Thrombo ASS^® (Tablets) Instructions for Use

Marketing Authorization Holder

Bausch Health, LLC (Russia)

Manufactured By

G.L. Pharma, GmbH (Austria)

Or

Pharmaceutical Works Jelfa, S.A. (Poland)

Or

ICN Polfa Rzeszow, S.A. (Poland)

Quality Control Release

G.L. PHARMA, GmbH (Austria)

Or

PHARMACEUTICAL WORKS JELFA, S.A. (Poland)

Or

ICN POLFA RZESZOW, S.A. (Poland)

Contact Information

BAUSH HEALTH LLC (Russia)

ATC Code

B01AC06 (Acetylsalicylic acid)

Active Substance

Acetylsalicylic acid (Ph.Eur. European Pharmacopoeia)

Dosage Forms

	Thrombo ASS®	Enteric-coated film-coated tablets, 50 mg: 28 or 100 pcs.
		Enteric-coated film-coated tablets, 100 mg: 28 or 100 pcs.

Dosage Form, Packaging, and Composition

Enteric-coated film-coated tablets white, round, biconvex; the tablet surface is smooth or slightly rough, shiny.

Excipients : lactose monohydrate, microcrystalline cellulose, colloidal silicon dioxide, potato starch; coating: talc, triacetin, methacrylic acid and ethyl acrylate copolymer (1:1) (Eudragit L).

14 pcs. – blisters (2) – cardboard packs.
20 pcs. – blisters (5) – cardboard packs.

Clinical-Pharmacological Group

NSAID. Antiplatelet agent

Pharmacotherapeutic Group

Antiaggregant agent

Pharmacological Action

Acetylsalicylic acid (ASA) is an ester of salicylic acid and belongs to the group of NSAIDs.

The mechanism of action is based on irreversible inhibition of the enzyme COX-1, resulting in blocked synthesis of prostaglandins, prostacyclins, and thromboxane.

It reduces platelet aggregation, adhesion, and thrombus formation by suppressing the synthesis of thromboxane A2 in platelets.

It increases the fibrinolytic activity of blood plasma and reduces the concentration of vitamin K-dependent coagulation factors (II, VII, IX, X).

The antiplatelet effect is most pronounced in platelets, as they are unable to re-synthesize COX.

The antiplatelet effect develops after the use of low doses of the drug and persists for 7 days after a single dose.

These properties of ASA are used in the prevention and treatment of myocardial infarction, coronary artery disease, and complications of varicose veins.

ASA also has anti-inflammatory, antipyretic, and analgesic effects.

Pharmacokinetics

Absorption

After oral administration, ASA is rapidly and completely absorbed from the gastrointestinal tract.

The tablets are coated with an enteric coating, which reduces the direct irritating effect of ASA on the gastric mucosa.

ASA is partially metabolized during absorption.

C_max of ASA in blood plasma is reached approximately 2-7 hours after taking the tablets, thus, the absorption of ASA in the form of enteric-coated film-coated tablets is delayed compared to conventional tablets (without an enteric coating).

When taken simultaneously with food, a delay in ASA absorption is noted without affecting the extent of absorption.

The lower absorption rate of enteric-coated ASA tablets does not affect the plasma exposure of ASA and its ability to inhibit platelet aggregation during long-term therapy with low doses of the drug.

Nevertheless, to ensure maximum stability of the ASA tablets in the stomach, it is recommended to take the drug at least 30 minutes before meals with plenty of fluid (see section “Dosage Regimen”).

Distribution

ASA and salicylic acid are largely bound to plasma proteins (from 49 to 70% for ASA; from 66 to 98% for salicylic acid, respectively, depending on the dose) and are rapidly distributed in the body.

After oral administration of ASA, salicylic acid crosses the placental barrier and is excreted in breast milk.

Metabolism

During and after absorption, ASA is converted into its main metabolite, salicylic acid, which is metabolized mainly in the liver under the influence of liver enzymes to form salicyluric acid, phenolic glucuronide of salicylic acid, salicyl glucuronide, and gentisic acid.

In women, the metabolic process is slower (lower activity of serum enzymes).

Elimination

The elimination of salicylic acid is dose-dependent, as its metabolism is limited by the capacity of the enzymatic system.

T_1/2 ranges from 2-3 hours when using ASA in low doses to 15 hours when using the drug in high doses (usual doses of acetylsalicylic acid as an analgesic).

Salicylic acid and its metabolites are excreted by the kidneys.

Unlike other salicylates, upon repeated administration of the drug, non-hydrolyzed ASA does not accumulate in the blood serum.

In patients with normal renal function, 80-100% of a single dose of the drug is excreted by the kidneys within 24-72 hours.

Indications

• Prevention of recurrent myocardial infarction;
• Unstable angina and stable angina;
• Prevention of recurrent ischemic stroke in patients who have previously had a cerebrovascular accident;
• Prevention of recurrent transient ischemic attack (TIA);
• Prevention of thrombotic complications after surgeries and invasive interventions on blood vessels (e.g., coronary artery bypass grafting, carotid endarterectomy, arteriovenous shunting, coronary artery angioplasty and stenting, carotid artery angioplasty).

ICD codes

Dosage Regimen

The drug is taken orally.

It is advisable to take the tablets at least 30 minutes before meals with plenty of water.

To ensure the release of ASA in the alkaline environment of the duodenum, the tablets should not be broken, crushed, or chewed.

Thrombo ASS^® tablets are taken once a day or every other day.

The drug Thrombo ASS^® is intended for long-term use.

The duration of therapy is determined by the doctor.

Prevention of recurrent myocardial infarction, stable and unstable angina 100-300 mg/day.

Prevention of recurrent ischemic stroke and recurrent transient ischemic attack (TIA) 100-300 mg/day.

Prevention of thrombotic complications after surgeries and invasive interventions on blood vessels 100-300 mg/day.

Actions in case of missing one or several doses of the drug

The missed tablet should be taken as soon as the patient remembers, and then continue taking it as usual.

To avoid doubling the dose, do not take the missed tablet if it is almost time for the next tablet.

Features of the drug’s action upon first administration and upon its discontinuation

No features of the drug’s action upon first administration or upon its discontinuation have been observed.

Special patient groups

The safety and efficacy of Thrombo ASS^® in children and adolescents under 18 years of age have not been established.

The use of the drug in patients under 18 years of age is contraindicated.

Thrombo ASS^® is contraindicated in patients with severe hepatic impairment.

Thrombo ASS^® should be used with caution in patients with hepatic impairment.

Thrombo ASS^® is contraindicated in patients with severe renal impairment.

Thrombo ASS^® should be used with caution in patients with renal impairment, as taking the drug may increase the risk of renal failure and acute renal failure.

Adverse Reactions

The frequency of adverse reactions is classified according to WHO recommendations, side effects are classified by frequency: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10000 and <1/1000), very rare (<1/10000), frequency unknown (cannot be estimated from the available data).

Adverse reactions also include data obtained from monitoring patients with rheumatic disorders who received high doses of ASA for a long period of time.

ASA can lead to complaints of abdominal pain, the development of gastric and duodenal ulcers, erosive gastritis, which can lead to serious gastrointestinal bleeding.

The likelihood of these effects increases with the use of higher doses, although the possibility of their occurrence at lower doses cannot be excluded.

If ASA is used for a long period of time, gastrointestinal bleeding can lead to the development of acute or chronic post-hemorrhagic/iron deficiency anemia.

Also, during therapy with NSAIDs, edema, arterial hypertension, and heart failure have been reported.

Blood and lymphatic system disorders uncommon – hemorrhagic anemia, iron deficiency anemia (with corresponding clinical and laboratory signs and symptoms); rare – thrombocytopenia, agranulocytosis, aplastic anemia, hemolytic anemia.

Immune system disorders uncommon – hypersensitivity, drug intolerance (urticaria, skin reactions such as rash and itching); rare – hypersensitivity reactions such as severe skin reactions (very rarely even erythema multiforme and toxic epidermal necrolysis [Lyell’s syndrome]), possibly accompanied by a drop in blood pressure, shortness of breath, anaphylactic reactions or angioedema (Quincke’s edema), especially in patients with a history of asthma, anaphylactic shock with corresponding laboratory and clinical manifestations.

Nervous system disorders rare – headache, dizziness, confusion; very rare – serious bleeding such as hemorrhagic stroke or intracranial bleeding have been reported, especially in patients with uncontrolled hypertension and/or concomitant treatment with anticoagulants, which in some cases can be life-threatening.

Ear and labyrinth disorders rare – hearing impairment, tinnitus.

Cardiac and vascular disorders rare – hemorrhages, surgical bleeding, hematomas, muscle hemorrhages. Cardiorespiratory distress syndrome associated with severe allergic reactions.

Respiratory, thoracic and mediastinal disorders uncommon – rhinitis, nasal congestion, nosebleed; rare – hypersensitivity reactions such as bronchospasm, asthma attacks.

Gastrointestinal disorders common – abdominal pain, gastrointestinal pain, gum bleeding, heartburn, nausea, vomiting, diarrhea, dyspepsia; uncommon – gastrointestinal bleeding, as well as ulcers of the gastric and duodenal mucosa, which very rarely can lead to perforation.

Bleeding can lead to the development of acute or chronic post-hemorrhagic/iron deficiency anemia (e.g., due to occult bleeding) with corresponding clinical and laboratory symptoms.

Hepatobiliary disorders very rare – increased activity of liver transaminases, impaired liver function.

Renal and urinary disorders very rare – bleeding from the genitourinary tract, impaired renal function, acute renal failure.

Skin and subcutaneous tissue disorders very rare – skin rash, skin itching, urticaria.

If side effects listed in the instructions occur, or if they worsen, or if any other side effects not listed in the instructions occur, the patient should inform the doctor.

Contraindications

• Hypersensitivity to acetylsalicylic acid, excipients in the drug or NSAIDs;
• Erosive and ulcerative lesions of the gastrointestinal tract (in the acute stage);
• Gastrointestinal bleeding;
• Hemorrhagic diathesis, thrombocytopenia, hemophilia;
• Bronchial asthma induced by the intake of salicylates and other NSAIDs, a combination of bronchial asthma, recurrent polyposis of the nose and paranasal sinuses and intolerance to ASA;
• Concomitant use with methotrexate at a dose of 15 mg per week or more;
• Pregnancy (I and III trimester);
• Breastfeeding period;
• Children and adolescents under 18 years of age (no data on efficacy and safety);
• Severe renal impairment;
• Severe hepatic impairment;
• Chronic heart failure of functional class III-IV according to the NYHA classification;
• Lactose intolerance, lactase deficiency and glucose-galactose malabsorption;
• Hyperoxaluria.

With caution

• In gout, hyperuricemia, because ASA in low doses reduces the excretion of uric acid, which in turn can provoke a gout attack in predisposed patients;
• History of ulcerative lesions of the gastrointestinal tract, including chronic and recurrent gastrointestinal lesions or gastrointestinal bleeding in history;
• In hepatic impairment (below class B according to the Child-Pugh classification);
• In renal impairment (creatinine clearance more than 30 ml/min);
• In bronchial asthma, chronic respiratory diseases, hay fever, nasal polyposis, as well as allergic reactions (skin reactions, itching, urticaria) to other drugs, including NSAIDs (analgesics, anti-inflammatory, antirheumatic agents);
• In circulatory disorders resulting from atherosclerosis of the renal arteries, congestive heart failure, hypovolemia, major surgery, sepsis, cases of massive bleeding;
• In the II trimester of pregnancy;
• In severe forms of glucose-6-phosphate dehydrogenase deficiency;
• In planned surgical intervention (including minor ones, e.g., tooth extraction);
• With concomitant use with the following drugs (see section “Drug Interactions”):
  • With methotrexate at a dose of less than 15 mg per week;
  • With anticoagulants, thrombolytic or other antiplatelet drugs;
  • With NSAIDs (including ibuprofen, naproxen);
  • With digoxin;
  • With oral hypoglycemic drugs (sulfonylurea derivatives) and insulin;
  • With valproic acid;
  • With alcohol (alcoholic beverages, in particular);
  • With selective serotonin reuptake inhibitors.

Use in Pregnancy and Lactation

Pregnancy

Inhibition of prostaglandin synthesis may have a negative effect on pregnancy and the development of the embryo or fetus.

Data from epidemiological studies on the use of prostaglandin synthesis inhibitors in early pregnancy indicate an increased risk of miscarriage and the development of congenital malformations of the fetus (including heart defects, cleft palate, as well as an increased risk of gastroschisis), presumably increasing with increasing drug dose and duration of treatment.

Animal studies have demonstrated reproductive toxicity of acetylsalicylic acid.

In the first trimester of pregnancy, the use of drugs containing acetylsalicylic acid is contraindicated.

In the second trimester of pregnancy, salicylates can be prescribed only after a strict assessment of the risk and benefit for the mother and fetus.

Women planning a pregnancy or in the second trimester of pregnancy should minimize the dose of acetylsalicylic acid and the duration of treatment as much as possible.

In the third trimester of pregnancy, prostaglandin synthesis inhibitors can cause suppression of uterine contractions, leading to inhibition of labor, increased bleeding time, and enhancement of the antiplatelet effect (even when using acetylsalicylic acid in low doses).

In the fetus, cardiopulmonary intoxication may develop with premature closure of the ductus arteriosus and the development of pulmonary hypertension, as well as impaired renal function, up to the development of renal failure accompanied by oligohydramnios.

The use of acetylsalicylic acid in the third trimester of pregnancy is contraindicated.

Breastfeeding period

Salicylates and their metabolites pass into breast milk in small amounts.

Occasional use of salicylates during breastfeeding is not accompanied by the development of adverse reactions in the child and does not require discontinuation of breastfeeding.

However, with long-term use of the drug or its prescription in a high dose, breastfeeding should be stopped immediately.

Use in Hepatic Impairment

Contraindicated in severe hepatic impairment.

The drug should be used with caution in hepatic impairment.

Use in Renal Impairment

Contraindicated in severe renal impairment.

The drug should be used with caution in renal impairment (creatinine clearance more than 30 ml/min).

Pediatric Use

Contraindication: children and adolescents under 18 years of age.

Geriatric Use

Overdose is especially dangerous in elderly patients.

Special Precautions

The drug Thrombo ASS^® should be used with caution under the following conditions.

• Hypersensitivity to analgesics, anti-inflammatory drugs, antirheumatic drugs, as well as allergic reactions to other substances.
• History of gastrointestinal ulcerative lesions, including chronic and recurrent gastrointestinal lesions or gastrointestinal bleeding in the medical history.
• Concomitant use with anticoagulants (see the section “Drug Interactions”).
• In case of impaired renal function or impaired circulation due to atherosclerosis of the renal arteries, congestive heart failure, hypovolemia, major surgery, sepsis, or cases of massive bleeding, since in all these cases ASA may increase the risk of acute renal failure and impaired renal function.
• In severe forms of glucose-6-phosphate dehydrogenase deficiency, ASA can cause hemolysis and hemolytic anemia. Factors that may increase the risk of hemolysis include fever, acute infections, and high doses of the drug.
• In case of impaired liver function.
• Some NSAIDs (ibuprofen, naproxen) may weaken the inhibitory effect of ASA on platelet aggregation. Patients taking ASA and planning to take NSAIDs should discuss this with their doctor (see the section “Drug Interactions”).
• ASA can provoke bronchospasm, as well as cause attacks of bronchial asthma and other hypersensitivity reactions. Risk factors include a history of bronchial asthma, hay fever, nasal polyposis, chronic respiratory diseases, and allergic reactions to other drugs (for example, skin reactions, itching, urticaria).
• The inhibitory effect of ASA on platelet aggregation persists for several days after administration, which may increase the risk of bleeding during surgery or in the postoperative period (including minor surgical procedures, such as tooth extraction).
• ASA in low doses reduces the excretion of uric acid, which may lead to gout attacks in patients predisposed to this disease.
• Exceeding the dose of ASA is associated with the risk of gastrointestinal bleeding.
• Overdose is especially dangerous in elderly patients.

The drug should be used after a doctor’s prescription.

Effect on the ability to drive vehicles and mechanisms

Taking the drug Thrombo ASS^® does not affect the ability to drive vehicles and mechanisms.

Overdose

In case of overdose, it is necessary to consult a doctor immediately.

Salicylate intoxication (develops when taking ASA at a dose of more than 100 mg/kg/day for more than 2 days) may result from prolonged use of toxic doses of the drug in the context of improper therapeutic use of the drug (chronic intoxication) or a single accidental or intentional intake of a toxic dose of the drug by an adult or child (acute intoxication).

Symptoms of chronic intoxication with salicylic acid derivatives are nonspecific and often difficult to diagnose. Mild intoxication usually develops only after repeated use of large doses of the drug and is manifested by dizziness, vertigo, tinnitus, hearing loss, increased sweating, nausea and vomiting, headache, and confusion. These symptoms disappear after reducing the dose of the drug. Tinnitus may occur at plasma ASA concentrations from 150 to 300 mcg/ml. More severe symptoms occur at plasma ASA concentrations above 300 mcg/ml.

The main manifestation of acute intoxication is a severe disturbance of the acid-base state, the manifestations of which may vary depending on the age of the patient and the severity of the intoxication. In children, the development of metabolic acidosis is most typical. Since the rate of ASA absorption may decrease due to delayed gastric emptying, formation of concretions, or intake of drugs resistant to the action of gastric juice, the severity of intoxication cannot be judged solely by the change in plasma salicylate concentration. Treatment of intoxication is carried out in accordance with accepted standards and depends on the severity of intoxication and the clinical picture and should be aimed mainly at accelerating the elimination of the drug and restoring water-electrolyte balance and acid-base state.

Symptoms in mild and moderate severity (single dose less than 150 mg/kg) dizziness, tinnitus, hearing loss, increased sweating, nausea and vomiting, headache, confusion, profuse sweating, tachypnea, hyperventilation, respiratory alkalosis.

Treatment gastric lavage, repeated administration of activated charcoal, forced alkaline diuresis, restoration of water-electrolyte balance and acid-base state.

Symptoms in moderate and severe severity (single dose 150-300 mg/kg – moderate severity, more than 300 mg/kg – severe poisoning)

• Respiratory alkalosis with compensatory metabolic acidosis;
• Hyperpyrexia;
• Respiratory disorders, hyperventilation, non-cardiogenic pulmonary edema, respiratory depression, asphyxia;
• From the cardiovascular system: heart rhythm disorders, arterial hypotension, depression of cardiac activity;
• From the water-electrolyte balance: dehydration, impaired renal function from oliguria up to the development of renal failure, characterized by hypokalemia, hypernatremia, hyponatremia;
• Impaired glucose metabolism: hyperglycemia, hypoglycemia (especially in children), ketoacidosis;
• Tinnitus, deafness;
• Gastrointestinal bleeding;
• Hematological disorders: from inhibition of platelet aggregation to coagulopathy, prolongation of prothrombin time, hypoprothrombinemia;
• Neurological disorders: toxic encephalopathy and depression of CNS function (drowsiness, confusion, coma, convulsions).

Treatment immediate hospitalization in specialized departments for emergency therapy – gastric lavage, repeated administration of activated charcoal, forced alkaline diuresis, hemodialysis, restoration of water-electrolyte balance and acid-base state, symptomatic therapy.

Drug Interactions

With simultaneous use, ASA enhances the effect of the following drugs

• Methotrexate due to reduced renal clearance and displacement from protein binding; the use of the drug Thrombo ASS^® together with methotrexate is contraindicated if the dose of the latter exceeds 15 mg per week (see the section “Contraindications”) and is possible with caution – at a methotrexate dose of less than 15 mg per week;
• Heparin and indirect anticoagulants due to impaired platelet function and displacement of indirect anticoagulants from protein binding;
• With simultaneous use with anticoagulants, thrombolytic and antiplatelet agents, an increase in the risk of bleeding is noted as a result of the synergy of the main therapeutic effects of the drugs used;
• With simultaneous use with drugs that have anticoagulant, thrombolytic or antiplatelet action, an increase in the damaging effect on the gastrointestinal mucosa is noted;
• Selective serotonin reuptake inhibitors, which may lead to an increased risk of bleeding from the upper gastrointestinal tract (synergism with ASA);
• Digoxin due to a decrease in its renal excretion, which may lead to its overdose;
• Hypoglycemic drugs (insulin, sulfonylurea derivatives) due to the hypoglycemic properties of ASA itself in high doses and displacement of sulfonylurea derivatives from plasma protein binding;
• With simultaneous use with valproic acid, its toxicity increases due to displacement from plasma protein binding;
• NSAIDs (increased risk of ulcerogenic effect and gastrointestinal bleeding as a result of synergy of action);
• Ethanol (alcoholic beverages) (increased risk of damage to the gastrointestinal mucosa and prolongation of bleeding time as a result of mutual enhancement of the effects of ASA and ethanol).

Simultaneous administration of ASA in high doses may weaken the effect of the following drugs

• Any diuretics (when used concomitantly with ASA in high doses, a decrease in GFR is noted due to a decrease in the synthesis of prostaglandins in the kidneys);
• ACE inhibitors (a dose-dependent decrease in GFR is noted) as a result of inhibition of prostaglandins that have a vasodilating effect, respectively, a weakening of the hypotensive effect;
• Drugs with uricosuric action – benzbromarone, probenecid (reduction of the uricosuric effect due to competitive suppression of renal tubular excretion of uric acid).

With simultaneous use with metamizole, a decrease in the effect of ASA on platelet aggregation is noted, therefore, in patients taking low doses of ASA for cardioprotection, this combination should be used with caution.

With simultaneous (within one day) use with ibuprofen and naproxen, antagonism in relation to irreversible platelet inhibition caused by the action of ASA is noted. The clinical significance of this effect is unknown. The combination of ASA with ibuprofen is not recommended in patients at high risk of cardiovascular disease due to a possible decrease in the cardioprotective effects of ASA.

With simultaneous use with systemic corticosteroids (except for hydrocortisone or another corticosteroid used for replacement therapy of Addison’s disease), an increase in the elimination of salicylates and, accordingly, a weakening of their action is noted. When using corticosteroids and salicylates in combination, it should be remembered that during treatment the level of salicylates in the blood is reduced, and after discontinuation of corticosteroids, an overdose of salicylates is possible.

Storage Conditions

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

Shelf Life

The shelf life is 3 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is available without a 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.