Clopidogrel 75mg pills №14

Trade name of the drug: Clopidogrel-SZ 

International non-proprietary name: Clopidogrel

Dosage Form: film coated tablets 

Composition:
1 tablet, film coated, contains:
active substance: clopidogrel hydrosulfate in terms of clopidogrel or clopidogrel bisulfate in terms of clopidogrel - 75 mg
excipients (core): lactose monohydrate (milk sugar) - 38.4 mg, microcrystalline cellulose - 129.48 mg, croscarmellose sodium (primellose) - 12.0 mg, colloidal silicon dioxide (aerosil) - 3.12 mg, sodium fumarate - 2.0 mg
excipients (shell): Opadry II - 8 mg (polyvinyl alcohol, partially hydrolyzed - 3.52 mg, talc - 1.6 mg, titanium dioxide E 171 - 1.5336 mg, macrogol (polyethylene glycol 3350) - 0.988 mg, soy lecithin E 322 - 0, 28 mg, dye-based aluminum varnish, azorubine - 0.0408 mg, dye-based aluminum varnish, crimson [Ponso 4R] – 0.0328 mg, aluminum lacquer based on indigo carmine dye - 0.0048 mg).

Description
Round, biconvex tablets, film-coated from pink to dark pink.

Pharmacotherapeutic group: antiplatelet agent.

PHARMACOLOGICAL PROPERTIES
Pharmacodynamics
Clopidogrel is a prodrug, one of the active metabolites of which is an inhibitor of platelet aggregation.The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to the P2Y12 platelet receptor and the subsequent ADP-mediated activation of the GPIIb / IIIa complex, leading to the suppression of platelet aggregation. Due to irreversible binding, platelets remain insensitive to stimulation of ADP for the remainder of their life (approximately 7-10 days), and restoration of normal platelet function occurs at a rate corresponding to the rate of platelet renewal. Platelet aggregation, caused by agonists other than ADP, is also inhibited due to the blockade of enhanced activation of platelets released by ADP. Since the formation of an active metabolite occurs with the help of isoenzymes of the P450 system, some of which may differ in polymorphism or may be inhibited by other drugs, not all patients can adequately suppress platelets.
Clopidogrel is able to prevent the development of atherothrombosis in any localization of atherosclerotic vascular lesions, in particular, in those with cerebral, coronary or peripheral arteries.
With daily intake of clopidogrel in a dose of 75 mg from the first day of administration, a significant suppression of ADP-induced platelet aggregation is noted, which gradually increases over 3-7 days and then goes to a constant level (when an equilibrium state is reached). In equilibrium, platelet aggregation is suppressed on average by 40-60%.After discontinuation of clopidogrel, platelet aggregation and bleeding time gradually return to the initial level on average within 5 days.
Pharmacokinetics
Suction
In exchange intake at a dose of 75 mg per day clopidogrel is rapidly absorbed.
The average maximum plasma concentrations of unchanged clopidogrel (approximately 2.2-2.5 ng / ml after ingesting a single dose of 75 mg) are reached approximately 45 minutes after administration. According to the excretion of clopidogrel metabolites by the kidneys, its absorption is approximately 50%.
Distribution
In vitro clopidogrel and its major inactive metabolite circulating in the blood bind reversibly to plasma proteins (98% and 94%, respectively), and this bond is unsaturated up to a concentration of 100 mg / l.
Metabolism
Clopidogrel is extensively metabolized in the liver. In vitro and in vivo, clopidogrel is metabolized in two ways: the first is through enzymes and subsequent hydrolysis to form an inactive carboxylic acid derivative (85% of circulating metabolites), and the second way is through the cytochrome P450 system. Initially, clopidogrel is metabolized to 2-oxo-clopidogrel, which is an intermediate metabolite. Subsequent metabolism of 2-oxo-clopidogrel leads to the formation of an active metabolite of clopidogrel, a thiol derivative of clopidogrel. In vitro, this pathway of metabolism occurs with the help of isoenzymes СYР2СI9, СYР1А2 and СYР2В6. The active thiol metabolite of clopidogrel, which was isolated in vitro studies, quickly and irreversibly binds to platelet receptors, thus blocking platelet aggregation.
Removal
Within 120 hours after ingestion of 14C-labeled clopidogrel by humans, about 50% of the radioactivity is excreted by the kidneys and approximately 46% of the radioactivity is excreted through the intestines. After a single oral dose of 75 mg, the half-life of clopidogrel is approximately 6 hours. After a single dose and repeated doses, the half-life of the main inactive metabolite circulating in the blood is 8 hours.
Pharmacogenetics
With the help of the CYP2C19 isoenzyme, both the active metabolite and the intermediate metabolite - 2-oxo-clopidogrel are formed. The pharmacokinetics and antiplatelet effect of the active metabolite of clopidogrel, in the study of platelet aggregation ex vivo, vary depending on the genotype of the CYP2C19 isoenzyme. The allele of the CYP2C19 * 1 gene corresponds to a fully functional metabolism, whereas the alleles of the CYP2C19 * 2 and CYP2C19 * 3 genes are non-functional. Alleles of the CYP2C19 * 2 and CYP2C19 * 3 genes are responsible for the decrease in metabolism in the majority of Caucasians (85%) and Mongoloid race (99%). Other alleles that are associated with a lack or decrease in metabolism are less common and include, but are not limited to, the CYP2C19 * 4, * 5, * 6, * 7, and * 8 gene alleles. Patients with low CYP2C19 isoenzyme activity should have the two alleles of the gene indicated above with loss of function. The published frequencies of phenotypes for people with low CYP2C19 isoenzyme are 2% for Caucasians, 4% for Negroids, and 14% for Chinese. To determine whether the patient has a genotype of CYP2C19 isoenzyme, relevant tests exist.
According to a cross-sectional study (40 volunteers) and a meta-analysis of six studies (335 volunteers). These included individuals with a very high, high, intermediate and low activity of the CYP2C19 isoenzyme, any significant differences in the exposure of the active metabolite and in the mean values ​​of inhibition of platelet aggregation (IAT) (induced by ADP) in volunteers with very high, high and intermediate activity no CYP2C19 isoenzyme was detected. In volunteers with a low activity of the CYP2C19 isoenzyme, the exposure of the active metabolite was reduced compared with volunteers with a high activity of the CYP2C19 isoenzyme.
When volunteers with a low activity of the CYP2C19 isoenzyme received a treatment regimen of 600 mg loading dose / 150 mg maintenance dose (600 mg / 150 mg), the active metabolite exposure was higher than with the 300 mg / 75 mg treatment regimen. In addition, IAT was similar to that in groups of patients with higher metabolic rates using the CYP2C19 isoenzyme who received the 300 mg / 75 mg treatment regimen. However, in studies taking into account clinical outcomes, the dosage regimen of clopidogrel for patients of this group (patients with low activity of the isoenzyme CYP2C19) has not yet been established.
Clinical studies conducted to date have not had enough sample size to detect differences in clinical outcome in patients with low CYP2C19 isoenzyme activity.
Selected patient groups
The pharmacokinetics of the active metabolite of clopidogrel in elderly patients, children, patients with kidney diseases and liver has not been studied.

INDICATIONS FOR USE
- Prevention of atherothrombotic events in patients after myocardial infarction (with prescription from several days to 35 days), ischemic stroke (with prescription from 7 days to 6 months) or having a diagnosed occlusive peripheral artery disease.
- Prevention of atherothrombotic events (in combination with acetylsalicylic acid) in patients with acute coronary syndrome:
- without ST segment elevation (unstable angina or myocardial infarction without a Q wave), including patients who underwent stenting for percutaneous coronary intervention;
- With the rise of the ST segment (acute myocardial infarction) with drug treatment and the possibility of thrombolysis.

CONTRAINDICATIONS
- Increased sensitivity to clopidogrel or any of the excipients of the drug.
- Severe liver failure.
- Acute bleeding, such as bleeding from a peptic ulcer or intracranial hemorrhage.
-Rare hereditary lactose intolerance, lactase deficiency and glucose-galactose malabsorption.
Pregnancy and lactation (see "Pregnancy and breastfeeding").
-Child age up to 18 years (safety and efficacy have not been established).
Carefully
- Moderate hepatic impairment, in which a predisposition to bleeding is possible (limited clinical experience of use).
- Renal failure (limited clinical experience).
- Trauma, surgical interventions (see. "Special Instructions").
- Diseases in which there is a predisposition to the development of bleeding (especially gastrointestinal or intraocular).
- Simultaneous administration of nonsteroidal anti-inflammatory drugs, including selective cyclooxygenase-2 inhibitors (COX-2).
- The simultaneous appointment of Warfarin, Heparin, glycoprotein IIb / IIIa inhibitors.
- In patients with a genetically determined decrease in the function of the isoenzyme CYP2C19 in recommended doses (there are literature data indicating that patients with a genetically determined decrease in the function of the isoenzyme CYP2C19 are exposed to a lower systemic exposure to the active metabolite of clopidogrel and have a less pronounced effect of the drug, in addition, they may there is a higher incidence of cardiovascular complications after myocardial infarction compared with patients with normal function of the isoenzyme CYP2C19).
Use during pregnancy and during breastfeeding
As a precaution, taking clopidogrel during pregnancy is not recommended due to the lack of clinical data on its use by pregnant women, although animal studies did not reveal any direct or indirect adverse effects on the course of pregnancy, fetal development, childbirth and postnatal development.Breastfeeding in the case of treatment with clopidogrel should be discontinued, since in studies in rats it has been shown that clopidogrel and / or its metabolites are excreted into breast milk. Whether clopidogrel penetrates human breast milk is unknown.

METHOD OF ADMINISTRATION AND DOSES
Adults and elderly patients with normal activity of the isoenzyme CYP2C19
Clopidogrel-SZ should be taken orally, regardless of the meal.
Myocardial infarction, ischemic stroke and diagnosed occlusive peripheral artery disease
The drug is taken at 75 mg once a day.
In patients with myocardial infarction (MI), treatment can be started from the first days to 35 days of MI, and in patients with ischemic stroke (AI), from 7 days to 6 months after AI.
Acute coronary syndrome without ST segment elevation (unstable stenocardia, myocardial infarction without Q wave)
Treatment with Klopidogrel-SZ should be started with a single dose of a loading dose of 300 mg and then continued with a dose of 75 mg once a day (in combination with Acetylsalicylic acid as an antiplatelet agent at doses of 75-325 mg per day). Since the use of higher doses of acetylsalicylic acid is associated with an increased risk of bleeding, the dose of acetylsalicylic acid recommended for this indication should not exceed 100 mg. The maximum therapeutic effect is observed by the third month of treatment. The course of treatment up to 1 year.
Acute coronary syndrome with ST segment elevation (acute myocardial infarction with ST segment elevation)
Clopidogrel-SZ is administered once at a dose of 75 mg once a day with an initial single dose of a loading dose in combination with acetylsalicylic acid as an antiplatelet agent and thrombolytic (or without thrombolytic). Combination therapy is started as soon as possible after the onset of symptoms and continues for at least four weeks. In patients older than 75 years, treatment with Klopidogrel-SZ should begin without taking its loading dose.
Patients with a genetically determined decrease in the function of the isoenzyme CYP2C19
The weakening of metabolism using the isoenzyme CYP2C19 can lead to a decrease in the antiplatelet effect of clopidogrel. The optimal dosing regimen for patients with a weakened metabolism using the isoenzyme CYP2C19 has not yet been established.
Patients with impaired renal function
After repeated administration of the drug Klopidogrel-SZ at a dose of 75 mg / day in patients with severe kidney damage (creatinine clearance from 5 to 15 ml / min), the inhibition of ADP-induced platelet aggregation (25%) was lower compared to that in healthy volunteers, however, the lengthening of the bleeding time was similar to that of healthy volunteers who received Klopidogrel-SZ at a dose of 75 mg per day. In addition, all patients had good tolerability.
Patients with impaired liver function
After daily administration of clopidogrel SZ at a dose of 75 mg daily for 10 days in patients with severe liver damage, the inhibition of ADP-induced platelet aggregation was similar to that in healthy volunteers. The average bleeding time was also comparable in both groups.
Patients of different ethnicity
The prevalence of CYP2C19 isoenzyme gene alleles, which are responsible for the intermediate and reduced metabolism of clopidogrel to its active metabolite, differs among members of different ethnic groups (see the Pharmacogenetics section). Only limited data are available for representatives of the Mongoloid race to assess the effect of the CYP2C19 isoenzyme genotype on the clinical outcomes.

SIDE EFFECT
Classification of the incidence of side effects (WHO):
often more than 1/100 and less than 1/10,
infrequently - more than 1/1000 and less than 1/100,
rarely more than 1/10000 and less than 1/1000,
very rarely - less than 1/10000).
From the central and peripheral nervous system:
infrequently - headache, dizziness and paresthesias:
rarely - vertigo;
very rarely - a violation of taste.
From the digestive system:
often - diarrhea, abdominal pain, dyspepsia ;
infrequently - gastric and duodenal ulcers, gastritis, vomiting, nausea, constipation, flatulence;
very rarely - pancreatitis, colitis (including ulcerative or lymphocytic colitis), stomatitis.
Hemostatic disorders:
infrequently - lengthening bleeding time.
Hematopoietic disorders:
infrequently - thrombocytopenia, leukopenia, neutropenia and eosinophilia,
very rarely - thrombocytopenic thrombo-hemolytic purpura, severe thrombocytopenia (platelet count ≤ 30x109 / l), agranulocytosis, granulocytopenia, aplastic anemia (pancytopenia), anemia.
Violations of the skin and subcutaneous tissues:
infrequently - skin rash and itching;
very rarely - angioedema, urticaria, erythematous rash (associated with clopidogrel or acetylsalicylic acid);
very rarely - bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), eczema and lichen planus.
Violations by the immune system:
very rarely - anaphylactoid reactions, serum sickness.
Mental disorders:
very rarely - confusion, hallucinations.
Violations of the vascular system:
very rarely - vasculitis, marked reduction in blood pressure (BP), intracranial hemorrhage, eye hemorrhages (conjunctival, in the tissue and retina), hematoma, nosebleeds, bleeding from the respiratory tract, Gastrointestinal bleeding, retroperitoneal hemorrhage, death in muscles and joints, hematuria, etc.
Respiratory disorders:
very rarely - bronchospasm, interstitial pneumonitis.
Violations of the hepato-biliary system:
very rarely - acute liver failure, hepatitis.
Violations of the musculoskeletal system:
very rarely - arthralgia, arthritis, myalgia.
Kidney and urinary tract disorders:
very rarely - glomerulonephritis.
General violations:
very rarely - fever.
Changes in laboratory parameters:
very rarely - a change in liver function tests, an increase in serum creatinine concentration.

OVERDOSE
Symptoms: prolongation of bleeding time with subsequent complications in the form of bleeding.
Treatment: stop bleeding, platelet mass transfusion. The antidote is unknown.

INTERACTION WITH OTHER MEDICINES
Warfarin:simultaneous use with clopidorrel can increase the intensity of bleeding, so the use of this combination is not recommended.
IIb / IIIa receptor blockers:appointment of blockers IIb / IIIa receptors, together with clopidogrel, requires caution in patients who have an increased risk of bleeding (for injuries and surgical interventions or other pathological conditions) (see section "Special Instructions").
Acetylsalicylic acid:acetylsalicylic acid does not alter the effect of clopidogrel, which inhibits ADP-induced platelet aggregation, but clopidogrel potentiates the effect of acetylsalicylic acid on collagen-induced platelet aggregation. However, the simultaneous use of acetylsalicylic acid as an antipyretic with clopidogrel, 500 mg 2 times a day for 1 day did not cause a significant increase in the bleeding time caused by clopidogrel administration.Between clopidogrel and acetylsalicylic acid pharmacodynamic interaction is possible, which leads to an increased risk of bleeding. Therefore, with their simultaneous use, care should be taken, although in clinical studies, patients received combination therapy with clopidogrel and acetylsalicylic acid for up to one year.
Heparin:According to a clinical study conducted with the participation of healthy volunteers, taking clopidogrel did not require a change in the dose of heparin and its anticoagulant effect did not change. The simultaneous use of heparin did not alter the antiplatelet effect of clopidogrel. Between clopidogrel and heparin, pharmacodynamic interaction is possible, which may increase the risk of bleeding, therefore the simultaneous use of these drugs requires caution.
Tombolitics:the safety of simultaneous use of clopidogrel, fibrin-specific or fibrin-specific thrombolytic drugs and heparin was studied in patients with acute myocardial infarction. Frequently clinically significant bleeding was similar to that observed in the case of simultaneous use of thrombolytic agents and heparin with acetylsalicylic acid.
Non-steroidal anti-inflammatory drugs (NSAIDs):in a clinical study conducted with the participation of healthy volunteers, the simultaneous use of clopidogrel and Naproxen increased latent blood loss through the gastrointestinal tract.However, due to the lack of research on the interaction of clopidogrel with other NSAIDs, it is currently not known whether there is an increased risk of gastrointestinal bleeding when taking clopidogrel along with other NSAIDs. Therefore, the appointment of NSAIDs, including selective inhibitors of COX-2, in combination with clopidogrel should be carried out with caution (see section "Special instructions").
Other combination therapy
Since clopidogrel is metabolized to the formation of its active metabolite partially using the isoenzyme CYP2C19, the use of drugs inhibiting this system can lead to a decrease in the level of the active metabolite of clopidogrel and a decrease in its clinical efficacy. Simultaneous administration of drugs inhibiting the isoenzyme СYP2C19 (for example, omeprazole) is not recommended.
A number of clinical studies were conducted with clopidogrel and other concomitantly prescribed drugs in order to study possible pharmacodynamic and pharmacokinetic interactions, which showed that:
- when using clopidogrel together with Atenolol, Nifedipine or with both drugs at the same time, no clinically significant pharmacodynamic interaction was observed;
- simultaneous use of phenobarbital, cimetidine and estrogen had no significant effect on clopidogrel pharmacodynamics;
- pharmacokinetic indices of Digoxin and theophylline did not change when they were applied simultaneously with clopidogrel.
- antiacid means did not reduce the absorption of clopidogrel.
- Phenytoin and tolbutamide can be safely applied simultaneously with clopidogrel, despite the fact that the data obtained during studies with human liver microsomes indicate that the carboxyl metabolite of clopidogrel may inhibit the activity of the CYP2C9 isoenzyme, which can lead to an increase in plasma concentrations drugs (phenytoin, tolbutamide, and some NSAIDs) that are metabolized by the isoenzyme CYP2C9.
- angiotensin-converting enzyme (ACE) inhibitors, diuretics, beta-blockers, slow Calcium channel blockers, hypoglycemic agents (including insulin), lipid-lowering drugs, antiepileptic drugs, hormone replacement therapy and GPIIb / IIIa receptors blockers : In clinical studies, no clinically relevant undesirable interactions were detected.

SPECIAL INSTRUCTIONS
When treating Klopidogrel-SZ, especially during the first weeks of treatment and / or after invasive cardiac procedures / surgery, it is necessary to carefully monitor patients to exclude signs of bleeding, including hidden ones.
Due to the risk of bleeding and hematological undesirable effects (see the “Side effect” section) if clinical symptoms that are suspicious of bleeding occur during the treatment,An urgent clinical blood test should be performed, the activated partial thromboplastin time (APTT), the number of platelets, the indicators of the functional activity of platelets and other necessary studies should be determined.
Clopidogrel-SZ, as well as other antiplatelet drugs, should be used with caution in patients with an increased risk of bleeding associated with injuries, surgical interventions or other pathological conditions, as well as in patients receiving acetylsalicylic acid, nonsteroidal anti-inflammatory drugs, including COX-2 inhibitors, heparin or glycoprotein IIb / IIIa inhibitors.
The combined use of clopidogrel with warfarin can increase the intensity of bleeding (see "Interaction with other drugs"), therefore, with the exception of special rare clinical situations (such as the presence of a floating thrombus in the left ventricle, stenting in patients with atrial fibrillation), the use of clopidogrel and warfarin is not recommended.
If the patient has a planned surgical intervention, and there is no need for an antiplatelet effect, then 7 days before the operation, the use of the drug Klopidogrel-SZ should be stopped.
Clopidogrel prolongs bleeding time and should be used with caution in patients with diseases that predispose to the development of bleeding (especially gastrointestinal and intraocular).
Patients should be warned that when taking the drug Klopidogrel-SZ (alone or in combination with acetylsalicylic acid) it may take longer to stop the bleeding, and that if they have unusual (by localization or duration) bleeding they should report this to their health care provider. Before any forthcoming operation and before the start of taking any new drug, patients should inform the doctor (including the dentist) about taking the drug Klopidogrel-SZ.
Very rarely, after use of the drug Klopidogrel-SZ (sometimes even briefly), there have been cases of thrombocytopenic thrombohemolytic purpura (THP), which is characterized by thrombocytopenia and microangiopathic hemolytic anemia, accompanied by neurological disorders, impaired kidney function and fever. TBD is a potentially life-threatening condition that requires immediate treatment, including plasmapheresis.
During the period of treatment it is necessary to control the functional activity of the liver. For severe violations of liver function, you should remember the risk of hemorrhagic diathesis. The use of Klopidogrel-SZ is not recommended for acute stroke with a prescription of less than 7 days (as there are no data on its use in this condition). Clopidogrel-SZ should not be taken in patients with rare hereditary galactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome ( see “Composition”).

INFLUENCE ON THE ABILITY TO DRIVE MOTOR TRANSPORT AND MANAGEMENT OF MECHANISMS
Klopidogrel-SZ does not have a significant impact on the ability to drive vehicles or work with machinery.

FORM ISSUE
Tablets, film coated, 75 mg. On 10, 14 or 30 tablets in a blister strip packaging. 30 tablets in a polymer can or in a polymer bottle. 3, 6 blister packs of 10 tablets, 1, 2, 4 blister packs of 14 tablets, 1, 2, 3 blister packs of 30 tablets, can or bottle with application instructions in a carton box.

STORAGE CONDITIONS
In dry, the dark place at a temperature of no higher than 25^aboutWITH. Keep out of the reach of children.