Instructions for Clovasc 75 mg/75 mg capsules No. 28
Composition
active ingredients: acetylsalicylic acid, clopidogrel;
1 capsule contains acetylsalicylic acid 75 mg and clopidogrel (as clopidogrel hydrosulfate) 75 mg;
excipients:
for acetylsalicylic acid tablets: microcrystalline cellulose, croscarmellose sodium, talc, hypromellose, titanium dioxide (E 171), colloidal anhydrous silicon dioxide, polyethylene glycol 6000 (macrogol 6000), anhydrous citric acid;
for clopidogrel tablets: microcrystalline cellulose, croscarmellose sodium, hypromellose, hydroxypropylcellulose, talc, titanium dioxide (E 171), polyethylene glycol 6000 (macrogol 6000), colloidal anhydrous silica, iron oxide (E 172), hydrogenated castor oil;
capsule (body and cap): gelatin, water, titanium dioxide (E 171).
Dosage form
The capsules are hard.
Main physicochemical properties: opaque, hard gelatin capsules of white or almost white color, containing one film-coated tablet of acetylsalicylic acid, white or almost white color, and two film-coated tablets of clopidogrel, yellow-brown color.
Pharmacotherapeutic group
Antithrombotic agents. Platelet aggregation inhibitors, excluding heparin. Combinations. ATX code B01A C30.
Pharmacological properties
Pharmacodynamics.
Mechanism of action
Clopidogrel is a prodrug, one of its metabolites is an inhibitor of platelet aggregation. To form the active metabolite that inhibits platelet aggregation, clopidogrel must be metabolized by enzymes of the cytochrome CYP450 system. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to the P2Y12 receptor on the platelet surface and the subsequent activation of the glycoprotein IIb/IIIa complex by ADP, thereby inhibiting platelet aggregation. Due to the irreversible nature of the binding, platelets that have interacted with clopidogrel remain under its action throughout their lifetime (approximately 7–10 days), and normal platelet function is restored at a rate that corresponds to the rate of platelet renewal. Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by the released ADP.
Since the active metabolite is formed by enzymes of the cytochrome CYP450 system, some of which are polymorphic or inhibited by other drugs, not all patients experience adequate platelet inhibition.
Pharmacodynamic effects
Repeated administration of clopidogrel at a dose of 75 mg per day significantly inhibited ADP-induced platelet aggregation from the first day of administration; this effect gradually increased and reached a constant level with steady state achieved on days 3–7. At steady state, the average level of platelet inhibition observed with a dose of 75 mg per day ranged from 40 to 60%. Platelet aggregation and bleeding time gradually returned to baseline levels over a total of 5 days.
Acetylsalicylic acid inhibits platelet aggregation by irreversible inhibition of prostaglandin cyclooxygenase and thus inhibits the formation of thromboxane A2, which causes platelet aggregation and vasoconstriction. This effect persists throughout the life of the platelet.
Pharmacokinetics.
Acetylsalicylic acid
Absorption
Acetylsalicylic acid is converted to salicylic acid by hydrolysis after absorption. The peak level of salicylic acid in the blood plasma is reached within 1 hour after administration. Thus, the level of acetylsalicylic acid in the blood plasma is beyond the detection limit 1.5–3 hours after administration of the drug.
Distribution
Acetylsalicylic acid is poorly bound to plasma proteins and has a low volume of distribution (10 l). Its metabolite, salicylic acid, is rapidly bound to plasma proteins, but the binding is concentration-dependent (non-linear). At low concentrations (< 100 μg/ml), approximately 90% of salicylic acid is bound to albumin. Salicylic acid readily penetrates all tissues and body fluids, including the central nervous system, breast milk, and fetal tissues.
Acetylsalicylic acid is rapidly converted by hydrolysis to salicylic acid, the half-life of which at doses of acetylsalicylic acid 75–100 mg is 0.3–0.4 hours. Salicylic acid is mainly conjugated in the liver, where salicyluric acid, phenolic glucuronide, acyl glucuronide and a number of secondary metabolites are formed. The plasma half-life of salicylic acid in the composition of the drug CLOVASK is approximately 2 hours. The metabolism of salicylates is saturated, the total body clearance decreases in the case of high serum concentrations due to the limited ability of the liver to form both salicyluric acid and phenolic glucuronide. In the case of toxic doses (10–20 g), the half-life from blood plasma may exceed 20 hours. In the case of high doses of acetylsalicylic acid, the elimination of salicylic acid follows zero-order kinetics (i.e. the elimination rate is constant relative to the plasma concentration), with an effective half-life of 6 hours or more. Renal excretion of unchanged active substance depends on the pH of the urine. As the pH of the urine exceeds 6.5, the renal clearance of free salicylate increases from 5 to 80%. After the use of therapeutic doses, approximately 10% is observed in the urine in the form of salicylic acid, 75% in the form of salicyluric acid, 10% in the form of phenolic and 5% in the form of acyl glucuronide of salicylic acid.
Given the pharmacokinetic and metabolic characteristics of both compounds, the occurrence of a clinically significant pharmacokinetic interaction is unlikely.
Clopidogrel
Absorption
Clopidogrel is rapidly absorbed after single and repeated oral administration of 75 mg/day. The mean peak plasma concentration of unchanged clopidogrel (approximately 2.2–2.5 ng/ml after a single oral dose of 75 mg) is reached approximately 45 minutes after administration. Absorption is at least 50%, based on the amount of clopidogrel metabolites excreted in the urine.
Distribution
In vitro, clopidogrel and the major circulating (inactive) metabolite are reversibly bound to human plasma proteins (98% and 94%, respectively). The binding is unsaturated in vitro over a wide concentration range.
Metabolism
Clopidogrel is extensively metabolized in the liver. In vitro and in vivo, clopidogrel metabolism occurs via two major metabolic pathways: the first is via esterase followed by hydrolysis to an inactive metabolite, which is a carboxylic acid derivative (85% of circulating metabolites), and the second is via various cytochromes P450. Initially, the metabolism of clopidogrel results in the formation of an intermediate metabolite, 2-oxo-clopidogrel. Further metabolism of the intermediate metabolite, 2-oxo-clopidogrel, results in the formation of an active metabolite, the thiol derivative of clopidogrel. In vitro, this metabolic pathway is mediated by CYP3A4, CYP2C19, CYP1A2 and CYP2B6 isoenzymes. The active thiol metabolite, which was isolated in vitro, binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation.
After a single dose of 300 mg clopidogrel, the Cmax of the active metabolite is 2 times higher than after a maintenance dose of 75 mg for 4 days. Cmax is reached approximately 30–60 minutes after administration of the drug.
Breeding
Within 120 hours after oral administration of 14C-labeled clopidogrel to humans, approximately 50% was excreted in the urine and approximately 46% in the feces. After a single oral dose of 75 mg, the elimination half-life was approximately 6 hours. The elimination half-life of the major circulating (inactive) metabolite was 8 hours after single or repeated administration.
Pharmacogenetics
Clopidogrel is activated by several polymorphic CYP450 isoenzymes. CYP2C19 is involved in the formation of both the active metabolite and the intermediate metabolite 2-oxo-clopidogrel. According to the quantitative determination of platelet aggregation ex vivo, the pharmacokinetic parameters and antithrombotic effect of the active metabolite of clopidogrel differ according to the CYP2C19 genotype.
The CYP2C19*1 allele corresponds to fully functional metabolism, while the CYP2C19*2 and CYP2C19*3 alleles correspond to reduced metabolism. The CYP2C19*2 and CYP2C19*3 alleles account for 85% of the reduced function alleles in Caucasians and 99% in Asians. Other alleles associated with reduced metabolism include CYP2C19*4, *5, *6, *7, and *8, but are less common in the general population.
A poor metabolizer has two functional alleles, as defined above. According to published data, CYP2C19 poor metabolizer genotypes are found in approximately 2% of Caucasians, 4% of Blacks, and 14% of Chinese. Tests are now available to determine a patient's CYP2C19 genotype.
Special patient groups
There is no information on the pharmacokinetic parameters of the active metabolite of clopidogrel in these patient groups.
After repeated administration of clopidogrel at a dose of 75 mg per day in patients with severe renal disease (creatinine clearance 5 to 15 ml/min), the inhibition of ADP-induced platelet aggregation was less (25%) than in healthy volunteers, but the prolongation of bleeding time was similar to that observed in healthy volunteers taking 75 mg of clopidogrel per day. In addition, clinical tolerability was satisfactory in all patients.
Liver failure
After repeated administration of clopidogrel at a dose of 75 mg daily for 10 days in patients with severe hepatic impairment, the inhibition of ADP-induced platelet aggregation was similar to that observed in healthy volunteers. The mean increase in bleeding time was also similar in the two groups.
Racial affiliation
The prevalence of CYP2C19 alleles that result in moderate or severe reduction in CYP2C19-mediated metabolism varies by race/ethnicity (see Pharmacogenetics). There are limited data in the literature in patients of Asian descent to assess the clinical relevance of CYP2C19 genotype determination for clinical outcomes.
Indication
Secondary prevention of atherothrombotic complications in adults already taking clopidogrel and acetylsalicylic acid.
KLOVASK is a fixed-dose combination drug for continued therapy in the case of:
acute coronary syndrome without ST segment elevation (unstable angina or myocardial infarction without pathological Q wave on ECG), including in patients who have undergone stenting during percutaneous coronary intervention;
acute myocardial infarction with ST segment elevation in patients receiving medical treatment and with the possibility of thrombolysis.
Contraindication
Hypersensitivity to the active substances or any excipient of the medicinal product;
severe liver failure;
acute pathological bleeding, such as bleeding from a peptic ulcer or intracranial hemorrhage;
hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs), bronchial asthma, rhinitis, nasal polyps. Mastocytosis, when the use of acetylsalicylic acid can cause severe hypersensitivity reactions (including circulatory shock with flushing, hypotension, tachycardia and vomiting);
severe renal failure (creatinine clearance < 30 ml/min);
acute peptic ulcers;
hemorrhagic diathesis;
severe heart failure;
simultaneous use of acetylsalicylic acid and methotrexate in doses of 15 mg/week or more (due to increased hematological toxicity of methotrexate, there is a decrease in renal clearance of methotrexate by anti-inflammatory agents and displacement of methotrexate from plasma protein binding by salicylates);
Third trimester of pregnancy (see section "Use during pregnancy or breastfeeding").
Interaction with other medicinal products and other types of interactions
Medicines associated with bleeding risk
There is an increased risk of bleeding due to potential additive synergism. Caution should be exercised when prescribing medicinal products with concomitant use associated with a risk of bleeding (see section 4.4).
Oral anticoagulants
The concomitant use of Clopidogrel with oral anticoagulants is not recommended as it may increase the intensity of bleeding (see section 4.4). Although administration of clopidogrel 75 mg/day to patients receiving long-term warfarin therapy did not alter the pharmacokinetics of S-warfarin or the international normalized ratio (INR), concomitant use of clopidogrel and warfarin increases the risk of bleeding due to the independent effects of these drugs on hemostasis.
Glycoprotein receptor IIb/IIIa inhibitors
The drug CLOVASK should be used with caution in patients who are simultaneously taking glycoprotein IIb/IIIa receptor inhibitors (see section "Special instructions").
Heparin
In a clinical study conducted in healthy volunteers, clopidogrel did not require a change in the dose of heparin and did not alter the effect of heparin on coagulation. Concomitant use of heparin does not affect the inhibitory effect of clopidogrel on platelet aggregation. A pharmacodynamic interaction is possible between CLOVASK and heparin, which may increase the risk of bleeding. Therefore, concomitant use requires caution (see section "Special instructions").
Thrombolytics
The safety of concomitant use of clopidogrel, fibrin-specific or non-fibrin-specific thrombolytic agents and heparins has been studied in patients with acute myocardial infarction. The incidence of clinically significant bleeding was similar to that observed with concomitant use of thrombolytic agents and heparin with acetylsalicylic acid (see section 4.8). The safety of concomitant use of acetylsalicylic acid/clopidogrel and other thrombolytic agents has not been formally established and caution should be exercised when using this combination (see section 4.8).
In a clinical study conducted in healthy volunteers, the concomitant use of clopidogrel and naproxen increased occult gastrointestinal (GI) blood loss. Therefore, concomitant use with NSAIDs, including COX-2 inhibitors, is not recommended (see section 4.4). The concomitant use of high doses of salicylates with NSAIDs (due to a mutual enhancement effect) increases the risk of ulcers and gastrointestinal bleeding.
Experimental data suggest that ibuprofen may inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation when given concomitantly. In one study, a single dose of ibuprofen 400 mg administered 8 hours before or 30 minutes after a dose of immediate-release acetylsalicylic acid (81 mg) was shown to reduce the effect of acetylsalicylic acid on thromboxane formation or platelet aggregation. However, the limitations of these data, as well as the statistical uncertainty in extrapolating ex vivo data to clinical cases, suggest that no firm conclusions can be drawn regarding the routine use of ibuprofen; it is unlikely that a clinically relevant effect will occur with occasional ibuprofen use.
Selective serotonin reuptake inhibitors (SSRIs)
SSRIs affect platelet activation and increase the risk of bleeding, so SSRIs should be used with caution when used concomitantly with clopidogrel.
Metamizole
When used simultaneously with acetylsalicylic acid, metamizole may reduce the effect of acetylsalicylic acid on platelet aggregation. Therefore, this combination should be prescribed with caution to patients taking low doses of acetylsalicylic acid in order to achieve a cardioprotective effect.
Other medicines used with clopidogrel
CYP2C19 inducers
Since the metabolism of clopidogrel to the active metabolite is mediated in part by CYP2C19, the use of medicinal products that inhibit the activity of this enzyme is likely to result in decreased levels of the active metabolite of clopidogrel. The clinical significance of this interaction has not been determined.
Rifampicin is a potent inducer of 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, it is recommended to avoid the concomitant use of potent inducers of CYP2C19 (see section 4.4).
CYP2C19 inhibitors
Since the metabolism of clopidogrel to the active metabolite occurs in part by CYP2C19, the use of drugs that inhibit the activity of this enzyme is likely to lead to a decrease in the level of the active metabolite of clopidogrel. The clinical significance of this interaction has not been determined. The simultaneous use of drugs that strongly or moderately inhibit the activity of CYP2C19 should be avoided (see sections "Pharmacokinetics" and "Special instructions").
Drugs that are strong or moderate CYP2C19 inhibitors include omeprazole and esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, carbamazepine, efavirenz.
Proton pump inhibitors
Omeprazole 80 mg once daily, administered either at the same time as clopidogrel or with an interval of 12 hours between the two drugs, reduced the exposure of the active metabolite by 45% (after a loading dose) and 40% (after a maintenance dose). This reduction in exposure was accompanied by a 39% (after a loading dose) and 21% (after a maintenance dose) reduction in inhibition of platelet aggregation. Esomeprazole is expected to interact in a similar manner with clopidogrel.
Observational and clinical studies have shown conflicting data on the clinical relevance of this pharmacokinetic/pharmacodynamic interaction for the risk of serious cardiovascular events. As a precautionary measure, it is recommended to avoid concomitant use of omeprazole or esomeprazole (see section 4.4).
A less pronounced decrease in clopidogrel metabolite exposure was observed when pantoprazole or lansoprazole was used.
During concomitant treatment with pantoprazole 80 mg once daily, plasma concentrations of the active metabolite decreased by 20% (after a loading dose) and 14% (after a maintenance dose). This was accompanied by a decrease in platelet aggregation inhibition by 15% and 11%, respectively. These results indicate that clopidogrel can be used together with pantoprazole.
There is currently no evidence that other drugs that reduce gastric acidity, such as histamine H2 receptor blockers (except cimetidine, which is a CYP2C19 inhibitor) or antacids, affect the antiplatelet activity of clopidogrel.
Booster antiretroviral therapy
Significantly reduced platelet inhibition has been observed in HIV patients receiving ritonavir-boosted ART or cobicistat. Although the clinical relevance of these findings is uncertain, there have been spontaneous reports of HIV-infected patients receiving ritonavir-boosted ART experiencing recurrent occlusive events after deobstruction or thrombotic events while receiving a loading dose of clopidogrel. Concomitant use of clopidogrel and ritonavir may result in reduced mean platelet inhibition.
Therefore, the concomitant use of clopidogrel with booster ART should be avoided.
Other medicines
No clinically significant pharmacodynamic interaction was observed when clopidogrel was co-administered with atenolol, nifedipine, or atenolol and nifedipine. Furthermore, co-administration of phenobarbital or estrogen had no significant effect on the pharmacodynamic activity of clopidogrel.
The pharmacokinetics of digoxin or theophylline were not altered when co-administered with clopidogrel. Antacids did not reduce the absorption of clopidogrel.
Data from human liver microsome studies suggest that the carboxyl metabolite of clopidogrel may inhibit cytochrome P4502C9 activity. This could potentially lead to increased plasma concentrations of some drugs, such as phenytoin and tolbutamide, as well as NSAIDs that are metabolized by cytochrome P4502C9. The CAPRIE data suggest that concomitant use of phenytoin and tolbutamide with clopidogrel is safe.
Medicinal products that are substrates of CYP2C8
In a study in healthy volunteers, administration of clopidogrel resulted in an increase in the clearance of repaglinide. In vitro studies have shown an increase in repaglinide exposure due to inhibition of CYP2C8 by the glucuronide metabolite of clopidogrel. Due to the risk of increased plasma concentrations, caution should be exercised when clopidogrel is co-administered with medicinal products that are primarily eliminated by CYP2C8 metabolism (e.g. repaglinide, paclitaxel) (see section 4.4).
Rosuvastatin
Clopidogrel has been shown to increase rosuvastatin exposure in patients by 1.4-fold (AUC) without affecting Cmax after repeated administration of 75 mg clopidogrel.
Other medicines used concomitantly with acetylsalicylic acid
Uricosuric agents (benzopromarone, probenecid, sulfinpyrazone) should be used with caution, as acetylsalicylic acid may reduce the effectiveness of uricosuric agents by competitively removing uric acid.
Methotrexate
Due to the presence of acetylsalicylic acid in the composition of the drug CLOVASK, the simultaneous use of methotrexate in doses exceeding 20 mg/week requires caution due to the possibility of inhibition of renal clearance of methotrexate, which may lead to myelotoxicity.
Tenofovir
Concomitant use of tenofovir disoproxil fumarate and NSAIDs may increase the risk of renal failure.
Valproic acid
Concomitant use of salicylates and valproic acid may result in decreased protein binding of the latter and inhibition of its metabolism, leading to increased serum levels of total and free valproic acid. When used simultaneously with valproic acid, acetylsalicylic acid displaces it from plasma protein binding, increasing the toxicity of the latter.
Chickenpox vaccine
It is not recommended that patients be given salicylates within six weeks of vaccination against varicella. Cases of Reye's syndrome have occurred after salicylates were given during chickenpox.
Acetazolamide
It is recommended to use salicylates with caution simultaneously with acetazolamide due to the increased risk of metabolic acidosis.
With the simultaneous use of high doses of acetylsalicylic acid and antidiabetic drugs from the group of sulfonylurea derivatives, the hypoglycemic effect of the latter is enhanced due to the displacement of sulfonylurea bound to plasma proteins by acetylsalicylic acid.
With simultaneous use of acetylsalicylic acid with digoxin, the concentration of the latter in the blood plasma increases due to a decrease in renal excretion.
Systemic glucocorticoids (including hydrocortisone, which is used for replacement therapy in Addison's disease) reduce the level of salicylates in the blood and increase the risk of overdose.
Angiotensin-converting enzyme (ACE) inhibitors in combination with high doses of acetylsalicylic acid cause a decrease in glomerular filtration due to inhibition of the vasodilator effect of prostaglandins and a decrease in the antihypertensive effect.
Nicorandil
Patients taking nicorandil and NSAIDs, in particular acetylsalicylic acid and lysine acetylsalicylate, are at increased risk of serious complications such as gastrointestinal ulcers, perforation and gastrointestinal bleeding (see section 4.4).
Cases of interaction with the following medicinal products used concomitantly with acetylsalicylic acid in higher (anti-inflammatory) doses have also been reported: ACE inhibitors, acetazolamide, anticonvulsants (phenytoin and valproic acid), beta-blockers, diuretics and oral hypoglycemic agents.
Alcohol
Alcohol contributes to damage to the gastrointestinal mucosa and prolongs bleeding time due to the synergy of acetylsalicylic acid and alcohol. Patients should be informed of the risk of damage to the gastrointestinal mucosa and bleeding when taking the drug with alcohol, especially if alcohol consumption is chronic or significant (see section "Special instructions").
Diuretics in combination with high doses of acetylsalicylic acid reduce glomerular filtration by reducing prostaglandin synthesis in the kidneys.
Other interactions with clopidogrel and acetylsalicylic acid
More than 30,000 patients have participated in clinical trials of the combination of clopidogrel with acetylsalicylic acid at maintenance doses not exceeding 325 mg and received a variety of concomitant medications, including diuretics, beta-blockers, ACE inhibitors, calcium antagonists, cholesterol-lowering agents, coronary vasodilators, antidiabetic agents (including insulin), antiepileptic agents and glycoprotein IIb/IIIa receptor antagonists, without evidence of clinically significant adverse interactions.
In addition to the information on interactions with individual drugs provided above, there is no data on the interaction of the acetylsalicylic acid/clopidogrel combination with some widely used drugs prescribed to patients with atherothrombotic disease, as studies have not been conducted.
As with other oral P2Y12 inhibitors, co-administration of opioid agonists may delay and reduce the absorption of clopidogrel, probably due to delayed gastric emptying. The clinical significance is unknown. The use of a parenteral antithrombotic agent should be considered in patients with acute coronary syndrome who require concomitant administration of morphine or other opioid agonists.
Application features
Bleeding and hematological disorders
Due to the risk of bleeding and haematological adverse reactions, if clinical symptoms associated with bleeding occur during treatment, a clinical blood test and/or other relevant parameters should be urgently performed (see section "Adverse reactions"). Since the drug KLOVASK is an antithrombotic drug containing two active substances, it should be used with caution in patients with an increased risk of bleeding associated with trauma, surgery or other pathological conditions, as well as when used in combination therapy with other NSAIDs, including COX-2 inhibitors, heparin, glycoprotein IIb/IIIa receptor inhibitors, SSRIs, strong CYP2C19 inducers, thrombolytics or other drugs that increase the risk of bleeding, such as pentoxifylline (see section "Interaction with other medicinal products and other types of interactions"). Patients should be closely monitored for any signs of bleeding, including occult bleeding, especially during the first weeks of treatment and/or after invasive cardiac procedures or surgery. The concomitant use of CLOVASK with oral anticoagulants is not recommended as it may increase the intensity of bleeding (see section 4.5).
Before any planned surgery, as well as before starting any new medication, patients should inform their doctors, including dentists, about taking CLOVASK. In the event of a planned surgery, the need for dual antiplatelet therapy should be reconsidered in favor of using a single antiplatelet drug. In the event of temporary discontinuation of antiplatelet therapy, CLOVASK should be discontinued 7 days before surgery.
CLOVASK increases bleeding time; it should be used with caution in patients with lesions that increase the tendency to bleed (including gastrointestinal and intraocular).
Patients should also be warned about the possible increase in the time required to stop bleeding when using CLOVASK, and about the need to inform their doctor about the occurrence of any unusual bleeding (by location or duration).
Thrombotic thrombocytopenic purpura (TTP)
Very rare cases of TTP have been reported with clopidogrel, sometimes even after short-term use. It was characterized by thrombocytopenia and microangiopathic hemolytic anemia in association with neurological symptoms, renal dysfunction, or fever. TTP can be life-threatening and requires urgent treatment, including plasmapheresis.
Cases of acquired hemophilia have been reported following the use of clopidogrel. In the case of confirmed isolated increases in activated partial thromboplastin time (aPTT), with or without bleeding, the diagnosis of acquired hemophilia should be considered. Patients with a confirmed diagnosis of acquired hemophilia should be monitored and treated; clopidogrel should be discontinued in such patients.
Recent transient ischemic attack or stroke
The use of clopidogrel in combination with acetylsalicylic acid in patients who have recently suffered a transient ischemic attack or stroke and are at high risk of developing recurrent ischemic events has been shown to increase significant bleeding. Therefore, caution should be exercised when using this combination, except in cases where its beneficial effect has been proven.
Cytochrome P450 2С19 (CYP2С19)
Pharmacogenetics
In patients who are poor metabolizers of CYP2C19, clopidogrel at recommended doses produces less of the active metabolite and has less effect on platelet function. Tests are available to determine the patient's CYP2C19 genotype.
Since the metabolism of clopidogrel to the active metabolite is mediated in part by CYP2C19, the use of medicinal products that inhibit the activity of this enzyme is likely to result in decreased levels of the active metabolite of clopidogrel. The clinical significance of this interaction has not been established. Concomitant use of medicinal products that inhibit CYP2C19 should be avoided (see sections 5.2 and 5.5).
It is likely that the use of medicinal products that induce CYP2C19 activity will lead to increased levels of the active metabolite of clopidogrel and may increase the risk of bleeding. As a precautionary measure, it is recommended to avoid the concomitant use of strong CYP2C19 inducers (see section 4.8).
CYP2C8 substrates
Caution should be exercised when clopidogrel is administered concomitantly with medicinal products that are substrates of CYP2C8 (see section 4.5).
Cross-reactivity between thienopyridines
Patients should be checked for a history of hypersensitivity to other thienopyridines (such as ticlopidine, prasugrel) as cross-reactivity between thienopyridines has been reported (see section 4.8). Thienopyridines may be associated with mild to severe allergic reactions such as rash, angioedema or haematological reactions (thrombocytopenia and neutropenia). Patients with a history of allergic and/or haematological reactions to one thienopyridine may be at increased risk of developing the same or a different reaction to another thienopyridine. Monitoring for cross-reactivity is recommended.
Acetylsalicylic acid should be used with caution:
patients with a history of bronchial asthma or allergic reactions, as they may increase the risk of hypersensitivity reactions;
patients with gout, since acetylsalicylic acid, even in low doses, can increase the concentration of uric acid;
children (under 18 years of age) as there is a possible association between the use of acetylsalicylic acid and the development of Reye's syndrome. Reye's syndrome is a very rare disease that can be life-threatening;
patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency due to the risk of hemolysis (see section "Adverse reactions"); in such cases this medicinal product should be used under close medical supervision;
Patients who abuse alcohol. Alcohol may increase the risk of gastrointestinal damage when taking acetylsalicylic acid. Patients should be advised of the risk of gastrointestinal damage and bleeding when drinking alcohol while taking clopidogrel and acetylsalicylic acid, especially if alcohol use is chronic or severe (see section 4.5).
Gastrointestinal diseases
CLOVASK should be used with caution in patients with a history of peptic ulcer or gastroduodenal bleeding, or other symptoms of upper gastrointestinal disorders, as they may be secondary to gastric ulceration, which may lead to gastric bleeding. Gastrointestinal adverse reactions may occur, including stomach pain, heartburn, nausea, vomiting and gastrointestinal bleeding. Although other symptoms of upper gastrointestinal disorders, such as dyspepsia, are common and may occur at any time during treatment, physicians should be aware of these symptoms.
