Acetylsalicylic acid

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ACETYLSALICYLIC ACID

Composition:

Active ingredient: 1 tablet contains 500 mg of acetylsalicylic acid;

Excipients: potato starch; talc; citric acid, monohydrate.

Pharmaceutical form. Tablets.

Main physico-chemical properties: intact, regular round cylinders, with flat upper and lower surfaces and beveled edges, with a score line, white in color. Marbling on the tablet surface is permissible.

Pharmacotherapeutic group.

Analgesics and antipyretics. ATC code N02B A01.

Pharmacological properties.

Pharmacodynamics.

Acetylsalicylic acid belongs to the group of nonsteroidal anti-inflammatory drugs with analgesic, antipyretic, and anti-inflammatory properties. Its mechanism of action involves irreversible inactivation of cyclooxygenase enzymes, which play an important role in the synthesis of prostaglandins.

When administered orally in doses of 0.3 g to 1 g, the drug is used to relieve pain and conditions associated with mild fever, such as cold and flu, as well as to reduce body temperature and alleviate joint and muscle pain.

Acetylsalicylic acid is also indicated for use in acute and chronic inflammatory diseases, such as rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. In such conditions, higher doses of the drug are typically used – from 4 g to 8 g of acetylsalicylic acid per day.

Acetylsalicylic acid inhibits platelet aggregation by blocking the synthesis of thromboxane A2, and is used in various vascular diseases at doses of 75–300 mg per day.

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, respectively.

Both acetylsalicylic and salicylic acids 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 undergoes hepatic metabolism.

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

Clinical characteristics.

Indications.

For symptomatic treatment of headache, toothache; sore throat due to colds; algodysmenorrhea; muscle and joint pain; back pain; moderate pain associated with arthritis.

For colds or acute respiratory infections, for symptomatic relief of pain and fever.

Contraindications.

Hypersensitivity to acetylsalicylic acid, other salicylates, or any component of the medicinal product. Bronchial asthma induced by salicylates or other nonsteroidal anti-inflammatory drugs (NSAIDs) in medical history. Acute gastrointestinal ulcers. Haemorrhagic diathesis. Severe renal impairment. Severe hepatic impairment. Severe heart failure. Combination with methotrexate at doses of 15 mg per week or more (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 allergy to other substances;
• history of gastrointestinal ulcers, including chronic or recurrent peptic ulcer or gastrointestinal bleeding;
• concomitant use of anticoagulants;
• renal function impairment or circulatory disorders (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;
• hepatic function impairment.

In patients with allergic complications, including bronchial asthma, allergic rhinitis, urticaria, skin pruritus, mucosal edema, and nasal polyps, especially when combined with chronic respiratory tract infections, and in patients with hypersensitivity to NSAIDs, treatment with acetylsalicylic acid may lead to bronchospasm, asthma attack, or other hypersensitivity reactions.

During surgical procedures (including dental surgery), the use of products containing acetylsalicylic acid may increase the likelihood of occurrence or intensification of bleeding due to inhibition of platelet aggregation for some time after administration of acetylsalicylic acid.

When low doses of acetylsalicylic acid are used, excretion of uric acid may be reduced. This may lead to the development of gout in patients with impaired uric acid excretion.

Administration of the medicinal product to children under 15 years of age as an antipyretic may promote the development of Reye's syndrome.

With prolonged use, to detect ulcerogenic effects, feces should be periodically tested for occult blood and blood tests performed (once every 2 weeks). The medicinal product should be discontinued 5–7 days before surgery.

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 administration, fever, or acute infections.

Caution should be exercised when prescribing the medicinal product to patients taking hypoglycemic agents (regular monitoring of blood glucose levels is required), glucocorticoids, antihypertensive agents, diuretics (adequate hydration and monitoring of renal function are necessary), non-absorbable antacids containing magnesium hydroxide and/or aluminum hydroxide (these may be administered no earlier than 2 hours after the medicinal product).

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

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

This medicinal product should be used with caution in patients with congestive heart failure and history of edema, as well as in arterial hypertension, eclampsia, and hyperaldosteronism, because it contains citric acid monohydrate.

Interaction with other medicinal products and other forms of interaction.

Contraindicated combinations.

The use of methotrexate at doses of 15 mg per week or more 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 methotrexate is used at doses less than 15 mg per week, the hematological toxicity of methotrexate increases (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 acetylsalicylic acid with anticoagulants, thrombolytics, and platelet aggregation inhibitors (e.g., ticlopidine, clopidogrel) increases the risk of bleeding. Therefore, in patients requiring thrombolytic therapy, symptoms of external or internal bleeding should be monitored.

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

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

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

Concomitant use of high doses of acetylsalicylic acid with oral antidiabetic agents of the sulfonylurea group or with 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 synthesis of renal prostaglandins.

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

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

Selective serotonin reuptake inhibitors (SSRIs): increased risk of upper gastrointestinal bleeding due to possible synergistic effect.

Concomitant use with valproic acid causes acetylsalicylic acid to displace valproic acid from plasma protein binding, increasing its toxicity.

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

Concomitant use of acetylsalicylic acid with metamizole may clinically significantly reduce platelet aggregation levels.

Citric acid interactions: citrate salts increase gastrointestinal absorption of aluminum, especially in patients with impaired renal function.

Acetazolamide. In combination with high doses of acetylsalicylic acid, the frequency of adverse effects increases, particularly metabolic acidosis, due to reduced elimination of acetylsalicylic acid caused by interaction with acetazolamide.

Anagrelide. Increased risk of bleeding.

Pemetrexed. In patients with normal renal function, there is a risk of increased pemetrexed toxicity due to reduced renal clearance.

Deferasirox. In combination with anti-inflammatory, analgesic, or antipyretic doses of acetylsalicylic acid, the risk of gastric ulcer and gastrointestinal bleeding increases.

Intrauterine devices. Risk of reduced contraceptive efficacy.

Locally acting gastrointestinal agents, antacids, and activated charcoal. Reduced gastrointestinal absorption of acetylsalicylic acid. It is recommended to take these products separately from acetylsalicylic acid with an interval of at least 2 hours.

Special precautions for use.

Use during pregnancy or breastfeeding.

Pregnancy.

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

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of miscarriage and congenital malformations following the use of prostaglandin synthesis inhibitors during early pregnancy. The risk increases with higher doses and prolonged duration of treatment.

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

Animal studies indicate reproductive toxicity.

During the first and second trimesters of pregnancy, acetylsalicylic acid-containing medicinal products should not be administered except in cases of exceptional medical necessity. If acetylsalicylic acid-containing products are used in women planning pregnancy or during the first and second trimesters of pregnancy, doses should be kept as low as possible and treatment duration as short as possible.

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

• Cardio-pulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
• Impaired renal function, potentially leading to renal failure associated with oligohydramnios.

Towards the end of pregnancy, prostaglandin synthesis inhibitors may affect both the mother and the fetus as follows:

• Prolonged bleeding time due to antiplatelet effect, which may occur even after very low doses;
• Inhibition of uterine contractions, potentially leading to delayed or prolonged labor.

Therefore, 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.

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, interruption of breastfeeding is generally not required. However, with long-term use of the drug or administration of high doses of acetylsalicylic acid, a decision should be made whether to discontinue breastfeeding.

Ability to influence reaction rate when 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 should be taken orally after meals, with sufficient fluid.

Acetylsalicylic acid must not be used for longer than 4 days without consulting a physician.

Adults and children aged 15 years and older.

Single dose — 500–1000 mg (1–2 tablets). Repeat dosing may be administered every 4–8 hours. The maximum daily dose must not exceed 3 g (6 tablets).

Warning.

For patients with concomitant liver or kidney dysfunction, the dose should be reduced or the interval between doses increased. This medicinal product should not be used on an empty stomach.

Children.

This medication is not recommended for children under 15 years of age. Medicinal products containing acetylsalicylic acid should not be used in children with acute viral respiratory infections (AVRI), whether or not accompanied by fever, without prior medical consultation. In certain viral diseases, particularly influenza A, influenza 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 if acetylsalicylic acid is used concomitantly; 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 overdose may occur either through chronic intoxication resulting from prolonged therapy (administration of more than 100 mg/kg/day for over 2 days may cause toxic effects), or acute intoxication, which is life-threatening (overdose), potentially caused, for example, by accidental ingestion in children or unintentional overdose.

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

Symptoms: impaired balance, dizziness, tinnitus, hearing loss, sweating, reversible visual disturbances, nausea and vomiting, headache, confusion, disturbances in blood rheological properties and coagulation. In cases of significant overdose — disorientation, drowsiness, collapse, tremor, dyspnea, hyperventilation, hyperthermia, dehydration, coma, metabolic acidosis, respiratory alkalosis, and disturbances in carbohydrate metabolism.

These symptoms may be controlled by dose reduction. Tinnitus may occur at plasma salicylate concentrations exceeding 150–300 µg/mL. More serious adverse reactions occur at plasma salicylate concentrations above 300 µg/mL.

Acute intoxication is indicated by marked disturbances in acid-base balance, which may vary depending on age and severity of intoxication. The most common sign in children is metabolic acidosis. The severity of the condition cannot be assessed solely based on plasma salicylate concentration. Absorption of acetylsalicylic acid may be delayed due to delayed gastric emptying, formation of gastric concretions, or administration of enteric-coated tablets.

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

• mild to moderate intoxication — tachypnea, hyperpnea, respiratory alkalosis, increased sweating, nausea, and vomiting;
• moderate to severe intoxication — respiratory alkalosis accompanied by compensatory metabolic acidosis, hyperpyrexia. Respiratory system: from hyperpnea and non-cardiogenic pulmonary edema to respiratory arrest and asphyxia. Cardiovascular system: from arrhythmia and arterial hypotension to cardiac arrest. Dehydration, oliguria progressing to renal failure, disturbances in glucose metabolism, ketosis, gastrointestinal bleeding, and hematological changes — from platelet inhibition to coagulopathies. Nervous system: toxic encephalopathy and CNS depression, manifesting as drowsiness, decreased 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, impaired 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 severity and clinical symptoms and involves standard measures used in poisoning management (gastric lavage, activated charcoal administration, forced diuresis, symptomatic treatment, fluid replacement). All interventions should aim to accelerate drug elimination and restore electrolyte and acid-base balance. Alkalinization of urine is performed to achieve a urinary 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 cases of intoxication.

Side effects

The list of side effects provided below includes all known adverse reactions reported to date during therapeutic use of acetylsalicylic acid. It also includes reactions observed in patients with rheumatism who received the drug in high doses over a prolonged period. Except for isolated cases, data on frequency refer to short-term use of acetylsalicylic acid at daily doses not exceeding 3 g.

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

very common: ≥ 1/10;
common: from ≥ 1/100 to < 1/10;
uncommon: from ≥ 1/1,000 to < 1/100;
rare: from ≥ 1/10,000 to < 1/1,000;
very rare: < 1/10,000;
frequency not known: cannot be estimated based on available data.

Gastrointestinal system: common — dyspepsia, epigastric pain, abdominal pain, heartburn, nausea, vomiting; rare — inflammation of the gastrointestinal tract, erosive and 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 — diaphragmatic intestinal disease (especially with long-term treatment); very rare — transient hepatic insufficiency with elevated liver transaminase levels.

Blood system: due to its antiplatelet effect, acetylsalicylic acid may increase the risk of bleeding. Rarely observed bleeding events include intraoperative hemorrhages, hematomas, bleeding from the genitourinary organs, nosebleeds, and gingival bleeding; rare or very rare — serious bleeding events such as gastrointestinal bleeding and cerebral hemorrhage (especially in patients with uncontrolled arterial hypertension and/or concomitant use of anticoagulant agents), which in isolated cases could potentially 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, thrombocytopenia, leukopenia, and Reye's syndrome (due to so-called occult microbleeding), with corresponding laboratory findings and clinical symptoms such as asthenia, pallor of the skin, and hypoperfusion.

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

Immune system: rare — in patients with individual hypersensitivity to salicylates, allergic reactions may occur, including symptoms such as rhinitis, dyspnea, nasal congestion, and decreased blood pressure. Rarely, severe hypersensitivity reactions have been observed, including anaphylactic shock, angioneurotic edema, 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: uncommon — hypersensitivity reactions, including skin reactions (e.g., rash, urticaria, pruritus, eczema); rare — severe hypersensitivity reactions, such as erythema multiforme.

Nervous system: headache, confusion, dizziness, tinnitus, and hearing loss, which may indicate overdose.

Urinary system: renal function impairment and development of acute renal failure have been reported.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug registration is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

4 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 pack.

10 tablets per blister; 1, 5, or 10 blisters per carton.

Prescription status.

Over-the-counter — № 10.

By prescription — № 50, № 100.

Manufacturer

JSC "Lubnipharm".

Manufacturer's address and location of manufacturing operations.

16 Barvinkova St., Lubny, Poltava region, 37500, Ukraine.