses of clopidogrel were administered to animals, poor gastric tolerability of the drug was observed (gastritis, erosive gastric lesions and/or vomiting occurred).
When clopidogrel was administered to mice for 78 weeks and rats for 104 weeks at doses up to 77 mg/kg/day (which was almost 25 times the therapeutic dose of 75 mg clopidogrel per day in humans), no evidence of carcinogenic effects of the drug was obtained.
A number of in vitro and in vivo genotoxicity studies of clopidogrel have been conducted, but they have not revealed any genotoxic effects of the drug.
Clopidogrel did not affect the reproductive function of male and female rats, and did not have a teratogenic effect in either rats or rabbits. When administered to lactating female rats, clopidogrel resulted in a slight delay in the development of the offspring. Special pharmacokinetic studies with radiolabeled clopidogrel have shown that the parent compound and its metabolites penetrate into breast milk. Therefore, both a direct effect of the drug on the offspring (slight toxic effect) and an indirect effect (due to a deterioration in the palatability of milk) cannot be excluded.
Indication
Secondary prevention of atherothrombosis in adults:
patients who have had a myocardial infarction (treatment should be started within a few days but no later than 35 days after the onset), ischemic stroke (treatment should be started within 7 days but no later than 6 months after the onset) or who have been diagnosed with peripheral arterial disease;
patients with acute coronary syndrome:
with acute coronary syndrome without ST segment elevation (unstable angina or non-Q wave myocardial infarction), including in patients who have had a stent inserted during percutaneous coronary angioplasty, in combination with acetylsalicylic acid (ASA);
with acute myocardial infarction with ST-segment elevation, in combination with acetylsalicylic acid (in patients receiving standard medical treatment and for whom thrombolytic therapy is indicated).
Moderate and high-risk transient ischemic attack (TIA) or minor ischemic stroke (II)
Clopidogrel in combination with ASA is indicated for adult patients with moderate to high-risk TIA (ABCD21 score ≥ 4) or minor ischemic stroke (NIHSS2 score ≤ 3) within 24 hours of the TIA or MI.
[1] Age, blood pressure, clinical features, duration and diagnosis of diabetes.
2 National Institutes of Health Stroke Scale.
Prevention of atherothrombotic and thromboembolic events in atrial fibrillation. Clopidogrel in combination with ASA is indicated in adult patients with atrial fibrillation who have at least one risk factor for vascular events, who have contraindications to treatment with vitamin K antagonists (VKAs) and who are at low risk of bleeding, for the prevention of atherothrombotic and thromboembolic events, including stroke.
For more information, see the Pharmacological Properties section.
Contraindication
Hypersensitivity to the active substance or to any of the excipients. Severe hepatic impairment. Acute bleeding (e.g. peptic ulcer or intracranial haemorrhage).
Interaction with other medicinal products and other types of interactions
Medicinal products associated with an increased risk of bleeding. Due to the potential additive effect, there is an increased risk of haemorrhagic complications, therefore the concomitant use of such medicinal products with clopidogrel requires caution (see section 4.4).
Oral anticoagulants: Concomitant use of clopidogrel with oral anticoagulants is not recommended as the combination may increase bleeding (see section 4.4). Although clopidogrel 75 mg daily does not alter the pharmacokinetic profile of S-warfarin or the international normalized ratio (INR) in patients receiving long-term warfarin therapy, concomitant use of clopidogrel and warfarin increases the risk of bleeding due to the existence of independent effects on hemostasis.
Acetylsalicylic acid (ASA). Acetylsalicylic acid does not alter the inhibitory effect of clopidogrel on ADP-induced platelet aggregation, but clopidogrel potentiates the effect of ASA on collagen-induced platelet aggregation. However, concomitant administration of 500 mg ASA twice daily for one day did not significantly increase the prolongation of bleeding time caused by clopidogrel. Since a pharmacodynamic interaction between clopidogrel and acetylsalicylic acid with an increased risk of bleeding is possible, caution should be exercised when these drugs are used concomitantly (see section 4.4). However, clopidogrel and ASA have been used concomitantly for up to 1 year (see section 5.1).
Heparin. In a clinical study conducted in healthy volunteers, clopidogrel did not require adjustment of the heparin dose and did not alter the effect of heparin on coagulation. Concomitant use of heparin did not alter the inhibitory effect of clopidogrel on platelet aggregation. Since a pharmacodynamic interaction between clopidogrel and heparin is possible, with an increased risk of bleeding, caution should be exercised when these drugs are used concomitantly (see section 4.4).
Thrombolytic agents: The safety of concomitant use of clopidogrel, fibrin-specific or non-fibrin-specific thrombolytic agents and heparins has been studied in patients with acute MI. The incidence of clinically significant bleeding was similar to that observed with concomitant use of thrombolytic agents and heparin with ASA (see section 4.8).
Nonsteroidal anti-inflammatory drugs (NSAIDs). In a clinical study conducted in healthy volunteers, the concomitant use of clopidogrel and naproxen increased the incidence of occult gastrointestinal bleeding. However, due to the lack of interaction studies with other NSAIDs, it is not yet clear whether the risk of gastrointestinal bleeding is increased with all NSAIDs. Therefore, caution should be exercised when NSAIDs, particularly COX-2 inhibitors, are co-administered with clopidogrel (see section 4.4).
Selective serotonin reuptake inhibitors (SSRIs): Caution should be exercised when SSRIs are used concomitantly with clopidogrel because SSRIs affect platelet activation and increase the risk of bleeding.
Concomitant use of other drugs.
CYP2C19 inducers
Since clopidogrel is metabolized to its active metabolite in part by CYP2C19, the use of medicinal products that induce the activity of this enzyme is expected to lead to increased levels of the active metabolite of clopidogrel.
Rifampicin strongly induces CYP2C19, leading to both increased levels of the active metabolite of clopidogrel and platelet inhibition, which may in particular increase the risk of bleeding. As a precautionary measure, concomitant use of strong CYP2C19 inducers should be avoided (see section 4.4).
CYP2C19 inhibitors
Since clopidogrel is converted to its active metabolite partly by CYP2C19, the use of drugs that reduce the activity of this enzyme is likely to lead to a decrease in the concentration of the active metabolite of clopidogrel in the blood plasma. The clinical significance of this interaction is not known. Therefore, as a precautionary measure, the simultaneous use of strong and moderate inhibitors of CYP2C19 should be avoided (see sections "Special instructions" and "Pharmacokinetics").
Drugs that inhibit CYP2C19 activity include omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, carbamazepine, and efavirenz.
Proton pump inhibitors (PPIs). Omeprazole 80 mg once daily, when co-administered with clopidogrel or within 12 hours of the two drugs, reduced the concentration of the active metabolite in the blood by 45% (loading dose) and 40% (maintenance dose). This reduction was accompanied by a 39% (loading dose) and 21% (maintenance dose) reduction in inhibition of platelet aggregation. Esomeprazole is expected to interact similarly with clopidogrel.
Observational and clinical studies have shown conflicting data regarding the clinical consequences of these pharmacokinetic and pharmacodynamic interactions in terms of major cardiovascular events. As a precautionary measure, omeprazole or esomeprazole should not be used concomitantly with clopidogrel (see section 4.4).
A less pronounced decrease in metabolite concentrations in the blood was observed with pantoprazole or lansoprazole.
When pantoprazole 80 mg once daily was co-administered, plasma concentrations of the active metabolite decreased by 20% (loading dose) and 14% (maintenance dose). This decrease was accompanied by a decrease in the mean platelet aggregation inhibition index by 15% and 11%, respectively. The results obtained indicate the possibility of concomitant use of clopidogrel and pantoprazole.
There is no evidence that other drugs that reduce stomach acid production, such as H2 blockers or antacids, affect the antiplatelet activity of clopidogrel.
Booster antiretroviral therapy. In HIV-infected patients receiving
