Clopidogrel-pharmex

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CLOPIDOGREL-PHARMEX (CLOPIDOGREL-PHARMEX)

Composition:

Active substance: clopidogrel;

One tablet contains 75 mg of clopidogrel hydrogen bisulfate, calculated as clopidogrel;

Excipients: mannitol (E 421), microcrystalline cellulose, hydroxypropylcellulose, macrogol 6000, hydrogenated castor oil, crospovidone, colloidal anhydrous silicon dioxide;

Coating: Opadry II Pink (hypromellose, lactose monohydrate, titanium dioxide (E 171), triacetin, iron oxide red (E 172)).

Dosage form. Film-coated tablets.

Main physicochemical properties: round, biconvex tablets, film-coated, pink in colour.

Pharmacotherapeutic group. Platelet aggregation inhibitors, excluding heparin.

ATC code B01AC04.

Pharmacological Properties.

Pharmacodynamics.

Clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its receptor on the platelet surface and subsequent ADP-mediated activation of the GPIIb/IIIa complex, thereby suppressing platelet aggregation. A biotransformation of clopidogrel is required to produce active inhibition of platelet aggregation. Clopidogrel also inhibits platelet aggregation induced by other agonists by blocking the amplification of platelet activation caused by released ADP. Clopidogrel irreversibly modifies platelet ADP receptors. Therefore, platelets exposed to clopidogrel are affected for the remainder of their lifespan. Normal platelet function gradually recovers at a rate consistent with platelet turnover.

Significant inhibition of ADP-induced platelet aggregation is observed from the first day of treatment with repeated daily doses of 75 mg. This effect progressively increases and stabilizes between days 3 and 7. At steady state, the average level of inhibition of aggregation with a daily dose of 75 mg ranges from 40% to 60%. Platelet aggregation and bleeding time return to baseline levels on average within 5 days after discontinuation of treatment.

Pharmacokinetics.

Absorption. After oral administration of single and multiple 75 mg daily doses, clopidogrel is rapidly absorbed. Mean peak plasma concentrations of unchanged clopidogrel (approximately 2.2–2.5 ng/mL after a single 75 mg oral dose) are reached about 45 minutes after dosing. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.

Distribution. Clopidogrel and the main (inactive) circulating metabolite are reversibly bound to human plasma proteins in vitro (98% and 94%, respectively). This binding remains non-saturable in vitro over a wide concentration range.

Metabolism. Clopidogrel is extensively metabolized in the liver. In vitro and in vivo, two major metabolic pathways exist: one involves esterases and leads to hydrolysis, producing an inactive carboxylic acid derivative (which accounts for about 85% of all metabolites circulating in plasma), while the other involves cytochrome P450 enzyme system. Initially, clopidogrel is converted into an intermediate metabolite, 2-oxo-clopidogrel. Further metabolism of 2-oxo-clopidogrel leads to a thiol derivative—the active metabolite. In vitro, this metabolic pathway is mediated by CYP3A4, CYP2C19, CYP1A2, and CYP2B6 enzymes. The active metabolite of clopidogrel (thiol derivative), isolated in vitro, rapidly and irreversibly binds to platelet receptors, thereby preventing platelet aggregation.

Elimination. Within 120 hours after administration of radiolabeled 14C-clopidogrel in humans, approximately 50% of the label was excreted in urine and about 46% in feces. After oral administration of a single 75 mg dose, the elimination half-life of clopidogrel is approximately 6 hours. The elimination half-life of the main (inactive) circulating metabolite is 8 hours after both single and multiple doses.

Pharmacogenetics. Clopidogrel is known to be activated by several polymorphic CYP450 enzymes. CYP2C19 is involved in the formation of both the active metabolite and the intermediate metabolite 2-oxo-clopidogrel. The pharmacokinetics of the active metabolite of clopidogrel and antiplatelet effects, as measured by ex vivo platelet aggregation, vary depending on the CYP2C19 genotype. The CYP2C19*1 allele corresponds to fully functional metabolism, whereas the CYP2C19*2 and CYP2C19*3 alleles correspond to non-functional metabolism. CYP2C19*2 and CYP2C19*3 alleles account for the majority of loss-of-function alleles in Caucasian (85%) and Mongoloid (99%) populations with reduced metabolism. Other alleles associated with absent or reduced metabolism occur much less frequently. These include CYP2C19*4, *5, *6, *7, and *8, which are much less common in the general population.

Special patient populations. The pharmacokinetics of the active metabolite of clopidogrel have not been studied in the special patient populations listed below.

Renal impairment. After repeated daily administration of 75 mg clopidogrel in patients with severe renal impairment (creatinine clearance 5–15 mL/min), inhibition of ADP-induced platelet aggregation was less pronounced (25%) compared to healthy volunteers, while bleeding time was prolonged to a similar extent as in healthy volunteers receiving 75 mg clopidogrel daily. Clinical tolerability was good in all patients.

Hepatic impairment. After repeated daily administration of 75 mg clopidogrel for 10 days in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that observed in healthy volunteers. The mean prolongation of bleeding time was also comparable between both groups.

Race. The prevalence of CYP2C19 alleles associated with intermediate and poor CYP2C19 metabolic activity varies according to racial/ethnic background (see section "Pharmacogenetics"). Data in patients of Mongoloid race are limited, making it difficult to assess the clinical significance of genotyping for this CYP.

Clinical characteristics.

Indications.

Secondary prevention of atherothrombotic events in adults:

• Patients who have suffered myocardial infarction (treatment initiation – within a few days, but no later than 35 days after the event), ischemic stroke (treatment initiation – within 7 days, but no later than 6 months after the event), or who have been diagnosed with peripheral arterial disease (arterial disease and atherothrombosis of lower limb vessels);
• Patients with acute coronary syndrome:
  • Acute coronary syndrome without ST-segment elevation (unstable angina or non-Q-wave myocardial infarction), including patients who underwent percutaneous coronary intervention with stent placement, in combination with acetylsalicylic acid (ASA);
  • Acute ST-elevation myocardial infarction, in combination with acetylsalicylic acid (in patients receiving standard medical therapy and for whom thrombolytic therapy is indicated).

Prevention of atherothrombotic and thromboembolic events in atrial fibrillation.

Clopidogrel in combination with ASA is indicated for adult patients with atrial fibrillation who have at least one risk factor for vascular events, in whom vitamin K antagonists (VKA) are contraindicated, and who have a low risk of bleeding, for the prevention of atherothrombotic and thromboembolic events, including stroke.

Contraindications.

Hypersensitivity to the active substance or to any component of the medicinal product. Severe hepatic impairment. Active bleeding (e.g., peptic ulcer or intracranial hemorrhage).

Interaction with other medicinal products and other forms of interaction.

MEDICINAL PRODUCTS ASSOCIATED WITH AN INCREASED RISK OF BLEEDING. Due to the potential additive effect, there is an increased risk of hemorrhagic complications; therefore, concomitant use of such medicinal products with clopidogrel requires caution (see section "Special warnings and precautions for use").

ORAL ANTICOAGULANTS. Concomitant use of Clopidogrel-Pharmex with oral anticoagulants is not recommended, as this combination may increase the intensity of bleeding (see section "Special warnings and precautions for use"). Although administration of clopidogrel at a dose of 75 mg daily does not alter the pharmacokinetic profile of S-warfarin or the international normalized ratio (INR) in patients on long-term warfarin therapy, concomitant use of clopidogrel and warfarin increases the risk of bleeding due to their independent effects on hemostasis.

GLYCOPROTEIN IIb/IIIa RECEPTOR INHIBITORS. Clopidogrel should be used with caution in patients receiving glycoprotein IIb/IIIa receptor inhibitors (see section "Special warnings and precautions for use").

ACETYLSALICYLIC ACID (ASA). Acetylsalicylic acid does not affect the inhibitory action of clopidogrel on ADP-induced platelet aggregation, but clopidogrel enhances the effect of ASA on collagen-induced platelet aggregation. However, concomitant administration of 500 mg ASA twice daily for one day did not cause a significant increase in bleeding time prolonged by clopidogrel. Since a pharmacodynamic interaction between clopidogrel and acetylsalicylic acid, increasing the risk of bleeding, is possible, concomitant use of these agents requires caution (see section "Special warnings and precautions for use"). Nevertheless, clopidogrel and ASA can be used concomitantly for up to 1 year (see section "Pharmacological properties").

HEPARIN. Data indicate that clopidogrel did not require dose adjustment of heparin and did not alter heparin's effect on coagulation. Concomitant administration of heparin did not affect the inhibitory effect of clopidogrel on platelet aggregation. However, since a pharmacodynamic interaction between clopidogrel and heparin, increasing the risk of bleeding, is possible, concomitant use of these agents requires caution.

THROMBOLYTIC AGENTS. In patients with acute myocardial infarction, the frequency of clinically significant bleeding events during concomitant administration of clopidogrel, fibrin-specific or non-fibrin-specific thrombolytic agents, and heparins was similar to that observed when thrombolytic agents and heparin were administered concomitantly with ASA.

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs). Concomitant use of clopidogrel and naproxen increases the number of occult gastrointestinal bleeding episodes. However, due to the lack of studies on the interaction of the drug with other NSAIDs, it is not yet established whether the risk of gastrointestinal bleeding increases with all NSAIDs. Therefore, caution is required when using NSAIDs, particularly COX-2 inhibitors, concomitantly with clopidogrel (see section "Special warnings and precautions for use").

SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs). Concomitant use of SSRIs with clopidogrel should be done with caution, as SSRIs affect platelet activation and increase the risk of bleeding.

CONCOMITANT USE OF OTHER DRUGS. Since clopidogrel is partially converted into its active metabolite via CYP2C19, the use of drugs that reduce the activity of this enzyme will most likely lead to decreased plasma concentrations of the active metabolite of clopidogrel and reduced clinical efficacy. Concomitant use of drugs that inhibit CYP2C19 activity should be avoided.

Drugs that inhibit CYP2C19 activity include omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, carbamazepine, and efavirenz.

PROTON PUMP INHIBITORS (PPIs). Omeprazole 80 mg once daily, when administered concomitantly with clopidogrel or within 12 hours between doses of these two drugs, reduced plasma concentrations of the active metabolite by 45% (loading dose) and 40% (maintenance dose). This reduction was associated with a 39% decrease in platelet aggregation inhibition (loading dose) and 21% (maintenance dose). The interaction between esomeprazole and clopidogrel is expected to be similar.

Observational and clinical trials have yielded conflicting data regarding the clinical consequences of these pharmacokinetic (PK) and pharmacodynamic (PD) interactions in terms of major cardiovascular events. As a precautionary measure, omeprazole or esomeprazole should not be used concomitantly with clopidogrel (see section "Special warnings and precautions for use").

A less pronounced reduction in metabolite plasma concentrations was observed with pantoprazole or lansoprazole.

When pantoprazole 80 mg once daily was administered concomitantly, plasma concentrations of the active metabolite decreased by 20% (loading dose) and 14% (maintenance dose). This reduction was associated with a mean decrease in platelet aggregation inhibition of 15% and 11%, respectively. These results suggest that concomitant use of clopidogrel and pantoprazole is possible.

There is no evidence that other medicinal products that reduce gastric acid production, such as H2-receptor antagonists (except cimetidine, which is a CYP2C9 inhibitor) or antacids, affect the antiplatelet activity of clopidogrel.

COMBINATION WITH OTHER MEDICINAL PRODUCTS. No clinically significant pharmacodynamic interaction was observed when clopidogrel was administered concomitantly with atenolol, nifedipine, or both. Furthermore, the pharmacodynamic activity of clopidogrel remained virtually unchanged when administered concomitantly with phenobarbital, cimetidine, or estrogens.

The pharmacokinetics of digoxin and theophylline are not altered by concomitant administration of clopidogrel.

Antacids do not affect the extent of clopidogrel absorption.

Carboxylic acid metabolites of clopidogrel may inhibit CYP2C9 enzyme activity. This may potentially lead to increased plasma levels of drugs such as phenytoin and tolbutamide, and NSAIDs metabolized by CYP2C9. Phenytoin and tolbutamide can be safely used concomitantly with clopidogrel.

DRUGS THAT ARE SUBSTRATES OF THE CYP2C8 ENZYME. Clopidogrel has been shown to increase repaglinide exposure in healthy volunteers. In vitro studies demonstrated that this increased repaglinide exposure is due to inhibition of the CYP2C8 enzyme by the glucuronide metabolite of clopidogrel. Due to the risk of increased plasma concentrations, concomitant use of clopidogrel with medicinal products primarily eliminated via CYP2C8-mediated metabolism (such as repaglinide, paclitaxel) requires caution (see section "Special warnings and precautions for use").

Except for the information on interactions with specific medicinal products mentioned above, no studies have been conducted on the interaction of clopidogrel with medicinal products commonly prescribed to patients with atherothrombosis. However, in patients receiving concomitant medications including diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, calcium antagonists, cholesterol-lowering agents, coronary vasodilators, antidiabetic agents (including insulin), antiepileptic drugs, hormone replacement therapy, and GPIIb/IIIa antagonists, no clinically significant adverse effects have been observed.

In HIV-infected patients receiving ritonavir- or cobicistat-boosted antiretroviral therapy (ART), a significant reduction in the effect of clopidogrel's active metabolite and reduced platelet inhibition has been demonstrated. Although the clinical significance of these findings is uncertain, spontaneous reports of recurrent occlusive events after revascularization or thrombotic events in HIV-infected patients receiving boosted ART during clopidogrel treatment have been reported. The effect of clopidogrel and mean platelet inhibition may be reduced when administered concomitantly with ritonavir. Therefore, concomitant use of clopidogrel and boosted ART is not recommended.

Special precautions for use.

Bleeding and hematological disorders. Due to the risk of bleeding and hematological adverse reactions, a complete blood count and/or other appropriate tests should be performed immediately if symptoms suggesting possible bleeding occur during treatment (see section "Adverse reactions"). As with other antiplatelet agents, clopidogrel should be used with caution in patients with an increased risk of bleeding due to trauma, surgical procedures, or other pathological conditions, and also when patients are receiving acetylsalicylic acid (ASA), heparin, glycoprotein IIb/IIIa inhibitors, or nonsteroidal anti-inflammatory drugs, including COX-2 inhibitors. Close monitoring for signs of bleeding, including occult bleeding, is required, especially during the first weeks of treatment and/or following cardiac invasive procedures or surgery. Concomitant use of clopidogrel with oral anticoagulants is not recommended, as this may increase the intensity of bleeding (see section "Interaction with other medicinal products and other forms of interaction").

In case of planned surgery that temporarily does not require antiplatelet therapy, clopidogrel treatment should be discontinued 7 days prior to the procedure. Patients should inform their physician (including dentist) that they are taking clopidogrel before any surgical procedure or before initiating a new medicinal product. Clopidogrel prolongs bleeding time; therefore, it should be used with caution in patients with an increased risk of bleeding (particularly gastrointestinal and intraocular bleeding).

Patients should be advised that bleeding may take longer than usual to stop during treatment with clopidogrel (alone or in combination with ASA), and they should report any episode of unusual bleeding (in site or duration) to their physician.

Thrombotic thrombocytopenic purpura (TTP). TTP has been reported very rarely after clopidogrel use, sometimes even after short-term treatment. TTP is characterized by thrombocytopenia and microangiopathic hemolytic anemia, along with neurological symptoms, renal dysfunction, or fever. TTP is a potentially life-threatening condition that may be fatal and requires immediate treatment, including plasma exchange (plasmapheresis).

Acquired hemophilia. Cases of acquired hemophilia have been reported following clopidogrel use. In cases of confirmed isolated prolongation of activated partial thromboplastin time (aPTT), with or without bleeding, the possibility of acquired hemophilia should be considered. Patients diagnosed with acquired hemophilia should be under medical supervision and receive appropriate treatment; clopidogrel should be discontinued.

Recent ischemic stroke. Due to insufficient data, clopidogrel is not recommended within the first 7 days after an acute ischemic stroke.

Cytochrome P450 2C19 (CYP2C19). Pharmacogenetics: Patients with genetically reduced CYP2C19 function have lower plasma concentrations of the active metabolite of clopidogrel and a less pronounced antiplatelet effect. Genetic tests are currently available to identify a patient's CYP2C19 genotype.

Since clopidogrel is partially metabolized to its active metabolite by CYP2C19, concomitant use of drugs that inhibit this enzyme will likely reduce plasma concentrations of the active metabolite of clopidogrel. However, the clinical significance of this interaction has not been fully established. As a precaution, concomitant use of strong and moderate CYP2C19 inhibitors should be avoided (see section "Interaction with other medicinal products and other forms of interaction"; list of CYP2C19 inhibitors is provided in section "Pharmacokinetics").

Cross-reactivity among thienopyridines. Patients should be screened for a history of hypersensitivity to other thienopyridines (e.g., ticlopidine, prasugrel), as cross-allergy among thienopyridines has been reported (see section "Adverse reactions"). Use of thienopyridines may lead to allergic reactions ranging from mild to severe, such as rash, Quincke's edema (angioedema), or hematological reactions such as thrombocytopenia and neutropenia. Patients with a history of allergic and/or hematological reactions to one thienopyridine may have an increased risk of similar or different reactions to another thienopyridine. Monitoring for cross-reactivity is recommended.

Renal function impairment. Experience with clopidogrel use in patients with renal impairment is limited; therefore, the drug should be administered with caution in such patients (see section "Posology and method of administration").

Hepatic function impairment. Experience with clopidogrel use in patients with moderate liver disease and a risk of hemorrhagic diathesis is limited; therefore, clopidogrel should be used with caution in these patients (see section "Posology and method of administration").

Excipients. Clopidogrel-Farmeks contains lactose. Patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Clopidogrel-Farmeks contains hydrogenated castor oil, which may cause gastrointestinal discomfort and diarrhea.

Special precautions for disposal of unused medicinal product or waste. Unused medicinal product or waste material must be disposed of in accordance with local requirements.

Use during pregnancy or breastfeeding.

As there are no clinical data on the use of clopidogrel during pregnancy, it is not recommended to administer clopidogrel to pregnant women.

Animal studies have not shown any direct or indirect adverse effects on pregnancy, embryonic/fetal development, parturition, or postnatal development.

It is unknown whether clopidogrel is excreted in human breast milk. Animal studies have shown excretion in milk. Therefore, breastfeeding should be discontinued during treatment with Clopidogrel-Farmeks.

Ability to affect reaction rate while driving or operating machinery.

Clopidogrel has no effect or a negligible effect on the ability to drive or operate machinery.

Method of Administration and Dosage

Adults and elderly patients. Clopidogrel should be taken at a dose of 75 mg once daily, independently of food intake.

For patients with acute coronary syndrome without ST-segment elevation (unstable angina or non-Q-wave myocardial infarction), treatment with clopidogrel should begin with a single loading dose of 300 mg, followed by a maintenance dose of 75 mg once daily (in combination with acetylsalicylic acid (ASA) at a dose of 75–325 mg daily). Since higher doses of ASA increase the risk of bleeding, it is recommended not to exceed an ASA dose of 100 mg. The optimal duration of treatment has not been formally established. Data suggest benefit from treatment up to 12 months, with the maximum effect observed after 3 months of therapy.

In patients with acute ST-segment elevation myocardial infarction, clopidogrel should be administered at 75 mg once daily, starting with a single 300 mg loading dose, in combination with ASA, with or without thrombolytic agents. In patients aged 75 years and older, treatment should be initiated without a loading dose of clopidogrel. Combination therapy should be started as early as possible after symptom onset and continued for at least 4 weeks. The benefit of using clopidogrel in combination with ASA beyond 4 weeks has not been studied in this condition.

In patients with atrial fibrillation, clopidogrel should be administered at a single daily dose of 75 mg. ASA (at a dose of 75–100 mg daily) should be initiated and continued concomitantly with clopidogrel.

Missed dose:

• If less than 12 hours have passed since the missed dose was due, the patient should take the missed dose immediately and take the next dose at the usual time;
• If more than 12 hours have passed, the patient should take the next scheduled dose at the usual time and should not double the dose to compensate for the missed dose.

Children and adolescents. Safety and efficacy of the drug in children and adolescents have not been established.

Renal impairment. Therapeutic experience with the use of the drug in patients with renal impairment is limited (see section "Special precautions for use").

Hepatic impairment. Therapeutic experience with the use of the drug in patients with moderate liver disease and potential for developing hemorrhagic diathesis is limited (see section "Special precautions for use").

Children.

Safety and efficacy of the drug in children have not been established; therefore, it should not be used in patients under 18 years of age.

Overdose.

Prolongation of bleeding time with subsequent complications may occur in case of clopidogrel overdose. If bleeding occurs, symptomatic treatment is recommended.

There is no known pharmacological antidote for clopidogrel. If immediate correction of prolonged bleeding time is required, the effect of clopidogrel can be reversed by transfusion of platelet concentrates.

Adverse Reactions

Adverse reactions are classified by the "Organ Class" system. The frequency of occurrence is defined as follows: common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), frequency not known (frequency cannot be estimated from the available data). For each organ system class, adverse effects are listed in descending order of severity.

Bleeding is the most commonly reported adverse reaction and occurs most frequently during the first month of treatment.

Blood and lymphatic system disorders.

Uncommon: Thrombocytopenia, leukopenia, eosinophilia.

Rare: Neutropenia, including severe neutropenia.

Very rare, frequency not known*: Thrombotic thrombocytopenic purpura (TTP) (see section "Special precautions"), aplastic anemia, pancytopenia, agranulocytosis, severe thrombocytopenia, acquired hemophilia A, granulocytopenia, anemia.

Cardiac disorders.

Very rare, frequency not known*: Kounis syndrome (vasospastic allergic angina / allergic myocardial infarction) as a result of hypersensitivity reaction to clopidogrel*.

Immune system disorders.

Very rare, frequency not known*: Serum sickness, anaphylactoid reactions, cross-sensitivity between thienopyridines (e.g., ticlopidine, prasugrel) (see section "Special precautions")*.

Psychiatric disorders.

Very rare, frequency not known*: Hallucinations, confusion.

Nervous system disorders.

Uncommon: Intracranial hemorrhage (in some cases fatal), headache, paresthesia, dizziness.

Very rare, frequency not known*: Taste disturbance.

Eye disorders.

Uncommon: Hemorrhage in the eye area (conjunctival, ocular, retinal).

Ear and labyrinth disorders.

Rare: Vertigo.

Vascular disorders.

Common: Hematoma.

Very rare, frequency not known*: Severe hemorrhage, surgical wound bleeding, vasculitis, arterial hypotension.

Respiratory, thoracic and mediastinal disorders.

Common: Epistaxis (nosebleed).

Very rare, frequency not known*: Respiratory tract hemorrhage (hemoptysis, pulmonary hemorrhage), bronchospasm, interstitial pneumonia, eosinophilic pneumonia.

Gastrointestinal disorders.

Common: Gastrointestinal hemorrhage, diarrhea, abdominal pain, dyspepsia.

Uncommon: Gastric and duodenal ulcer, gastritis, vomiting, nausea, constipation, flatulence.

Rare: Retroperitoneal hemorrhage.

Very rare, frequency not known*: Gastrointestinal and retroperitoneal hemorrhage with fatal outcome, pancreatitis, colitis (including ulcerative or lymphocytic colitis), stomatitis.

Hepatobiliary disorders.

Very rare, frequency not known*: Acute liver failure, hepatitis, abnormal liver function test results.

Skin and subcutaneous tissue disorders.

Common: Subcutaneous hemorrhage.

Uncommon: Rash, pruritus, intradermal hemorrhages (purpura).

Very rare, frequency not known*: Bullous dermatitis (toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme), acute generalized exanthematous pustulosis, angioneurotic edema, erythematous rash, urticaria, drug hypersensitivity syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), erythematous or exfoliative rash, eczema, lichen planus.

Reproductive and breast disorders.

Rare: Gynecomastia.

Musculoskeletal and connective tissue disorders.

Very rare, frequency not known*: Musculoskeletal hemorrhages (hemarthrosis), arthritis, arthralgia, myalgia.

Renal and urinary disorders.

Uncommon: Hematuria.

Very rare, frequency not known*: Glomerulonephritis, increased blood creatinine levels.

General disorders.

Common: Bleeding at injection site.

Very rare, frequency not known*: Fever.

Investigations.

Uncommon: Prolonged bleeding time, decreased neutrophil and platelet counts.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after marketing authorization is an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report all suspected adverse reactions.

* - information with frequency category "frequency not known".

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging.

10 tablets per blister; 1 or 3 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

LLC "FARMEX GROUP".

Manufacturer's address and place of business.

100 Shevchenka Street, Boryspil, Kyiv region, Ukraine, 08301.

All cases of adverse reactions should be reported to the manufacturer:

LLC "FARMEX GROUP", 100 Shevchenka Street, Boryspil, Kyiv region, Ukraine, 08301, tel.: +38(044)391-19-19, fax: +38(044)391-19-18, or via the form on the website: http://www.pharmex.com.ua/kontakty/farmakonadzor*