Aspirin®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ASPİRİN® (ASPIRIN®)

Composition:

Active substance: acetylsalicylic acid;

1 tablet contains 500 mg of acetylsalicylic acid;

Excipients: powdered cellulose, corn starch.

Pharmaceutical form. Tablets.

Main physicochemical properties: white, round tablets with an engraving of the "Bayer cross" on one side and the inscription "ASPIRIN 0.5" on the other.

Pharmacotherapeutic group. Nervous system. Analgesics. Other analgesics and antipyretics. Salicylic acid and derivatives. Acetylsalicylic acid.

ATC code N02BA01.

Pharmacological properties.

Pharmacodynamics.

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

Orally, in doses of 0.3 g to 1 g, acetylsalicylic acid is used to relieve pain and fever-associated conditions such as colds, to reduce fever 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 the 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 gentisuric acid.

The elimination kinetics of salicylic acid are dose-dependent, as metabolism is limited by hepatic enzyme activity. The elimination half-life depends on the dose and increases from 2–3 hours with low-dose administration to 15 hours with high-dose administration. 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 ligament pain, back pain).
• Symptomatic treatment of fever and/or pain associated with common colds.

Contraindications.

• Hypersensitivity to acetylsalicylic acid, other salicylates, or any component of the drug.
• Bronchial asthma induced by salicylates or other NSAIDs in medical history.
• Acute gastrointestinal ulcers.
• Hemorrhagic diathesis.
• Severe renal impairment.
• Severe hepatic impairment.
• Severe heart failure.
• Combination 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.

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 diseases may reduce the cardioprotective effect of acetylsalicylic acid.

The simultaneous use of high-dose salicylates with NSAIDs increases the risk of gastrointestinal ulcers and bleeding due to a mutually enhancing effect.

When the medicinal product Aspirin® 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 uric acid excretion (due to competition for renal tubular secretion of uric acid).

When used concomitantly with digoxin, digoxin plasma concentrations increase due to reduced renal excretion.

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

Diuretics, when combined with high doses of acetylsalicylic acid, reduce glomerular filtration due to decreased renal prostaglandin synthesis.

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

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

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

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

Ethanol promotes damage to the gastrointestinal mucosa and prolongs bleeding time due to the synergistic effect of acetylsalicylic acid and alcohol.

Special precautions for use.

Aspirin® should be used with caution in:

• hypersensitivity to analgesics, anti-inflammatory, or antirheumatic agents, as well as in the presence of allergy to other substances;
• history of gastrointestinal ulcers, including chronic or recurrent peptic ulcer disease or gastrointestinal bleeding;
• concomitant use of anticoagulants;
• impaired kidney function 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;
• impaired liver function.

In patients with allergic complications, including bronchial asthma, allergic rhinitis, urticaria, skin itching, mucosal swelling, nasal polyps, as well as their combination with chronic respiratory tract infections, and in patients with hypersensitivity to NSAIDs, treatment with Aspirin® may lead to the development of 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 an attack of gout in patients with reduced 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 medication, fever, or acute infections.

Long-term use of analgesics may lead to the development of headaches.

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

Use during pregnancy or breastfeeding.

Pregnancy.

Aspirin® 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/fetal development. Epidemiological data indicate a risk of miscarriage and congenital malformations following the use of prostaglandin synthesis inhibitors during early pregnancy. The risk increases with higher doses and longer duration of treatment.

Epidemiological data on the occurrence of birth defects are inconsistent; however, an increased risk of gastroschisis cannot be excluded 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 prescribed 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 fetus as follows:

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

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

• potential prolongation of bleeding time, anti-aggregatory effect, which may occur even after very low doses;
• inhibition of uterine contractions, which may lead to delayed or prolonged labor.

Therefore, acetylsalicylic acid is contraindicated during the third trimester of pregnancy.

Fertility.

There is some evidence that medicinal products inhibiting prostaglandin synthesis may impair female reproductive function 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 a short period have not been observed, breastfeeding interruption is generally not required. However, prolonged use of acetylsalicylic acid at high doses necessitates discontinuation of breastfeeding.

Ability to influence reaction speed when driving or operating machinery.

No effects on the ability to drive vehicles or operate machinery have been reported.

Method of Administration and Dosage

Aspirin® is taken orally after meals, with sufficient fluid (e.g., a glass of water). Patients with impaired swallowing may dissolve the tablets in a spoonful of water.

Aspirin® must not be used for longer than 4 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 must not exceed 3 g (6 tablets).

Warning.

Dosage reduction or prolonged dosing intervals are required for patients with concomitant hepatic or renal impairment. This medicinal product should not be administered on an empty stomach.

Children.

This product is indicated for children aged 15 years and older.

Acetylsalicylic acid-containing products should not be used in children with acute viral respiratory infections (AVRI), whether accompanied by fever or not, without prior medical consultation. In certain viral diseases—particularly influenza A, influenza B, and varicella—there is a risk of Reye’s syndrome, a very rare but life-threatening condition requiring immediate medical intervention. The risk may increase if acetylsalicylic acid is used concomitantly; however, a causal relationship has not been definitively established. Persistent vomiting in such cases may be a sign of Reye’s syndrome.

Overdose.

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

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

Symptoms: Dizziness, tinnitus, hearing loss, sweating, nausea and vomiting, headache, confusion. These symptoms may be managed by reducing the dose. Tinnitus may occur at plasma salicylate concentrations above 150–300 mcg/mL. More severe adverse reactions occur at plasma 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, formation of gastric concretions, or when the drug is administered in enteric-coated tablet form.

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, non-cardiogenic 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, coma, and seizures.

Laboratory and other test abnormalities: alkalemia, alkaluria, acidemia, aciduria, changes in blood pressure, ECG changes, hypokalemia, hypernatremia, hyponatremia, impaired renal function, hyperglycemia, hypoglycemia (particularly in children), elevated ketone bodies, hypoprothrombinemia.

Treatment.

In suspected salicylate poisoning, immediate hospitalization in a specialized unit is required. Management of intoxication due to acetylsalicylic acid overdose depends on severity and clinical symptoms and includes standard detoxification procedures (gastric lavage, activated charcoal, forced diuresis, symptomatic treatment, fluid replacement). All interventions should aim to accelerate drug elimination and restore electrolyte and acid-base balance. Infusion of electrolyte solutions should be administered according to the patient’s acid-base and electrolyte status. 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 cases of severe intoxication.

Side effects

The list of side effects 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 gastrointestinal lesions, 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 and lymphatic system disorders.
Due to its antiplatelet effect, acetylsalicylic acid may increase the risk of bleeding. Rarely observed bleeding events include 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 anticoagulant agents), which in isolated cases may be life-threatening. The tendency to bleed 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, 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 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.

Shelf life. 4 years.

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

Storage conditions.
Store at temperatures not exceeding 30 °C in a place inaccessible to children.

Incompatibility.
The use of 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).

Packaging.
10 tablets in a blister; 1, 2, or 10 blisters in a cardboard box.

Prescription status. Over-the-counter.

Manufacturer.
Bayer Bitterfeld GmbH.

Name and address of manufacturer.
Ortsteil Greppin, Salegaster Chaussee 1, 06803 Bitterfeld-Wolfen, Germany.