Composition, form of production and packaging
The tablets covered with a film cover of pink color, round, slightly biconcave; a cross-sectional view is a white or almost white, rough mass with a pink film sheath.
clopidogrel hydrogen sulfate 97.875 mg,
which corresponds to the content of clopidogrel 75 mg
Excipients: lactose anhydrous - 108.125 mg, microcrystalline cellulose - 30 mg, pregelatinized starch - 12 mg, macrogol 6000 - 8 mg, castorized hydrogenated oil - 4 mg.
Composition of the film membrane: hypromellose 6cp - 5.6 mg, titanium dioxide (E171) - 1.46 mg, talc - 0.5 mg, iron oxide red oxide (E172) - 0.04 mg, propylene glycol 0.4 mg.
7 pcs. - blisters (2) - packs of cardboard.
7 pcs. - blisters (4) - packs of cardboard.
7 pcs. - blisters (12) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2015.
Antiaggregant. Clopidogrel is a prodrug that selectively inhibits the binding of adenosine diphosphate (ADP) to P2Y 12 receptor platelets and the subsequent ADP-mediated activation of the glycoprotein GPIIb / IIIa complex, which leads to inhibition of platelet aggregation.
Suppression of platelet aggregation is irreversible and continues throughout the cell life cycle (about 7-10 days), so the rate of recovery of normal platelet function corresponds to the rate of their renewal. Aggregation of platelets induced by other agonists other than ADP is also inhibited due to blockade of enhanced platelet activation by ADP.
The active metabolite is formed by the action of CYP450 isoenzymes, some of which may be polymorphic or may be inhibited by other drugs, so that adequate inhibition of platelet aggregation is not observed in all patients.
In the treatment of clopidogrel at a dose of 75 mg / day from the first day of therapy, there is a significant suppression of ADP-induced platelet aggregation, which gradually increases for 3-7 days and then reaches a constant level (when reaching C ss ). In the equilibrium state, the degree of inhibition of platelet aggregation with clopidogrel at a dose of 75 mg / day, on average, was 40 to 60%. After stopping the use of clopidogrel, platelet aggregation and bleeding time gradually returned to baseline values, on average, for 5 days.
Clopidogrel prevents the development of atherothrombotic complications in patients with atherosclerotic lesions of vessels of any location, especially with damage to the cerebral, coronary or peripheral arteries.
After a single and repeated oral administration at a dose of 75 mg / day, clopidogrel is rapidly absorbed. Mean C max values вЂ‹вЂ‹of unchanged clopidogrel in blood plasma (2.2-2.5 ng / ml after ingestion of a single dose of 75 mg) are reached after about 45 minutes. According to the study of kidney excretion of clopidogrel metabolites, the degree of absorption is approximately 50%.
Clopidogrel and the main circulating metabolite reversibly bind to plasma proteins in vitro (98% and 94%, respectively). This bond is unsaturated in a wide range of concentrations.
Clopidogrel is actively metabolized in the liver. Under in vitro and in vivo conditions, clopidogrel is metabolized in two ways: the first is mediated by esterases and leads to hydrolysis with the formation of a pharmacologically inactive metabolite, a carboxylic acid derivative (85% of the circulating metabolites), and the other is catalyzed by various cytochrome P450 isoenzymes. Initially, clopidogrel is converted to an intermediate metabolite - 2-oxo-clopidogrel. Subsequent metabolism to 2-oxo-clopidogrel leads to the formation of an active metabolite of clopidogrel-thiol derivative. In in vitro conditions, this route is mediated by isoenzymes CYP3A4, CYP2S19, CYP1A2, CYP2B6. The active thiol metabolite, isolated under in vitro conditions, quickly and irreversibly interacts with the platelet receptors, blocking their aggregation.
C max of the active metabolite in blood plasma after taking a loading dose (300 mg) of clopidogrel is 2 times higher than C max after 4-day use of clopidogrel in a maintenance dose (75 mg / day). C max in blood plasma is reached approximately in 30-60 minutes after reception of a preparation.
Within 120 hours after ingestion of 14 C-labeled clopidogrel, approximately 50% is excreted by the kidneys and 46% by the intestine. After a single admission, clopidogrel at a dose of 75 mg T 1/2 is approximately 6 hours. T 1/2 of the main circulating metabolite in the blood plasma after a single and repeated application is 8 hours.
Pharmacokinetics in special clinical cases
The pharmacokinetics of the active metabolite in certain patient groups (elderly patients, children, patients with impaired renal and hepatic function) has not been studied.
Isozyme CYP2C19 takes part in the formation of both active metabolite and intermediate metabolite - 2-oxo-clopidogrel. The pharmacokinetics and antiplatelet effect of the active metabolite of clopidogrel, as well as the results of the evaluation of platelet aggregation under ex vivo conditions, differ depending on the genotype of the isoenzyme CYP2C19.
The allele of the CYP2C19 * 1 isoenzyme gene corresponds to a fully functional metabolism, whereas the alleles of the CYP2C19 * 2 and CYP2C19 * 3 isoenzymes are non-functional. The alleles of the CYP2C19 * 2 and CYP2C19 * 3 isoenzymes genes cause a decrease in metabolism in the majority of representatives of the Caucasoid (85%) and Mongoloid
(99%) of the races. Other alleles associated with a lack or decrease in metabolism are less common and include, but not
are limited to alleles of the genes of isoenzymes CYP2C19 * 4, * 5, * 6, * 7 and * 8. Patients with a low activity of the isoenzyme CYP2C19 should have the two alleles of the loss-of-function gene mentioned above. According to published studies, the frequency of genotypes with a low activity of the CYP2C19 isoenzyme, accompanied by a decrease in metabolism, is approximately 2% in the representatives of the Caucasoid race, 4% in the Negroid and 14% in the persons of the Mongoloid race. There are tests to determine the genotype of the isoenzyme CYP2C19. According to the study and meta-analysis, which included people with very high, high, intermediate and low activity of the isoenzyme CYP2C19, a significant difference in exposure of the active metabolite and moderate inhibition of ADP-induced platelet aggregation in volunteers with very high, high and intermediate isoenzyme activity CYP2C19 was absent. In volunteers with a low activity of this isoenzyme, the exposure of the active metabolite decreased compared to that of volunteers with high activity of the isoenzyme CYP2C19.
Using clopidogrel at doses of 600 mg loading dose / 150 mg maintenance dose (600 mg / 150 mg) in patients with low metabolism, the exposure of the active metabolite was higher than with the 300 mg / 75 mg treatment regimen. In addition, the degree of inhibition of platelet aggregation was similar to that in groups of patients with high CYP2C19 isoenzyme activity who received clopidogrel under the 300 mg / 75 mg schedule. However, the dosage regimen of clopidogrel in the group of patients with a low activity of the isoenzyme CYP2C19 is not defined in studies suggesting the study of clinical outcomes. The clinical trials conducted to date have had insufficient sample size to detect differences in clinical outcome in patients with low CYP2C19 isoenzyme activity.
Ethnic features: the prevalence of alleles of CYP2C19 isoenzyme genes associated with intermediate or decreased metabolism is different in representatives of different racial / ethnic groups . There are limited literature data to assess the genotyping of the isoenzyme CYP2C19 on clinical outcomes for patients of the Mongoloid race.
Prevention of atherothrombotic complications in adult patients:
- with myocardial infarction (prescription from several days to 35 days), with ischemic stroke (prescription from 7 days to 6 months) or with diagnosed occlusive disease of peripheral arteries;
- with acute coronary syndrome without ST segment elevation (unstable angina or myocardial infarction without Q wave formation), including patients who underwent stenting with percutaneous coronary intervention, in combination with acetylsalicylic acid;
- with acute coronary syndrome with ST segment elevation (acute myocardial infarction) with drug treatment and the possibility of performing thrombolytic therapy in combination with acetylsalicylic acid.
Prevention of atherothrombotic and thromboembolic complications, including stroke, in atrial fibrillation (atrial fibrillation):
- in adults with atrial fibrillation (atrial fibrillation) who have at least one risk factor for vascular complications, can not take indirect anticoagulants and have a low risk of bleeding (in combination with acetylsalicylic acid).
The drug is taken orally, regardless of food intake, 1 time / day.
Adults and elderly patients with normal activity of the isoenzyme CYP2C19
With myocardial infarction, ischemic stroke or diagnosed occlusive disease of peripheral arteries, the preparation Zilt В® is recommended to take 1 tab. (75 mg) 1 time / day.
In acute coronary syndrome without ST segment elevation (unstable angina or myocardial infarction without Q wave), treatment with ZiltВ® should be started with a single 300 mg loading dose and then continued with a 75 mg dose once a day (in combination with acetylsalicylic acid acid in a dose of 75-325 mg / day). Since the use of acetylsalicylic acid in high doses is associated with a high risk of bleeding, the recommended dose of acetylsalicylic acid should not exceed 100 mg. The maximum favorable effect is observed by the 3rd month of treatment. The optimal duration of treatment with this indication is not officially defined. The results of clinical studies confirm the advisability of using clopidogrel up to 12 months after the development of acute coronary syndrome without ST segment elevation.
In acute coronary syndrome with ST segment elevation (acute myocardial infarction) with drug treatment and the possibility of carrying out thrombolytic therapy , ZiltВ® is administered at a dose of 75 mg 1 time / day, starting with a loading dose, in combination with acetylsalicylic acid in combination or without thrombolytics.For patients older than 75 years, treatment with ZiltВ® should be performed without the use of a loading dose. Combination therapy starts as soon as possible after the onset of symptoms and lasts for at least 4 weeks. The effectiveness of combined therapy with clopidogrel and acetylsalicylic acid for more than 4 weeks in such patients has not been studied.
When atrial fibrillation (atrial fibrillation) , Zilt В® is prescribed in a dose of 75 mg 1 time / day. In combination with clopidogrel, you should start and then continue therapy with acetylsalicylic acid at a dose of 75-100 mg / day.
Skipping the next dose
If less than 12 hours have elapsed after missing the next dose, you should immediately take the missed dose of Zilt В® and then take the next dose at the usual time.
If more than 12 hours have passed after missing the next dose, then the next dose should be taken at the usual time; Do not double the dose.
Adults and elderly patients with genetically determined reduced activity of the isoenzyme CYP2C19
The low activity of the isoenzyme CYP2C19 is associated with a decrease in the antiplatelet effect of clopidogrel. The use of Zilt В® at higher doses (loading dose 600 mg, then 150 mg 1 time / day) in patients with low activity of the isoenzyme CYP2C19 leads to an increase in the antiplatelet effect of clopidogrel. However, clinical studies on clinical outcomes have not established an optimal dosing regimen for clopidogrel in patients with reduced metabolism due to the genetically determined low activity of the CYP2C19 isoenzyme.
Special patient groups
In elderly volunteers (over 75 years old), when compared with young volunteers, no differences in platelet aggregation and bleeding time were found. Dose adjustments in elderly patients are not required.
After repeated use of clopidogrel at a dose of 75 mg / day in patients with severe renal dysfunction (SC 5-15 ml / min), the degree of inhibition of ADP-induced platelet aggregation is lower by 25% than in healthy volunteers. However, the degree of lengthening of bleeding time was similar to that of healthy volunteers who received clopidogrel at a dose of 75 mg / day. The tolerability of the drug in all patients was good.
After using clopidogrel at a dose of 75 mg / day for 10 days in patients with severe impairment of liver function, the degree of inhibition of ADP-induced platelet aggregation and the mean elongation of bleeding time were comparable to those of healthy volunteers.
The prevalence of the alleles of the CYP2C19 isoenzyme genes associated with intermediate or low metabolism is different in representatives of different racial / ethnic groups . There are limited literature data to assess the genotyping of the isoenzyme CYP2C19 on clinical outcomes for patients of the Mongoloid race.
When comparing the pharmacodynamic properties of clopidogrel in men and women, a less inhibition of ADP-induced platelet aggregation was observed in women, but there was no difference in lengthening the bleeding time. When comparing clopidogrel with acetylsalicylic acid in patients at risk of developing ischemic complications, the frequency of clinical outcomes, other side effects and deviations from the norm of clinical and laboratory indicators was the same for both men and women.
The safety of clopidogrel was investigated in patients who received clopidogrel therapy for 1 year or more. The safety of clopidogrel at a dose of 75 mg / day was comparable with that of acetylsalicylic acid at a dose of 325 mg / day, regardless of age, gender and race. The undesirable reactions observed in clinical studies are listed below. In addition, spontaneous reports of unwanted reactions are indicated.
In clinical studies and post-marketing surveillance of clopidogrel, bleeding was reported most frequently, mainly during the first month of therapy.
Classification of the incidence of adverse events (WHO): very often (? 1/10), often (from? 1/100 to <1/10), infrequently (from? 1/1000 to <1/100), rarely (from? 1/10 000 to <1/1000), very rarely (<1/10 000), the frequency is unknown (can not be estimated based on available data).
From the hemopoietic system: infrequently - thrombocytopenia, leukopenia, eosinophilia; rarely - neutropenia, including cases of severe neutropenia; very rarely thrombotic thrombocytopenic purpura (TTP), aplastic anemia, pancytopenia, agranulocytosis, severe thrombocytopenia, granulocytopenia, anemia.
From the nervous system: infrequently - intracranial hemorrhage (there are reports of several fatal cases), headache, paresthesia, dizziness; very rarely - hallucinations, confusion.
From the cardiovascular system: often - hematoma; very rarely - vasculitis, arterial hypotension.
From the respiratory system: often - nosebleeds; very rarely - bleeding from the respiratory tract (hemoptysis, pulmonary hemorrhage), bronchospasm, interstitial pneumonitis.
From the digestive system: often - diarrhea, abdominal pain, indigestion, gastrointestinal bleeding; infrequently - ulcers of the stomach and duodenum, gastritis, vomiting, nausea, constipation, flatulence; rarely - retroperitoneal hemorrhage; very rarely - gastrointestinal and retroperitoneal bleeding sometimes fatal, pancreatitis, colitis (including ulcerative colitis or lymphocytic colitis), stomatitis, impaired liver function, hepatitis, acute liver failure.
From the skin: often - subcutaneous hematomas; infrequent - rash, itching, skin hemorrhage (purpura); very rarely - bullous dermatitis (toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme), erythematous rash, urticaria, eczema, flat lichen.
From the musculoskeletal system: very rarely - hemorrhages in the muscles and joints (hemarthrosis), arthritis, arthralgia, myalgia.
From the genitourinary system: infrequently - hematuria; very rarely - glomerulonephritis, an increase in the concentration of creatinine in the blood serum.
From the sense organs: infrequently - intraocular hemorrhages (conjunctival, retinal); rarely - vertigo; very rarely - a violation of taste perception.
Allergic reactions: very rarely - angioedema, eczema, serum sickness, anaphylactoid reactions; frequency unknown - cross-reactive hypersensitivity to thienopyridine (eg, ticlopidine, prasugrel), frequency unknown - drug-induced hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS syndrome).
Laboratory indicators: often - lengthening the time of bleeding, reducing the number of neutrophils, reducing the number of platelets.
Other: often - bleeding from the point of vascular puncture; very rarely - fever, serious bleeding from the operating wound.
- hypersensitivity to clopidogrel and / or any of the components of the drug;
severe liver dysfunction;
- acute bleeding (e.g., bleeding peptic ulcers or intracranial hemorrhage);
- lactation period (breastfeeding);
- child and adolescence to 18 years (Safety and efficacy have not been established);
- lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome.
- mild liver function abnormalities with a predisposition to bleeding (limited experience);
- renal dysfunction (limited use experience);
- pathological conditions that increase the risk of bleeding (including trauma, surgery);
- a disease in which there is a predisposition to bleeding (especially gastrointestinal and intraocular);
- simultaneous application of NSAIDs, including COX-2 inhibitors;
- the simultaneous use of warfarin, heparin or inhibitors of the glycoprotein IIb / IIIa;
- Patients with low activity isoenzyme CYP2C19 (with clopidogrel at recommended doses produce less active metabolite of clopidogrel and weaker expressed its antiplatelet effect, and therefore the application of clopidogrel at recommended doses for acute coronary syndrome or percutaneous coronary intervention frequency of cardiovascular complications can be higher than in patients with normal activity isoenzyme CYP2C19);
- hypersensitivity to other thienopyridine (e.g., ticlopidine, prasugrel).
PREGNANCY AND LACTATION
Since clinical data on the use of clopidogrel during pregnancy are not available, the drug is not recommended during pregnancy. Studies in animals did not reveal any direct or indirect adverse effects on pregnancy, embryo / fetus during childbirth or postnatal development.
In animal studies it has been proved the penetration of clopidogrel in breast milk. Therefore, it is recommended to stop breast-feeding if necessary therapy with clopidogrel.
APPLICATION FOR FUNCTIONS OF THE LIVER
Precautions must be prescribed to patients with impaired renal function in chronic renal failure.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
When the use of severe liver disease is contraindicated.
With caution should be prescribed to patients with impaired liver function, moderate hepatic insufficiency.
APPLICATION FOR CHILDREN
Do not use this medication in children and adolescents under the age of 18 years.
APPLICATION IN ELDERLY PATIENTS
Elderly volunteers (over 75 years) have not revealed when compared to young volunteers in terms of differences in platelet aggregation and bleeding time. Dose adjustment in elderly patients is not required.
For patients older than 75 years treated with clopidogrel should be carried out without the use of a loading dose.
During treatment with clopidogrel, particularly in the first weeks and / or after invasive cardiac procedures / surgeries, you must be closely monitored for the patient to rule out signs of bleeding (including hidden). Given the risk of bleeding and haematological adverse events, with the appearance of clinical symptoms of a possible bleeding during treatment, you must immediately perform a clinical blood tests, APTT, platelet function indicators, with counting the number of platelets and conduct other necessary investigations.
Clopidogrel prolongs bleeding time. Therefore, caution should be prescribed to patients with an increased risk of bleeding after injuries, operations or due to other pathological conditions, patients with a tendency to bleeding (especially gastrointestinal and intraocular hemorrhage) as well as patients receiving aspirin, NSAIDs (including COX inhibitors -2), heparin and inhibitors of glycoprotein IIb / IIIa.
Concomitant use of clopidogrel with warfarin may increase the risk of bleeding. Therefore, caution should be exercised while the use of warfarin and clopidogrel.
In carrying out elective surgery when the antiplatelet effect is not desired, clopidogrel should be discontinued for 5-7 days prior to surgery.
The patient should be informed that the application of clopidogrel (as monotherapy or in combination with acetylsalicylic acid) may require more time to stop bleeding. Patients should inform the doctor about every case of unusual (for location or duration) bleeding. It is also necessary to inform the doctor about taking clopidogrel if patient to be surgery (including dental) or before starting a new drug.
Very rarely during treatment with clopidogrel (sometimes short) have been reported cases of thrombotic thrombocytopenic purpura. The condition is characterized by thrombocytopenia and microangiopathic hemolytic anemia associated with neurological disorders, renal dysfunction, and fever. Thrombotic thrombocytopenic purpura - a potentially life-threatening condition that requires immediate treatment including plasmapheresis.
The period of treatment is necessary to control liver function. In severe liver dysfunction should be aware of the risk of hemorrhagic diathesis.
Clopidogrel is not recommended for patients with acute ischemic stroke prescription of at least 7 days (no data for use in such a state).
Patients should be evaluated to identify hypersensitivity to other thienopyridine (e.g., ticlopidine, prasugrel), because aware of cross-reactive hypersensitivity between thienopyridine. Patients with hypersensitivity to other thienopyridines history should be monitored carefully in order to detect signs of hypersensitivity to clopidogrel during therapy.
Zilt В® should not be taken in patients with lactase deficiency, lactose intolerance syndrome glucose-galactose malabsorption, since formulation contains lactose.
Preparation Zilt В® contains hydrogenated castor oil, which can cause patients indigestion and diarrhea.
Impact on the ability to drive vehicles and manage mechanisms
Zilt В® has no significant effect on the ability to manage road and engage in other potentially hazardous activities that require high concentration and psychomotor speed reactions.
Symptoms: an overdose of clopidogrel could lead to a lengthening of the time of bleeding and hemorrhagic complications.
Treatment: in order to correct the extended bleeding time is recommended that a platelet transfusions. An antidote to clopidogrel is not installed.
The simultaneous use of clopidogrel and oral anticoagulants is not recommended (possibly increased bleeding intensity).
Use of clopidogrel 75 mg / day of warfarin does not alter the pharmacokinetics (substrate isoenzyme CYP2C9) or MHO in patients receiving long-term treatment with warfarin. However, the simultaneous use with warfarin increases the risk of bleeding due to its additional independent effect on blood clotting. Therefore, caution should be exercised while the use of warfarin and clopidogrel.
The simultaneous use of clopidogrel and inhibitors of glycoprotein IIb / IIIaIt requires caution in patients at increased risk of bleeding (trauma, surgery or other pathological conditions).
Acetylsalicylic acidIt does not affect the induced clopidogrel inhibition of platelet aggregation induced by ADP, but clopidogrel potentiates the effect of acetylsalicylic acid on collagen-induced platelet aggregation. However, simultaneous reception of acetylsalicylic acid in a dose of 500 mg of 2 times / day for one day did not significantly prolongs bleeding time caused by clopidogrel. Pharmacodynamic interaction between clopidogrel and acetylsalicylic acid possibly leads to increased risk of bleeding. Given this, caution while receiving these drugs, although in a clinical trial, patients received a combination therapy with clopidogrel and acetylsalicylic acid within one year.
According to a clinical study in healthy subjects when taking clopidogrel did not need to change the dose of heparin , and did not change the anticoagulant effects of heparin. Simultaneous administration of heparin had no effect on inhibition of platelet aggregation clopidogrel. Perhaps pharmacodynamic interaction between heparin and clopidogrel, which leads to increased risk of bleeding. Therefore, the simultaneous use of these drugs requires caution.
Safety of simultaneous administration of clopidogrel, fibrinspetsificheskih or non-specific thrombolyticsand heparin was assessed in patients with acute myocardial infarction. The incidence of clinically relevant bleeding was comparable with that of frequency while the use of thrombolytics, heparin, acetylsalicylic acid.
According to a clinical study involving healthy volunteers, concurrent use of clopidogrel and naproxen increased the hidden gastrointestinal bleeding. However, due to lack of interaction studies with other NSAIDs is currently unknown whether the increased risk of gastrointestinal bleeding for all NSAIDs. Therefore, simultaneous NSAID therapy, including COX-2 inhibitors and clopidogrel should be done with caution.
Inhibitors of the isoenzyme CYP2C19:Clopidogrel is metabolized to form its active metabolite partially under isoenzyme CYP2C19. Therefore, drugs that inhibit this isoenzyme may cause a decrease in concentration of the active metabolite of clopidogrel. The clinical significance of this interaction is unknown. Avoid the simultaneous application with strong or moderate inhibitors isoenzyme CYP2C19. By isoenzyme CYP2C19 inhibitors include omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine and chloramphenicol.
The use of omeprazole80 mg 1 time / day simultaneously with clopidogrel, or a 12-hour interval between the reception of two drugs has reduced the value of systemic exposure (AUC) of the active metabolite of clopidogrel by 45% (after receiving clopidogrel loading dose) and 40% (after receiving a maintenance dose of clopidogrel ). Reducing the AUC of the active metabolite of clopidogrel is associated with a decrease in the degree of inhibition of platelet aggregation (39% - after receiving a loading dose of clopidogrel and 21% - after receiving a maintenance dose of clopidogrel). It assumed similar interaction with clopidogrel esomeprazole. In observational and clinical studies have documented conflicting evidence about the clinical manifestations on the part of the cardiovascular system with respect to this pharmacokinetic / pharmacodynamic interaction.To avoid the simultaneous application of omeprazole or esomeprazole.
By proton pump inhibitors with minimal inhibitory action on isoenzyme CYP2C19 include pantoprazole and lansoprazole . With simultaneous use of pantoprazole in the dose of 80 mg 1 time / day observed reduction in the concentration of the active metabolite of clopidogrel in blood plasma by 20% (after receiving clopidogrel loading dose) and 14% (after receiving a maintenance dose of clopidogrel). This is accompanied by a reduction of inhibition of platelet aggregation, on average, 15% and 11% respectively. Therefore, the simultaneous use of clopidogrel with pantoprazole possible.
Another combination therapy
In a study of the pharmacokinetic and pharmacodynamic interaction of clopidogrel and other drugs revealed the following:
- while the use of clopidogrel with atenolol and / or nifedipine clinically significant pharmacodynamic interaction was not detected;
- pharmacodynamic activity of clopidogrel is not substantially changed while the use of phenobarbital, cimetidine or estrogen;
- The pharmacokinetics of digoxin or theophylline was not changed;
- Antacids do not affect the extent of absorption of clopidogrel;
- phenytoin and tolbutamide safely combined with clopidogrel. It is unlikely that clopidogrel may affect the metabolism of other drugs, such as phenytoin and tolbutamide and NSAIDs are metabolized by the action of the enzyme CYP2C9;
- in clinical studies there was no evidence of clinically significant adverse interaction with diuretics, beta-blockers, ACE inhibitors, calcium channel blockers slow, hypolipidemic agents, coronary vasodilators, hypoglycemic agents (including insulin), antiepileptic drugs, drugs for hormone replacement therapy .
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored in reach of children, in the original package, at a temperature not higher than 25 В° C. Shelf life - 3 years.