Detromb^® (Tablets) Instructions for Use

Marketing Authorization Holder

AnviLab, LLC (Russia)

Manufactured By

Vizag Pharmaceuticals (P), Ltd. (India)

ATC Code

B01AC04 (Clopidogrel)

Active Substance

Clopidogrel (Rec.INN WHO registered)

Dosage Form

Detromb®

Film-coated tablets, 75 mg: 7 or 10 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets pink with a brownish tint, round, biconvex.

Excipients: sodium carboxymethyl starch, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, macrogol 6000, mannitol, microcrystalline cellulose.

Film coating composition hypromellose, iron oxide red dye (E172), talc, titanium dioxide (E171), water (removed during the manufacturing process).

7 pcs. – blister packs (2) – cardboard packs.
10 pcs. – blister packs (3) – cardboard packs.

Clinical-Pharmacological Group

Antiplatelet agent

Pharmacotherapeutic Group

Antiaggregant agent

Pharmacological Action

Antiplatelet agent. Clopidogrel selectively reduces the binding of adenosine diphosphate (ADP) to its receptors on platelets and the activation of the glycoprotein IIb/IIIa receptor complex by ADP, thereby weakening platelet aggregation.

It reduces platelet aggregation induced by other agonists by preventing their activation by released ADP. It irreversibly binds to ADP receptors on platelets, which remain unresponsive to ADP stimulation for their entire lifespan (about 7 days).

Significant inhibition of platelet aggregation is noted from the first day of drug use. The inhibitory effect on platelet aggregation increases, and a steady state is reached after 3-7 days. On average, the level of aggregation suppression under the influence of the drug at a daily dose of 75 mg was from 40% to 60%. Platelet aggregation and bleeding time return to baseline levels on average 5 days after discontinuation of treatment.

Pharmacokinetics

Absorption and Distribution

Absorption is high; bioavailability is high; plasma concentration is low and 2 hours after administration does not reach the limit of quantification (0.025 µg/L). Clopidogrel and the main circulating metabolite reversibly bind to plasma proteins (98% and 94%, respectively).

Metabolism

It is metabolized in the liver. The main metabolite is an inactive carboxylic acid derivative, whose C_max after repeated oral administration of a 75 mg dose is reached after 1 hour and is about 3 mg/L.

Clopidogrel is a prodrug. Its active metabolite, a thiol derivative, is formed by the oxidation of clopidogrel to 2-oxo-clopidogrel and subsequent hydrolysis. The oxidative process is regulated primarily by cytochrome P450 isoenzymes 3A4 and 2B6, and to a lesser extent by 1A1, 1A2 and 2C19. The active metabolite is not detected in plasma.

Excretion

Excreted in urine – 50%, in feces – 46% (within 120 hours after administration). T_1/2 of the main metabolite after single and repeated administration is 8 hours.

Pharmacokinetics in Special Clinical Situations

The plasma concentration of the main metabolite after administration of the drug at a dose of 75 mg/day is lower in patients with severe renal disease (CrCl 5-15 ml/min) compared to patients with moderate renal disease (CrCl from 30 to 60 ml/min) and healthy individuals.

In patients with liver cirrhosis, administration at a daily dose of 75 mg for 10 days was safe and well tolerated. The maximum concentration of clopidogrel, both after a single dose and at steady state, was significantly higher in patients with cirrhosis than in healthy individuals. However, the plasma level of the main metabolite and the inhibitory effect on platelet aggregation were comparable in both groups.

Indications

Prevention of atherothrombotic complications in patients who have had a myocardial infarction, ischemic stroke, or with diagnosed occlusive peripheral arterial disease.

Prevention of atherothrombotic events (in combination with acetylsalicylic acid) in patients with acute coronary syndrome

• Without ST-segment elevation (unstable angina or non-Q-wave myocardial infarction), including patients who underwent stenting during percutaneous coronary intervention;
• With ST-segment elevation (acute myocardial infarction) during drug therapy and the possibility of thrombolysis.

ICD codes

Dosage Regimen

The drug is prescribed to adults at a dose of 75 mg once/day, regardless of meals. Treatment can be started from several days to 35 days after myocardial infarction and from 7 days to 6 months after ischemic stroke.

For acute coronary syndrome without ST-segment elevation (unstable angina, non-Q-wave myocardial infarction), treatment should be started with a single loading dose of 300 mg, and then continued at a dose of 75 mg once/day (in combination with acetylsalicylic acid at doses of 75-325 mg/day). Since the use of acetylsalicylic acid in higher doses is associated with an increased risk of bleeding, the recommended dose of acetylsalicylic acid for this indication does not exceed 100 mg. The maximum beneficial effect is observed by the 3rd month of treatment. The course of treatment is up to 1 year.

For acute coronary syndrome with ST-segment elevation (acute myocardial infarction with ST-segment elevation), the drug is prescribed as a single dose of 75 mg once/day with an initial single loading dose in combination with acetylsalicylic acid and thrombolytics (or without thrombolytics). Combined therapy should be started as early as possible after the onset of symptoms and continued for at least 4 weeks.

In patients over 75 years of age, treatment should be started without a loading dose.

Adverse Reactions

From the hematopoietic system sometimes – leukopenia, decreased neutrophil count and eosinophilia, decreased platelet count; very rarely – thrombotic thrombocytopenic purpura (1 in 200,000 patients), severe thrombocytopenia (platelet count ≤ 30,000/µL), granulocytopenia, agranulocytosis, anemia and aplastic anemia, pancytopenia.

From the central and peripheral nervous system sometimes – headache, dizziness, paresthesia; rarely – vertigo; very rarely – confusion, hallucinations.

From the digestive system often – dyspepsia, diarrhea, abdominal pain; sometimes – nausea, gastritis, flatulence, constipation, vomiting, gastric and duodenal ulcer; very rarely – colitis (including ulcerative or lymphocytic colitis), pancreatitis, taste perversion, stomatitis; hepatitis, acute liver failure, increased activity of liver enzymes.

From the blood coagulation system most often – bleeding (in most cases – during the first month of treatment). Several fatal cases are known (intracranial, gastrointestinal and retroperitoneal bleeding); there are reports of severe cases of skin hemorrhages (purpura), musculoskeletal bleeding (hemarthrosis, hematoma), eye hemorrhages (conjunctival, ocular, retinal), epistaxis, hemoptysis, pulmonary bleeding, hematuria and bleeding from the surgical wound; in patients taking Clopidogrel simultaneously with acetylsalicylic acid or with acetylsalicylic acid and heparin, cases of severe bleeding were also noted.

Dermatological reactions often – bruising; sometimes – rash and itching; very rarely – bullous rash (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), erythematous rash, eczema, lichen planus.

From the cardiovascular system: very rarely – vasculitis, arterial hypotension.

From the respiratory system very rarely – bronchospasm, interstitial pneumonitis.

From the musculoskeletal system very rarely – arthralgia, arthritis, myalgia.

From the urinary system very rarely – glomerulonephritis, increased blood creatinine.

Allergic reactions very rarely – angioedema, urticaria, anaphylactoid reactions, serum sickness.

Other very rarely – increased body temperature.

Contraindications

• Severe hepatic impairment;
• Active bleeding, e.g., peptic ulcer bleeding or intracranial hemorrhage;
• Pregnancy;
• Lactation period (breastfeeding);
• Children under 18 years of age;
• Hypersensitivity to the components of the drug.

The drug should be prescribed with caution in cases of moderate hepatic and/or renal impairment, trauma, and pre-operative conditions.

Use in Pregnancy and Lactation

The drug is contraindicated for use during pregnancy and lactation.

Use in Hepatic Impairment

The drug should be prescribed with caution in cases of moderate hepatic impairment.

The drug is contraindicated in severe hepatic impairment.

Use in Renal Impairment

The drug should be prescribed with caution in cases of moderate renal impairment.

Pediatric Use

Contraindication: children under 18 years of age.

Geriatric Use

In patients over 75 years of age, treatment should be started without a loading dose.

Special Precautions

When treating with Detromb^®, especially during the first weeks of treatment and/or after invasive cardiac procedures/surgery, patients should be carefully monitored for signs of bleeding, including occult bleeding. Due to the risk of bleeding and hematological adverse effects, if clinical symptoms suspicious for bleeding occur during treatment, a clinical blood test, activated partial thromboplastin time, platelet count, platelet function activity indicators, and other necessary tests should be urgently performed.

Clopidogrel, like other antiplatelet drugs, should be used with caution in patients with an increased risk of bleeding associated with trauma, surgery, or other pathological conditions, as well as in patients receiving acetylsalicylic acid, NSAIDs, including COX-2 inhibitors, heparin, or glycoprotein IIb/IIIa inhibitors.

Concomitant use of clopidogrel with warfarin may increase the intensity of bleeding, therefore, except for special rare clinical situations (such as the presence of a floating thrombus in the left ventricle, stenting in patients with atrial fibrillation), concomitant use of clopidogrel and warfarin is not recommended.

Clopidogrel prolongs bleeding time and should be used with caution in patients with conditions predisposing to bleeding (especially gastrointestinal and intraocular).

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

Liver function should be monitored during treatment. In cases of severe liver damage, the risk of hemorrhagic diathesis should be considered.

The use of clopidogrel is not recommended for acute stroke of less than 7 days duration (as there is no data on its use in this condition).

Overdose

Symptoms prolongation of bleeding time and subsequent complications in the form of bleeding development.

Treatment if bleeding occurs, appropriate therapy should be administered. If rapid correction of prolonged bleeding time is necessary, platelet transfusion is recommended. There is no specific antidote.

Drug Interactions

It enhances the antiplatelet effect of acetylsalicylic acid, heparin, indirect anticoagulants, non-steroidal anti-inflammatory drugs, and increases the risk of gastrointestinal bleeding. However, in patients with acute coronary syndrome without ST-segment elevation, long-term concomitant use of clopidogrel and acetylsalicylic acid (up to 1 year) is recommended.

Prescription of glycoprotein IIb/IIIa inhibitors together with clopidogrel requires caution in patients with an increased risk of bleeding (with trauma and surgery or other pathological conditions).

No clinically significant pharmacodynamic interaction was found when clopidogrel was used concomitantly with atenolol, nifedipine, phenobarbital, cimetidine, estrogens, digoxin, theophylline, phenytoin, tolbutamide, and antacids.

Storage Conditions

The drug should be stored in a dry, light-protected place, out of the reach of children, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.