Acetylsalicylic acid

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ACETYLSALICYLIC ACID (ACIDUM ACETYLSALICYLICUM)

Composition:

Active ingredient: acetylsalicylic acid;

1 tablet contains acetylsalicylic acid (calculated as 100 % substance) 500 mg;

Excipients: microcrystalline cellulose, sodium croscarmellose, colloidal anhydrous silicon dioxide (aerosil), magnesium stearate, lemon flavor, anhydrous citric acid.

Pharmaceutical form. Tablets.

Main physicochemical properties: white or almost white, round-shaped tablets with flat surface, with a score line and bevelled edge, with a slight lemon odor. Marbling on the surface of the tablets is permissible.

Pharmacotherapeutic group.

Analgesics and antipyretics. Acetylsalicylic acid. ATC code N02BA01.

Pharmacological properties.

Pharmacodynamics.

Acetylsalicylic acid belongs to the group of non-steroidal anti-inflammatory drugs (NSAIDs) with analgesic, antipyretic, and anti-inflammatory properties. Its mechanism of action involves the irreversible inactivation of cyclooxygenase enzymes, which play a key role in the synthesis of prostaglandins.

Acetylsalicylic acid is administered orally in doses of 0.3 to 1 g for the relief of pain and fever-associated conditions such as colds, to reduce body temperature and alleviate joint and muscle pain.

Acetylsalicylic acid inhibits platelet aggregation by blocking the synthesis of thromboxane A2.

Pharmacokinetics.

After oral administration, acetylsalicylic acid is rapidly and completely absorbed from the gastrointestinal tract. During and after absorption, it is converted into its main active metabolite—salicylic acid. Maximum plasma concentration of acetylsalicylic acid is reached within 10–20 minutes, and of salicylates within 20–120 minutes.

Acetylsalicylic acid and salicylic acid are completely bound to plasma proteins and rapidly distributed throughout the body.

Salicylic acid crosses the placenta and is excreted into breast milk.

Salicylic acid is metabolized in the liver. Metabolites of salicylic acid include salicyluric acid, salicyl phenol glucuronide, salicyl acyl glucuronide, gentisic acid, and gentisic acid sulfate.

The elimination kinetics of salicylic acid are dose-dependent, as metabolism is limited by the activity of hepatic enzymes. The elimination half-life depends on the dose, increasing from 2–3 hours with low doses to 15 hours with high doses. Salicylic acid and its metabolites are primarily excreted by the kidneys.

Clinical characteristics.

Indications.

• Treatment of mild to moderate acute pain (headache, toothache, joint and muscle pain, back pain).
• Symptomatic treatment of fever and/or pain associated with colds and respiratory tract infections.

Contraindications.

• Hypersensitivity to acetylsalicylic acid, other salicylates, or any component of the medicinal product.
• Bronchial asthma induced by salicylates or other NSAIDs in medical history.
• Active gastrointestinal ulcers.
• Hemorrhagic diathesis.
• Severe renal impairment.
• Severe hepatic impairment.
• Severe heart failure.
• Concomitant use with methotrexate at doses of 15 mg/week or higher (see section "Interaction with other medicinal products and other forms of interaction").
• Third trimester of pregnancy.

Special precautions.

Acetylsalicylic acid should be used with caution in:

• Hypersensitivity to analgesics, anti-inflammatory, or antirheumatic agents, as well as in patients with allergies to other substances;
• History of gastrointestinal ulcers, including chronic or recurrent peptic ulcer disease or gastrointestinal bleeding;
• Concomitant use of anticoagulants;
• Impaired renal function or impaired circulation (such as renal vascular disease, congestive heart failure, dehydration, major surgical procedures, sepsis, or significant blood loss), since acetylsalicylic acid may further increase the risk of kidney damage and may cause acute renal failure;
• Impaired liver function.

In patients with allergic complications, including bronchial asthma, allergic rhinitis, urticaria, skin itching, mucosal edema, nasal polyps, or their combination with chronic respiratory infections, and in patients with hypersensitivity to NSAIDs, treatment with acetylsalicylic acid may provoke bronchospasm, asthma attacks, or other hypersensitivity reactions.

Due to its inhibitory effect on platelet aggregation, which persists for several days after administration, acetylsalicylic acid may increase the risk of bleeding during and after surgical procedures (including minor surgeries such as tooth extraction).

When low doses of acetylsalicylic acid are used, excretion of uric acid may be reduced. This may trigger gout attacks in patients with impaired uric acid excretion.

In patients with glucose-6-phosphate dehydrogenase deficiency, acetylsalicylic acid may cause hemolysis or hemolytic anemia. Factors increasing the risk of hemolysis include, for example, high-dose drug use, fever, or acute infections.

Prolonged use of analgesics may lead to the development of headache.

Frequent use of analgesics may cause temporary kidney dysfunction with a risk of developing renal failure (analgesic nephropathy). The risk is particularly high when multiple different analgesics are used concomitantly.

Interaction with other medicinal products and other forms of interaction.

Contraindicated combinations.

The use of acetylsalicylic acid with methotrexate at doses of 15 mg/week or higher increases the hematological toxicity of methotrexate (due to reduced renal clearance of methotrexate by anti-inflammatory agents and displacement of methotrexate from plasma protein binding by salicylates).

Combinations requiring caution.

When acetylsalicylic acid is used concomitantly with methotrexate at doses less than 15 mg/week, the hematological toxicity of methotrexate may increase (due to reduced renal clearance of methotrexate by anti-inflammatory agents and displacement of methotrexate from plasma protein binding by salicylates).

Concomitant use of ibuprofen interferes with the irreversible inhibition of platelets by acetylsalicylic acid. Treatment with ibuprofen in patients at risk of cardiovascular disease may reduce the cardioprotective effect of acetylsalicylic acid.

Concomitant use of high-dose salicylates with NSAIDs increases the risk of ulcers and gastrointestinal bleeding due to synergistic effects.

Concomitant use of medicinal products containing acetylsalicylic acid and metamizole may reduce clinically significant platelet aggregation.

When acetylsalicylic acid is used concomitantly with anticoagulants, thrombolytics, and platelet aggregation inhibitors (e.g., ticlopidine, clopidogrel), the risk of bleeding increases. Therefore, in patients requiring thrombolytic therapy, symptoms of external or internal bleeding should be closely monitored.

Concomitant use with uricosuric agents, such as benzbromarone or probenecid, reduces the uric acid excretion effect (due to competition for renal tubular excretion of uric acid).

When used concomitantly with digoxin, digoxin plasma concentration increases due to reduced renal excretion.

Concomitant use of high doses of acetylsalicylic acid with oral antidiabetic agents of the sulfonylurea group or insulin enhances the hypoglycemic effect of the latter due to the hypoglycemic effect of acetylsalicylic acid and displacement of sulfonylurea from plasma protein binding.

Diuretics in combination with high doses of acetylsalicylic acid reduce glomerular filtration due to decreased renal prostaglandin synthesis.

Systemic glucocorticosteroids (except hydrocortisone used for replacement therapy in Addison's disease). When acetylsalicylic acid is used concomitantly with corticosteroids, salicylate blood levels decrease, increasing the risk of overdose after discontinuation of treatment, and the risk of gastrointestinal bleeding increases.

ACE inhibitors in combination with high doses of acetylsalicylic acid lead to reduced glomerular filtration due to inhibition of vasodilatory prostaglandins and reduced antihypertensive effect.

Selective serotonin reuptake inhibitors (SSRIs). The risk of upper gastrointestinal bleeding increases due to possible synergistic effects.

When used concomitantly with valproic acid, acetylsalicylic acid displaces it from plasma protein binding, increasing its toxicity.

Ethanol promotes damage to the gastrointestinal mucosa and prolongs bleeding time due to synergism between acetylsalicylic acid and alcohol.

Special precautions for use.

Use during pregnancy or breastfeeding.

Pregnancy.

Acetylsalicylic acid may be used during pregnancy only if other medicinal products are ineffective and only after careful assessment of the benefit-risk ratio.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/foetal development. Epidemiological data indicate a risk of miscarriage and congenital malformations following the use of prostaglandin synthesis inhibitors in early pregnancy. The risk increases with increasing dose and duration of therapy.

Available epidemiological data on the occurrence of congenital malformations are inconsistent; however, an increased risk of gastroschisis cannot be ruled out with the use of acetylsalicylic acid.

Animal studies indicate reproductive toxicity.

During the first and second trimesters of pregnancy, medicinal products containing acetylsalicylic acid should not be administered without clear clinical necessity. In women planning pregnancy, or during the first and second trimesters, the dose of medicinal products containing acetylsalicylic acid should be as low as possible and the duration of treatment as short as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may affect the foetus as follows:

• cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
• impairment of renal function with possible subsequent development of renal failure associated with oligohydramnios.

In women and the foetus towards the end of pregnancy, prostaglandin synthesis inhibitors may have the following effects:

• increased possibility of prolonged bleeding time, antiplatelet effect, which may occur even after very low doses;
• inhibition of uterine contractions, which may lead to delayed or prolonged duration of labour.

For these reasons, acetylsalicylic acid is contraindicated during the third trimester of pregnancy.

Fertility.

There is some evidence that medicinal products which inhibit prostaglandin synthesis may impair female fertility by affecting ovulation. This effect is reversible and resolves after discontinuation of treatment.

Period of breastfeeding.

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

Since adverse reactions in infants whose mothers have taken acetylsalicylic acid for short periods have not been observed, breastfeeding interruption is generally not required. However, prolonged use of acetylsalicylic acid at high doses requires discontinuation of breastfeeding.

Ability to influence reaction rate while driving or operating machinery.

No effects on the ability to drive a vehicle or operate machinery have been observed.

Method of Administration and Dosage.

Acetylsalicylic acid is taken orally after meals, with a sufficient amount of liquid.

Acetylsalicylic acid should not be used for longer than 3–5 days without consulting a physician.

Adults and children aged 15 years and older.

1–2 tablets as a single dose. Repeat dosing may be administered every 4–8 hours. The maximum daily dose should not exceed 4 g (8 tablets).

Warning.

For patients with concomitant hepatic or renal function impairment, the dose of the drug should be reduced or the interval between administrations increased.

Children.

The drug is indicated for children aged 15 years and older.

Do not use medications containing acetylsalicylic acid in children with acute respiratory viral infections (ARVI), whether or not accompanied by fever, without prior medical consultation. In certain viral diseases, particularly influenza type A, influenza type B, and varicella (chickenpox), there is a risk of developing Reye's syndrome—a very rare but life-threatening condition requiring immediate medical intervention. The risk may be increased when acetylsalicylic acid is used as a concomitant medication; however, a causal relationship has not been definitively established. If the aforementioned conditions are accompanied by persistent vomiting, this may be a sign of Reye's syndrome.

Overdose.

Salicylate toxicity (administration exceeding 100 mg/kg/day for more than 2 days may cause toxicity) may result from chronic intoxication due to prolonged therapy, or from acute intoxication (overdose), which is potentially life-threatening and may be caused, for example, by accidental ingestion in children or intentional overdose.

Chronic intoxication with salicylates may have an insidious onset, as its symptoms are nonspecific. Moderate chronic intoxication, or salicylism, typically occurs only after repeated administration of high doses.

Symptoms: Dizziness, tinnitus, hearing loss, sweating, nausea and vomiting, headache, confusion. These symptoms can usually be controlled by reducing the dose. Tinnitus may occur at plasma salicylate concentrations above 150–300 mcg/mL. More serious adverse reactions occur at plasma salicylate concentrations exceeding 300 mcg/mL.

Acute intoxication is characterized by significant disturbances in acid-base balance, which vary depending on the patient's age and severity of intoxication. In children, metabolic acidosis is the most typical manifestation. The severity of intoxication cannot be assessed solely based on plasma salicylate concentration. Absorption of acetylsalicylic acid may be delayed due to delayed gastric emptying or formation of concretions in the stomach.

Due to complex pathophysiological effects, signs and symptoms of salicylate poisoning may include:

Mild to moderate intoxication – tachypnea, hyperpnea, respiratory alkalosis, sweating, nausea, and vomiting.

Moderate to severe intoxication – respiratory alkalosis accompanied by compensatory metabolic acidosis, hyperpyrexia. Respiratory system: hyperpnea, noncardiogenic pulmonary edema, respiratory failure, apnea, and asphyxia. Cardiovascular system: arrhythmias, hypotension, up to cardiac arrest. Dehydration, oliguria progressing to renal failure; disturbances in glucose metabolism, ketosis; gastrointestinal hemorrhage; hematological changes ranging from platelet inhibition to coagulopathies. Nervous system: toxic encephalopathy and CNS depression manifesting as drowsiness, depressed consciousness progressing to coma, and seizures.

Changes in laboratory and other parameters: alkalemia, alkaluria, acidemia, aciduria, changes in blood pressure, ECG abnormalities, hypokalemia, hypernatremia, hyponatremia, alterations in renal function, hyperglycemia, hypoglycemia (especially in children), elevated ketone bodies, hypoprothrombinemia.

Treatment.

In suspected salicylate poisoning, immediate hospitalization in a specialized unit is required. Treatment of intoxication caused by acetylsalicylic acid overdose depends on the severity and clinical symptoms and involves standard poisoning management (gastric lavage, activated charcoal administration, forced diuresis, symptomatic treatment, fluid replacement). All measures should aim to accelerate drug elimination and restore electrolyte and acid-base balance. Infusion of electrolyte solutions is administered depending on the acid-base status and electrolyte balance. Alkalinization of urine is performed to achieve a urine pH of 7.5–8. Forced alkaline diuresis is indicated when plasma salicylate concentration exceeds 500 mg/L (3.6 mmol/L) in adults or 300 mg/L (2.2 mmol/L) in children. Hemodialysis is indicated in severe intoxication.

Adverse Reactions

The list of adverse reactions provided below includes all known adverse reactions associated with the therapeutic use of acetylsalicylic acid, including those observed in patients with rheumatism treated with high doses over a prolonged period. Data on frequency, except for isolated cases, refer to short-term use of daily doses up to a maximum of 3 g of acetylsalicylic acid.

The following classification was used to define the frequency of adverse reactions:

Very common: ≥ 1/10
Common: ≥ 1/100 to < 1/10
Uncommon: ≥ 1/1,000 to < 1/100
Rare: ≥ 1/10,000 to < 1/1,000
Very rare: < 1/10,000
Frequency not known: cannot be estimated from the available data.

Gastrointestinal system disorders.
Common: dyspepsia, including epigastric pain and abdominal pain, heartburn, nausea, vomiting;
Rare: gastrointestinal inflammation, erosive-ulcerative lesions of the gastrointestinal tract, which in isolated cases may lead to gastrointestinal bleeding and perforation, with corresponding laboratory and clinical manifestations;
Frequency not known: diaphragm disease of the intestine (particularly with long-term treatment);
Very rare: transient hepatic insufficiency with elevated levels of liver transaminases.

Blood and lymphatic system disorders.
Due to its antiplatelet effect, acetylsalicylic acid may increase the risk of bleeding. Rarely observed bleeding includes perioperative bleeding, hematomas, urogenital bleeding, epistaxis, and gingival bleeding; rare or very rare serious bleeding events such as gastrointestinal hemorrhage and cerebral hemorrhage (especially in patients with uncontrolled arterial hypertension and/or concomitant use of antihemostatic agents), which in isolated cases may be life-threatening. The tendency to bleeding may persist for 4–8 days after administration of acetylsalicylic acid.

Very rarely, bleeding may lead to acute and chronic post-hemorrhagic anemia/iron-deficiency anemia (due to so-called occult microbleeding), with corresponding laboratory findings and clinical symptoms such as asthenia, pallor of the skin, hypoperfusion.

In patients with severe deficiency of glucose-6-phosphate dehydrogenase, hemolysis and development of hemolytic anemia have been reported.

Immune system disorders.
Rare: in patients with individual hypersensitivity to salicylates, allergic reactions may occur, including symptoms such as rhinitis, dyspnea, nasal congestion, and hypotension. Rarely, severe hypersensitivity reactions have been observed, including anaphylactic shock, angioedema, and non-cardiogenic pulmonary edema. In patients with bronchial asthma, increased frequency of bronchospasm and allergic reactions ranging from mild to moderate severity may occur, potentially affecting the skin, respiratory system, gastrointestinal tract, and cardiovascular system.

Skin and subcutaneous tissue disorders.
Uncommon: hypersensitivity reactions, including skin reactions (e.g., rash, urticaria, pruritus, eczema).
Rare: severe hypersensitivity reactions, such as erythema multiforme.

Nervous system disorders.
Headache, dizziness, hearing disturbances; tinnitus and confusion may be signs of overdose.

Renal and urinary system disorders.
Impaired renal function and development of acute renal failure have been reported.

Reporting of suspected adverse reactions.
Reporting suspected adverse reactions after product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions in accordance with applicable legal requirements.

Shelf life. 4 years.

Do not use after the expiry date stated on the packaging.

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

Packaging.
10 tablets in a blister; 10 tablets in a strip.
10 tablets in a blister, 2 blisters per carton.

Marketing authorization category. Over-the-counter (without prescription).

Manufacturer.

1. JSC "Kyivmedpreparat".
2. JSC "Halychpharm".

Manufacturer's address and place of business.

1. 139 Saksaganskogo Street, Kyiv, 01032, Ukraine.
2. 6/8 Opryshkovska Street, Lviv, 79024, Ukraine.