DEPLETT -75 - instructions for use, doses, side effects, contraindications

Excipients: micro-lacquer (lactose monohydrate 75% and microcrystalline cellulose 25%) 122.875 mg, mannitol 5 mg, low-substituted giprolose 16 mg,macrogol-6000 12.5 mg, hydrogenated castor oil 2.5 mg, magnesium stearate 1.3 mg, silicon dioxide colloid 2 mg;

Film sheath: hypromellose 2910 4.2 mg, iron dye oxide red 0.08 mg, titanium dioxide 0.52 mg, macrogol-6000 0.4 mg.

Description:

Round, smooth, biconcave tablets with a bevel, covered with a film shell of pink color. On the cross-section: the core is white or almost white.

Pharmacotherapeutic group:Antiaggregant agent

ATX: & nbsp

B.01.A. C.04 Clopidogrel

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 P2Y₁₂-receptor of platelets and subsequent activation of the complex GPIIb/IIIa under the action of ADP, thereby inhibiting the aggregation of platelets. Due to irreversible binding, platelets remain immune to stimulation of ADP for the rest of their life (about 7-10 days), and restoration of normal platelet function occurs at a rate corresponding to the rate of platelet renewal.Aggregation of platelets caused by agonists other than ADP is also inhibited by blockade of enhanced platelet activation by the released ADP.

Since the formation of an active metabolite occurs by means of isozymes of cytochrome P450, some of which may be different or polymorphism can be inhibited by other drugs, not all patients may adequate inhibition of platelet aggregation (see. Subsection "Pharmacokinetics" section of "Pharmacological properties").

With daily administration of clopidogrel at a dose of 75 mg from day reception marked significant inhibition of ADP-induced platelet aggregation, which gradually increases after 3-7 days and then discharged at a constant level (when reaching equilibrium). In the equilibrium state, platelet aggregation is suppressed on average by 40-60%. Platelet aggregation, and bleeding time are returned to the initial level within an average of 5 days after cessation of clopidogrel.

In a small study comparing the pharmacodynamic properties of clopidogrel in patients of both sexes, in females there was minimal inhibition of ADP-induced platelet aggregation, but differences in the elongation of bleeding time was not.In a large controlled study CAPRIE (clopidogrel in comparison with acetylsalicylic acid in patients with the 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.

Pharmacokinetics:

Suction

With a single and course administration in a dose of 75 mg per day clopidogrel quickly absorbed in the intestine. The maximum concentration (C_mOh) in the blood plasma of unchanged clopidogrel after a single oral intake at a dose of 75 mg is about 2.2-2.5 ng / ml; time to reach the maximum concentration (TC_mOh) is approximately 45 minutes. According to the excretion of metabolites of clopidogrel with kidneys, its absorption is approximately 50%.

Distribution

In vitro Clopidogrel and its main circulating non-active metabolite in the blood reversibly bind to plasma proteins (by 98% and 94%, respectively), and this bond is unsaturated in a wide range of concentrations.

Metabolism

Clopidogrel is extensively metabolized in the liver. In vitro and in vivo Clopidogrel is metabolized by two metabolic pathways: the first route is carried out through esterases and subsequent hydrolysis with the formation of an inactive metabolite,a derivative of carboxylic acid (85% of circulating metabolites), and the second way through the cytochrome P450 system. at first 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-thiol clopidogrel derivative.

In vitro this pathway of metabolism occurs by means of isoenzymes CYP2C19, CYP1A2 and CYP2B6. Active thiol metabolite of clopidogrel, which was isolated in studies in vitro, quickly and irreversibly binds to platelet receptors, blocking the aggregation of platelets. FROM_mOh active metabolite of clopidogrel after receiving its loading dose of 300 mg is 2 times higher than C_mOh after 4 days of taking a maintenance dose of clopidogrel 75 mg. In this case, when taking 300 mg clopidogrel C_mOh is achieved within about 30-60 minutes.

Excretion

Within 120 hours after ingestion of 14C-labeled clopidogrel, approximately 50% of the radioactivity is released by the kidneys and approximately 46% of the radioactivity - through the intestine. After a single oral dose of 75 mg half-life (T_1/2) of clopidogrel is approximately 6 hours. After a single and course admission T_1/2The main circulating inactive blood metabolite is 8 hours.

Pharmacogenetics

Isozyme CYP2C19 is involved in the formation of both an active metabolite and an intermediate metabolite, 2-oxo-clopidogrel. Pharmacokinetics and antiplatelet effect of the active metabolite clopidogrel, studied through platelet aggregation ex vivo, vary depending on the genotype of the isoenzyme CYP2C19. Gene allele CYP2C19 * 1 corresponds to fully functional metabolism, whereas gene alleles CYP2C19 * 2 and CYP2C19 * 3 are non-functional. Alleles of genes CYP2C19 * 2 and CYP2C19 * 3 cause a decrease in metabolism in the majority of representatives of the Caucasoid (85%) and Mongoloid races (99%). Other alleles that cause a lack or decrease in metabolism are represented by gene alleles CYP2C19*4, *5, *6, *7 and * 8, but they are rarely found in the general population. Pharmacokinetic testing allows you to determine the genotype with a variability of isoenzyme activity CYP2C19. Genetic variants of other enzymes of the P450 system with the influence on the formation of active metabolites of clopidogrel are also possible.

Individual patient groups

Elderly patients

In elderly volunteers (over 75 years), when compared with young volunteers, there was no difference in platelet aggregation and bleeding time, so dose adjustment is not required.

Patients of childhood

No data available.

Patients with impaired renal function

In patients with severe renal damage (creatinine clearance 5 to 15 ml / min) after repeated clopidogrel administration at a dose of 75 mg / day, the inhibition of ADP-induced platelet aggregation was 25% lower than that of healthy volunteers, however the prolongation of bleeding time was similar to that of healthy volunteers who received clopidogrel in a dose of 75 mg / day. In addition, all patients had good tolerability of the drug.

Patients with impaired hepatic function

In patients with severe impairment of liver function after daily 10-day administration of clopidogrel at a daily dose of 75 mg, the inhibition of ADP-induced platelet aggregation was similar to that of healthy volunteers. The mean bleeding time was also comparable in both groups.

Patients of different race

Prevalence of alleles of isoenzyme genes CYP2C19, responsible for an intermediate or decreased metabolism, is different in representatives of different racial groups. Available literature data on prevalence in representatives of the Mongoloid race are insufficient to assess the significance of the effect of genotypes of the isoenzyme CYP2C19 on clinical outcomes.

Indications:

Prevention of atherothrombotic complications:

- Have adult patients with myocardial infarction (with a duration of several days to 35 days), ischemic stroke (with a duration of 7 days to 6 months) or with diagnosed occlusive disease of the peripheral arteries;

- Have adult patients with acute coronary syndrome:

without ST segment elevation (unstable angina or myocardial infarction without Q wave), including patients who underwent stenting with percutaneous coronary intervention (in combination with acetylsalicylic acid (ACA));
with the rise of the ST segment (acute myocardial infarction) with drug treatment and the possibility of carrying out thrombolysis (in combination with ASA).

Prevention of atherothrombotic and thromboembolic complications, including stroke, with atrial fibrillation (atrial fibrillation)

- In adults with atrial fibrillation (atrial fibrillation), which have at least one risk factor for vascular complications, they can not take indirect anticoagulants and have a low risk of bleeding (in combination with ASA).

Contraindications:

Hypersensitivity to clopidogrel or any auxiliary substance included in the preparation.

Severe hepatic insufficiency.

Acute bleeding, eg bleeding from a peptic ulcer or intracranial hemorrhage).

Rare hereditary conditions: lactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome (due to the presence of lactose in the formulation).

Age to 18 years (efficacy and safety of use not established).

Pregnancy and the period of breastfeeding.

Carefully:

Carefully under the following conditions:

- With moderate hepatic insufficiency, which can predispose to bleeding (limited clinical experience of use).

- In chronic renal failure of mild and moderate severity (limited clinical experience of use).

- In diseases in which there is a predisposition to the development of bleeding (especially gastrointestinal and intraocular) and in patients taking medications that can cause damage to the gastrointestinal mucosa (such as ASA and non-steroidal anti-inflammatory drugs (NSAIDs) , including selective inhibitors of cyclooxygenase-2 (COX-2)).

- In patients who have an increased risk of bleeding: due to trauma, surgery or other pathological conditions, as well as in patients receiving ASA treatment, heparin, oral anticoagulants, glycoprotein inhibitors IIb/IIIa, NSAIDs, including selective inhibitors of COX-2, or selective serotonin reuptake inhibitors (SSRIs) (see section "Specific guidance").

- If you have a history of allergic and hematologic reactions to other thienopyridine (such as ticlopidine, prasugrel) in connection with the possibility of developing cross-reactions (see section "Special instructions").

- With a recent transient impairment of cerebral circulation or ischemic stroke (withsimultaneous application with ASK, see section "Special instructions").

- In patients with low isoenzyme activity CYP2C19 (see subsection "Pharmacokinetics" under "Pharmacological properties", sections "Dosage and administration", "Special instructions").

Pregnancy and lactation:

Pregnancy

Studies in animals have not revealed direct or indirect adverse effects on the course of pregnancy, embryonic development, childbirth and postnatal development. Since it is not always possible to predict the reaction in humans from the results of animal studies, and in view of the absence of data from controlled clinical studies on the use of clopidogrel by pregnant women, clopidogrel is not recommended as a precautionary measure during pregnancy,

Breastfeeding period

Data on the excretion of clopidogrel in breast milk of women are absent.

In animal studies, it was shown that clopidogrel excreted in breast milk. As a precautionary measure during the treatment with the drug Depplat^®-75 should stop breastfeeding

Dosing and Administration:

Inside, regardless of food intake.

Adults and elderly patients with normal isoenzyme activity CYP2C19:

Myocardial infarction, ischemic stroke, or diagnosed peripheral arterial occlusive disease

The drug is taken 1 tablet (75 mg) once a day.

Acute coronary syndrome without segment elevation ST (unstable angina, myocardial infarction without a tooth Q)

Treatment with the drug Deplat®-75 begins with a single dose of 300 mg, and then taken 75 mg once a day (in combination with ASK in doses of 75-325 mg / day). Since the use of higher doses of ASA is associated with an increased risk of bleeding, the recommended dosage for ASA should not exceed 100 mg.

The optimal duration of treatment is not officially defined. Clinical trials confirm the feasibility of taking the drug for up to 12 months, and the maximum beneficial effect was observed after 3 months of treatment.

Acute coronary syndrome with segment elevation ST (acute myocardial infarction with segment elevation ST)

Clopidogrel should be taken once a day at a dose of 75 mg with the initial single dose 300 mg loading dose in combination with ASA in combination with thrombolytics or without them.In patients older than 75 years, treatment with clopidogrel should begin without taking its loading dose. Combination therapy is initiated as soon as possible after the onset of symptoms and continues for at least 4 weeks. The efficacy of using a combination of clopidogrel and ASA with this indication for more than 4 weeks has not been studied.

Atrial fibrillation (atrial fibrillation)

Clopidogrel should be taken once a day at a dose of 75 mg. In combination with clopidogrel, you should start and then continue taking ASA (75-100 mg / day).

Skipping the next dose

- If less than 12 hours have passed after missing the next dose, the missed dose of the drug should be taken immediately, and then the following doses should be taken at the usual time.

- If more than 12 hours have passed after missing the next dose, the patient should take the next dose at the usual time (do not take a double dose).

Patients with genetically determined reduced isoenzyme activity CYP2C19

Low isoenzyme activity CYP2C19 is associated with a decrease in the antiplatelet effect of clopidogrel. The mode of application of higher doses (600 mg-loading dose, then-150 mg once a day daily) in patients with low isoenzyme activity CYP2C19 increases the antiplatelet effect of clopidogrel (cf."Pharmacokinetics"). However, at the moment, clinical trials that take into account clinical outcomes have not established an optimal dosing regimen for clopidogrel for patients with reduced metabolism due to genetically determined low isoenzyme activity CYP2C19.

Special patient groups

Children. There is no experience of using the drug in children.

Patients of advanced age. In elderly patients, correction of the dosing regimen is not required.

Patients with impaired renal function. There is limited therapeutic experience with the drug in patients with mild to moderate renal failure. Therefore, when using the drug DEPPLET®-75 in these patients should be careful.

Patients with impaired liver function. The experience of using the drug in patients with hepatic insufficiency is limited. After daily for 10 days of taking clopidogrel at a daily dose of 75 mg in patients with severe liver dysfunction, inhibition of ADP-induced platelet aggregation was similar to that of healthy volunteers. The mean bleeding time was also comparable in both groups.

Side effects:

Data, obtained in clinical trials

The safety of clopidogrel was studied in more than 44,000 patients, including more than 12,000 patients who received treatment for a year or more. In general, the tolerability of clopidogrel at a dose of 75 mg / day in the study CAPRIE corresponded to the tolerability of ASA at a dose of 325 mg / day, irrespective of age, gender and race of patients. The following are clinically significant adverse effects observed in five large clinical trials: CAPRIE, CURE, CLARITY, COMMIT and ACTIVE A.

Bleeding and hemorrhage

Comparison of monotherapy with clopidogrel and ASA

In a clinical study CAPRIE the total frequency of all bleeding in patients taking clopidogrel, and patients taking ASA, was 9.3%. The incidence of severe bleeding with clopidogrel and ASA was comparable: 1.4% and 1.6%, respectively.

In general, the incidence of gastrointestinal bleeding in patients taking clopidogrel, and in patients taking ASA, was (2% and 2.7%, respectively), including the incidence of gastrointestinal bleeding, requiring hospitalization, was (0.7% and 1.1% respectively).The overall frequency of bleeding from another site with clopidogrel in comparison with ASA was higher (7.3% vs. 6.5%, respectively). However, the incidence of severe bleeding with clopidogrel and ASA was comparable (0.6% and 0.4%, respectively). The most frequently reported development of the following bleeding: purpura / bruising, epistaxis. Less commonly reported on the development of hematomas, hematuria and ocular hemorrhage (mainly conjunctival).

The incidence of intracranial hemorrhages with clopidogrel and ASA was comparable (0.4% and 0.5%, respectively).

Comparison of combination therapy with clopidogrel + ASA and placebo + ASA

In a clinical study CURE in patients taking clopidogrel + ASA, compared with patients taking placebo + ASA, there was an increase in the incidence of major bleeding (3.7% vs. 2.7%) and small bleeding (5.1% vs. 2.4%). Basically, the sources of large bleeding were the gastrointestinal tract and the puncture site of the arteries.

The frequency of life-threatening bleeding in patients who took clopidogrel + ASA, in comparison with patients,(2.2% and 1.8%, respectively), the incidence of fatal bleeding was similar (0.2% for both therapies).

The incidence of non-life-threatening large bleeding was significantly higher in patients taking clopidogrel + ASA, compared with patients taking placebo + ASA (1.6% and 1%, respectively), but the incidence of intracranial hemorrhage was similar (0.1% for both therapies). The frequency of major bleeding in the group clopidogrel + ASA depended on the dose of ASA (<100 mg: 2.6%, 100-200 mg: 3.5%,> 200 mg: 4.9%), as well as the incidence of major bleeding in the placebo + ASA group (<100 mg: 2%, 100-200 mg: 2.3%,> 200 mg: 4%).

Patients who stopped antiplatelet therapy more than 5 days before coronary artery bypass grafting did not experience a higher incidence of major bleeding within 7 days after the intervention (4.4% in the group clopidogrel + ASA and 5.3% in the placebo + ASA group). Patients who continued antiplatelet therapy for the last five days before aortocoronary bypass surgery, the incidence of these events after intervention was 9.6% (in the group clopidogrel + ASA) and 6.3% (in the placebo + ASA group).

In a clinical study CLARITY frequency of major bleeding (defined as intracranial hemorrhage or hemorrhage with a decrease in hemoglobin> 5 g / dL) in both groups (clopidogrel + ASA and placebo + ASA) was comparable in both treatment groups (1.3% vs. 1.1% in the group clopidogrel + ASA and placebo + ASA group, respectively). It was the same in subgroups of patients divided by baseline characteristics and by types of fibrinolytic therapy or heparin therapy.

The incidence of fatal bleeding (0.8% vs. 0.6%) and intracranial hemorrhage (0.5% vs 0.7%) with clopidogrel + ASA and placebo + ASA, respectively, was low and comparable in both treatment groups.

In a clinical study COMMIT the overall incidence of non-cerebral large bleeding or cerebral bleeding was low and the same (0.6% in the group clopidogrel + ASA and 0.5% in the placebo + ASA group).

In a clinical study ACTIVE-A frequency of major bleeding in the group clopidogrel + ASA was higher than in the placebo + ASA group (6.7% vs. 4.3%, respectively). The large bleeding was mainly extracranial in both groups (5.3% vs. 3.5%), mainly from the gastrointestinal tract (3.5% vs. 1.8%).

In a group clopidogrel + ASA of intracranial hemorrhages was greater in comparison with the placebo + ASK group (1.4% vs. 0.8%, respectively). There were no statistically significant differences between these treatment groups in the frequency of fatal bleeding (1.1% vs. 0.7%) and hemorrhagic stroke (0.8 vs. 0.6%).

Blood disorders

In the study CAPRIE severe neutropenia (<0.45 x 10⁹/ l) was observed in 4 patients (0.04%) who received clopidogrel, and in 2 patients (0.02%) who received ASA.

In two of the 9599 patients who took clopidogrel, there was a complete absence of neutrophils in the peripheral blood, which was not observed in any of the 9586 patients taking ASA. Despite the fact that the risk of developing myelotoxic action when taking clopidogrel is low enough, in case the patient taking clopidogrel, there is a fever or other signs of infection, the patient should be examined for possible neutropenia.

In the treatment of clopidogrel in one case, development of aplastic anemia was observed. The incidence of severe thrombocytopenia (<80 x 10⁹/ l) was 0.2% in patients taking clopidogrel, and 0.1% of patients taking ASA reported very rare cases of a decrease in the number of platelets ≤ 30 x 10⁹/ l.

In studies CURE and CLARITY A comparable number of patients with thrombocytopenia or neutropenia in both treatment groups were observed.

Other clinically significant adverse reactions observed in clinical trials CAPRIE, CURE, CLARITY COMMIT, ACTIVE-A

The incidence of adverse reactions that were observed during the above clinical trials is presented in accordance with the WHO classification: very often ≥10%; often ≥1% and <10%; infrequently ≥0.1% and <1%; rarely ≥ 0.01% and <0.1%; very rarely <0.01%; the frequency is unknown - it is not possible to determine the frequency of occurrence of an undesired reaction from the available data.

Disturbances from the nervous system: infrequently - headache, dizziness, paresthesia; rarely - vertigo.

Disorders from the gastrointestinal tract: often - dyspepsia, abdominal pain, diarrhea; infrequently - nausea, gastritis, bloating, constipation, vomiting, stomach ulcer, duodenal ulcer.

Disturbances from the skin and subcutaneous tissue: infrequently - skin rash, itching.

Violations from the blood and lymphatic system: infrequently - an increase in bleeding time, a decrease in the number of platelets in the peripheral blood, leukopenia, a decrease in the number of neutrophils in the peripheral blood, eosinophilia.

Post-registration experience of drug use

Violations from the blood and lymphatic system: frequency is unknown - cases of severe bleeding, predominantly subcutaneous, skeletal muscle, eye hemorrhage (conjunctival, in the tissue and the retina), bleeding from the airways (hemoptysis, pulmonary hemorrhage), epistaxis, hematuria, and bleeding from postoperative wounds and cases of bleeding with fatal (particularly intracranial hemorrhage, gastrointestinal bleeding and retroperitoneal haemorrhage), agranulocytosis, granulocytopenia, aplastic anemia / pancytopenia, trombot thrombocytopenic purpura (TTP), acquired hemophilia A.

Immune system disorders: frequency unknown - anaphylactic reactions, serum sickness, cross allergic and hematologic reactions with other thienopyridines (such as ticlopidine, prasugrel) (see section "Special instructions").

Mental disorders: frequency is unknown - confusion, hallucinations.

Impaired nervous system: the frequency is unknown - the violation of taste perception.

Vascular disorders: the frequency is unknown - vasculitis, lowering blood pressure.

Heart Disease: frequency is unknown - dyspnea.

Disturbances from the respiratory system, chest and mediastinal organs: frequency unknown - bronchospasm, interstitial pneumonia, eosinophilic pneumonia.

Disorders from the gastrointestinal tract: frequency unknown - colitis (including ulcerative colitis or lymphocytic colitis), pancreatitis, stomatitis.

Disorders from the liver and bile ducts: frequency unknown - hepatitis (non-infectious), acute liver failure.

Disturbances from the skin and subcutaneous tissue: frequency unknown - maculopapular erythematous or exfoliative rash, hives, itching, angioedema, bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis),acute generalized exanthematous pustulosis, drug hypersensitivity syndrome, drug rash with eosinophilia and systemic manifestations (DRESS-syndrome), eczema, flat lichen.

Disturbances from the musculoskeletal and connective tissue: frequency unknown - arthralgia (joint pain), arthritis, myalgia.

Disorders from the kidneys and urinary tract: frequency unknown - glomerulonephritis.

Violations of the genitals and breast: frequency unknown - gynecomastia.

Common disorders and reactions at the site of administration: frequency is unknown - fever.

Laboratory and instrumental data: the frequency is unknown - the deviation from the norm of laboratory indicators of the functional state of the liver, increasing the concentration of creatinine in the blood.

Overdose:

Symptoms: an overdose of clopidogrel may lead to an increase in bleeding time with subsequent complications in the form of development of bleeding.

Treatment: when bleeding occurs, appropriate treatment is required. The antidote of clopidogrel is not established. If rapid correction of prolonged bleeding time is necessary,transfusion of platelet mass is recommended.

Interaction:

Drugs associated with risk of bleeding: there is an increased risk of bleeding due to a possible additive effect. Caution should be exercised when combined use of clopidogrel with drugs associated with risk of bleeding.

Oral anticoagulants: simultaneous use of clopidogrel and oral anticoagulants may increase the intensity of bleeding, and therefore the use of this combination is not recommended. Clopidogrel at a dose of 75 mg / day does not affect the pharmacokinetics of warfarin and does not change the values of the international normalized ratio (INR) in patients taking long-term warfarin. Nevertheless, simultaneous administration of warfarin with clopidogrel may increase the risk of bleeding due to the independent effect of these drugs on hemostasis.

Appointment inhibitors of glycoprotein IIb/IIIa together with clopidogrel requires caution in patients who have an increased risk of bleeding (with trauma and surgical interventions or other pathological conditions) (see.section "Special instructions").

Acetylsalicylic acid: ASA does not alter the effect of clopidogrel, an inhibitor of ADP-induced platelet aggregation, but clopidogrel enhances the effect of ASA on collagen-induced aggregation of platelets. Nevertheless, simultaneous reception with clopidogrel 500 mg ASA 2 times a day for 1 day did not lead to a significant increase in bleeding time caused by the use of clopidogrel. Between clopidogrel and ASA, pharmacodynamic interaction is possible, which leads to an increased risk of bleeding. Therefore, with their simultaneous use, care should be taken, although in clinical trials patients received combined therapy with clopidogrel and ASA for up to one year.

Heparin: according to a clinical study conducted with the participation of healthy volunteers, when taking clopidogrel did not require a change in the dose of heparin and did not change its anticoagulant effect. The combined use of heparin did not alter the inhibitory effect of clopidogrel on platelet aggregation. Between clopidogrel and heparin, pharmacodynamic interaction is possible,which can increase the risk of bleeding, so the simultaneous use of this combination requires caution (see section "Special instructions").

Thrombolytic agents: the safety of the combined use of clopidogrel, fibrin-specific or fibrin-specific thrombolytic agents, and heparin was investigated in patients with acute myocardial infarction. The frequency of clinically significant bleeding was similar to that observed in the joint use of thrombolytic agents and heparin with ASA.

Non-steroidal anti-inflammatory drugs (NSAIDs): in the clinical a study conducted with the participation of healthy volunteers, the combined use of clopidogrel and naproxen increased hidden blood loss through the gastrointestinal tract. However, due to the lack of research on the interaction of clopidogrel with other NSAIDs, it is currently unknown whether there is an increased risk of gastrointestinal bleeding when taking clopidogrel along with other NSAIDs. Therefore, the use of NSAIDs, including COX-2 inhibitors. in combination with clopidogrel should be carried out with caution (see section "Special instructions").

Selective serotonin reuptake inhibitors (SSRIs): since SSRIs disrupt platelet activation and increase the risk of bleeding, joint use of SSRI with clopidogrel should be carried out with caution.

Another combination therapy with clopidogrel

Inhibitors CYP2C19

As clopidogrel metabolized to its active metabolite in part by isoenzyme CYP2C19, it is expected that the use of drugs that inhibit the activity of this isoenzyme may lead to a decrease in the concentration of the active metabolite clopidogrel. The clinical significance of this interaction is not established. As a precaution, it is recommended to avoid the combined use of clopidogrel and strong or moderate isoenzyme inhibitors CYP2C19. Strong or moderate isoenzyme inhibitors CYP2C19 are, for example, omeprazole and esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine, chloramphenicol, efavirenz.

Proton Pump Inhibitors:

The simultaneous use with clopidogrel of proton pump inhibitors, which are strong or moderate inhibitors of the isoenzyme CYP2C19 (for example omeprazole, esomeprazole) Not recommended. If the patient still needs the use of proton pump inhibitors simultaneously with clopidogrel, then a proton pump inhibitor with the least inhibition of the isoenzyme CYP2C19, such as pantoprazole and lantoprazole.

There is no evidence that other drugs that reduce the acidity of gastric juice, such as H₂-blocks (except cimetidine, which is an inhibitor of the isoenzyme CYP2C19), or antacids affect the antiplatelet properties of clopidogrel.

A number of clinical studies with clopidogrel and other concomitant medications have been conducted to study possible pharmacodynamic and pharmacokinetic interactions that have shown that:

- when clopidogrel was used in conjunction with atenolol, nifedipine, or both, concomitantly, there was no clinically significant pharmacodynamic interaction;

- simultaneous use of phenobarbital, cimetidine and estrogens had no significant effect on the pharmacodynamics of clopidogrel;

- pharmacokinetic indices of digoxin and theophylline did not change when combined with clopidogrel;

- antacids did not reduce the absorption of clopidogrel;

- phenytoin and tolbutamide can be safely used together with clopidogrel (according to the results of the study CAPRIE), despite the fact that the data obtained during research with macrosomes of human liver indicate that the carboxylic metabolite clopidogrel can inhibit the activity of the isoenzyme CYP2C9, which can lead to an increase in plasma concentrations of certain drugs, for example, phenytoin, tolbutamide and certain NSAIDs that are metabolized by isoenzyme CYP2C9.

In addition to the information presented above, no studies of other drug interactions have been conducted. Nevertheless, patients who participated in clinical trials with clopidogrel received a number of other drugs, including diuretics, beta-blockers, ACE inhibitors, calcium channel blockers, lipid-lowering drugs (incl.with insulin), coronary vasodilators, antiepileptics and glycoprotein receptor blockers IIb/IIIa, without signs of clinically significant adverse interaction.

Special instructions:

Bleeding and blood disorders

In connection with the risk of bleeding and blood disorders (see section "Side effect"), if clinical symptoms appear during treatment that indicate the possibility of bleeding, it is urgent to make a general clinical blood test, determine activated partial thromboplastin time (APTT) , the number of platelets, the indices of the functional activity of thrombocytes, and conduct other necessary studies. Clopidogrel as well as other antiplatelet drugs, should be used with caution in patients at increased risk of bleeding due to trauma, surgery or other pathological conditions, as well as in patients receiving ASA, heparin, glycoprotein inhibitors IIb/IIIa or NSAIDs (including COX-2 inhibitors) or SSRIs or other drugs associated with an increased risk of bleeding (eg, pentoxifylline).Patients should be closely monitored for the exclusion of bleeding symptoms, including latent, especially during the first weeks of treatment and / or after invasive cardiac procedures / surgery. The simultaneous use of clopidogrel with oral anticoagulants is not recommended, as this may increase the intensity of bleeding (see section "Interaction with other drugs").

If the patient is to undergo a planned surgical procedure and there is no need to achieve an antithrombotic effect, then 7 days before the operation, the preparation of DEPPLET®-75 should be withdrawn. Clopidogrel prolongs the time of bleeding and should be used with caution in patients with diseases and conditions predisposing to the development of bleeding, especially bleeding from the gastrointestinal tract and intraocular hemorrhages.

Patients should be cautioned that it may take longer than usual to stop bleeding while taking the Déplat®-75 (with or without ASA) and that if they develop any unusual (for localization or duration) bleeding should inform your doctor about it.Before any future surgical intervention and before starting any new drug, patients should inform the doctor (including the dentist) about taking clopidogrel.

Thrombotic thrombocytopenic purpura

Very rarely, after the use of clopidogrel (sometimes even a short one), there have been cases of thrombotic thrombocytopenic purpura (TTP), which is characterized by thrombocytopenia and microangiopathic hemolytic anemia, accompanied by neurological disorders, impaired renal function and fever. TTP is a potentially life-threatening condition requiring immediate treatment, including plasmapheresis.

Acquired hemophilia

The cases of development of acquired hemophilia with the use of clopidogrel were reported. With a confirmed isolated increase in APTT, accompanied or not accompanied by bleeding, consideration should be given to the possibility of developing acquired hemophilia. Patients with a confirmed diagnosis of acquired hemophilia should be observed and treated by specialists in this disease and stop taking clopidogrel.

Recently suffered ischemic stroke

Taking clopidogrel is not recommended during the first 7 days after an acute ischemic stroke (since there is no data on its use in this condition).

Functional activity of the isoenzyme CYP2C19

In patients with low isoenzyme activity CYP2C19 when clopidogrel is used in recommended doses, less active metabolite of clopidogrel is formed, its effect on platelet function is reduced. There are tests to determine the genotype CYP2C19.

As clopidogrel metabolized to its active metabolite in part by isoenzyme CYP2C19, it is expected that the use of drugs that inhibit the activity of this isoenzyme may lead to a decrease in the concentration of the active metabolite clopidogrel. The clinical significance of this interaction is not established. As a precaution, it is recommended to avoid the combined use of clopidogrel and strong or moderate isoenzyme inhibitors CYP2C19 (see subsection "Pharmacokinetics" of the section "Pharmacological properties" and the section "Interaction with other medicinal products").

Cross-allergic and / or hematologic reactions between thienopyridines

Patients should collect anamnesis for any previously allergic and / or hematologic reactions to other thienopyridine (such as ticlopidine, prasugrel), since cases of cross-allergic and / or hematological reactions between thienopyridines have been described (see the "Side effect" section).

Tienopyridines can cause mild to severe allergic reactions (such as rash, angioedema) or hematologic reactions (such as thrombocytopenia, neutropenia).

Patients who had previously experienced allergic and / or hematologic reactions one of the drugs of the thienopyridine group may have an increased risk of developing similar reactions to another drug of the thienopyridine group. It is recommended to monitor signs of hypersensitivity in patients with a known allergic reaction to thienopyridines.

Effect on the ability to drive transp. cf. and fur:

Decplat®-75 does not significantly affect the ability to drive vehicles and engage in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.However, in the event that the patient develops adverse reactions from the nervous system and the psyche, it is possible to reduce the concentration of attention and the speed of psychomotor reactions, which may hinder the employment of such activities. In such cases, the question of the possibility of performing potentially hazardous activities should be decided by the doctor.

Form release / dosage:

Tablets coated with a film coating, 75 mg.

Packaging:

For 7 or 10 tablets in a blister of aluminum foil.

By 1, 2, 3, 4, 6, 9, 10 blisters with instructions for use in a cardboard box.

Storage conditions:

Store in a dry place, at a temperature not exceeding 30 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-000685

Date of registration:28.09.2011 / 29.09.2016

Expiration Date:Unlimited

The owner of the registration certificate:Torrent Pharmaceuticals Co., Ltd.Torrent Pharmaceuticals Co., Ltd. India

Manufacturer: & nbsp

TORRENT PHARMACEUTICALS, Ltd. India

Representation: & nbspTORRENT PHARMACEUTICALS LTD. TORRENT PHARMACEUTICALS LTD. India

Information update date: & nbsp23.04.2017

Illustrated instructions

Instructions

Déplat®-75 (Deplatt®-75)