Acetylsalicylic acid

I N S T R U C T I O N for medical use of the medicinal product ACETYLSALICYLIC ACID (ACIDUM ACETYLSALICYLICUM)

Composition:

active substance: acetylsalicylic acid;

1 tablet contains 500 mg (0.5 g) of acetylsalicylic acid;

excipients: citric acid monohydrate; stearic acid; potato starch.

Pharmaceutical form. Tablets.

Main physicochemical properties: white tablets with a flat surface, bevelled edges, and a score line.

Pharmacotherapeutic group. Analgesics and antipyretics. Acetylsalicylic acid.

ATC code N02BA01.

Pharmacological properties.

Pharmacodynamics.

Acetylsalicylic acid belongs to the group of nonsteroidal anti-inflammatory drugs (NSAIDs) 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, acetylsalicylic acid is used to relieve pain and fever-associated conditions such as colds, to reduce temperature, and to alleviate joint and muscle pain.

Acetylsalicylic acid inhibits platelet aggregation by blocking thromboxane A2 synthesis.

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 sulfonic 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, 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 ligament pain, back pain).

Symptomatic treatment of fever and/or pain associated with common cold.

Contraindications.

Hypersensitivity to acetylsalicylic acid, other salicylates, or to any component of the medicinal product.

Bronchial asthma induced by salicylates or other NSAIDs, in medical history.

Acute gastrointestinal ulcers.

Hemorrhagic diathesis.

Severe renal insufficiency.

Severe hepatic insufficiency.

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").

Special precautions.

Acetylsalicylic acid should be used with caution in:

• hypersensitivity to analgesics, anti-inflammatory or antirheumatic agents, as well as in presence of 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, nasal polyps, or their combination 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.

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

When using low doses of acetylsalicylic acid, excretion of uric acid may be reduced. This may trigger gout attacks 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 administration, fever, or acute infections.

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

Frequent use of analgesics may cause temporary kidney dysfunction with 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.

Concomitant use of acetylsalicylic acid with methotrexate at doses less than 15 mg/week 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).

Simultaneous 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.

Concomitant use of acetylsalicylic acid with metamizole may reduce the clinically significant level of platelet aggregation.

When high doses of salicylates are used concomitantly with NSAIDs, the risk of ulceration and gastrointestinal bleeding increases due to synergistic effects.

Concomitant use of acetylsalicylic acid and anticoagulants increases the risk of bleeding.

Simultaneous 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 the latter increases due to reduced renal excretion.

When high doses of acetylsalicylic acid are used concomitantly with oral antidiabetic agents of the sulfonylurea group or insulin, the hypoglycemic effect of the latter is enhanced due to the hypoglycemic effect of acetylsalicylic acid and displacement of sulfonylureas from plasma protein binding.

Diuretics in combination 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, the blood level of salicylates decreases, increasing the risk of overdose after discontinuation of treatment, and the risk of gastrointestinal bleeding also increases.

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).

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.

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

Special precautions for use.

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 have adverse effects on pregnancy and/or embryonic/foetal development. Epidemiological data suggest a risk of miscarriage and congenital malformations following use of prostaglandin synthesis inhibitors in early pregnancy. The risk increases with increasing dose and duration of therapy. However, a causal relationship between acetylsalicylic acid use and increased risk of miscarriage has not been confirmed by available data.

Existing epidemiological data on the occurrence of congenital malformations are inconsistent, but an increased risk of gastroschisis cannot be ruled out with acetylsalicylic acid use. Results from a prospective study on early pregnancy exposure (1st to 4th month) involving approximately 14,800 mother-child pairs did not indicate any association with an increased risk of malformations.

Animal studies indicate reproductive toxicity.

During the first and second trimesters of pregnancy, acetylsalicylic acid-containing medicinal products should not be administered unless clearly necessary. In women who may become pregnant, or during the first and second trimesters of pregnancy, the dose of acetylsalicylic acid-containing products should be kept 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, potentially leading to renal failure with oligohydramnios.

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

• prolonged bleeding time, 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 upon discontinuation of treatment.

Breast-feeding.

Salicylates and their metabolites are excreted into breast milk in small amounts.

Since adverse reactions in infants breast-fed by mothers taking acetylsalicylic acid have not been observed, interruption of breast-feeding is generally not required. However, when the drug is used long-term or at high doses, a decision should be made whether to discontinue breast-feeding.

Ability to influence reaction speed when driving or operating machinery.

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

Dosage and Administration

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

Acetylsalicylic acid should not be used for more 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:

In patients with concomitant liver or kidney dysfunction, the dose should be reduced or the dosing interval prolonged.

Children:

The drug may be used in children aged 15 years and older.

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 when acetylsalicylic acid is used concomitantly; however, a causal relationship has not been definitively established. If such 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 drug overdose.

Chronic salicylate intoxication may have a covert presentation, as its symptoms are nonspecific. Moderate chronic intoxication (salicylism) caused by salicylates usually occurs only after repeated administration of high doses.

Symptoms: Dizziness, tinnitus, hearing loss, sweating, nausea and vomiting, headache, confusion. These symptoms can be managed 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, 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: from hyperpnea, non-cardiogenic pulmonary edema, to respiratory arrest and asphyxia. Cardiovascular system: from arrhythmias and hypotension to cardiac arrest. Dehydration, oliguria progressing to renal failure; disturbances in glucose metabolism, ketosis; gastrointestinal bleeding; hematological changes – from platelet inhibition to coagulopathies. Nervous system: toxic encephalopathy and CNS depression manifesting as drowsiness, impaired consciousness progressing to coma and seizures.

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

Treatment:

Management of intoxication caused by acetylsalicylic acid overdose depends on the severity and clinical symptoms, and involves standard procedures used in poisoning (gastric lavage, activated charcoal administration, forced diuresis). All measures should aim at accelerating drug elimination and restoring electrolyte and acid-base balance. Depending on the acid-base status and electrolyte balance, intravenous electrolyte solutions should be administered. Hemodialysis is indicated in severe cases of poisoning.

Side effects.

Gastrointestinal system. Dyspepsia, vomiting, nausea, diarrhea, epigastric and abdominal pain, heartburn; in individual cases – inflammation of the gastrointestinal tract, erosive-ulcerative lesions of the gastrointestinal tract, which may in rare instances lead to gastrointestinal bleeding and perforations, with corresponding laboratory and clinical manifestations.

Rarely – transient hepatic insufficiency with increased levels of liver transaminases.

Blood and lymphatic system. Due to the antiplatelet effect of acetylsalicylic acid, the risk of bleeding may be increased. Bleeding events observed include perioperative bleeding, hematomas, urogenital bleeding, epistaxis, and gingival bleeding; rarely or very rarely – serious bleeding such as gastrointestinal bleeding and cerebral hemorrhage (particularly in patients with uncontrolled arterial hypertension and/or concomitant use of antihemostatic agents), which in isolated cases may be life-threatening.

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, and hypoperfusion.

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

Immune system. In patients with individual hypersensitivity to salicylates, allergic reactions may occur, including symptoms such as toxicoderma, rash, urticaria, edema, pruritus, eczema, rhinitis, nasal congestion, and hypotension. Very rarely, severe hypersensitivity reactions have been observed, including anaphylactic shock, angioneurotic edema, and non-cardiogenic pulmonary edema. In patients with bronchial asthma, an increased frequency of bronchospasm may occur; allergic reactions ranging from mild to moderate severity potentially affecting the skin, respiratory system, gastrointestinal tract, and cardiovascular system.

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

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

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 in a strip; 1 strip in a paper envelope;

10 tablets in a strip; 2 or 10 strips in a cardboard pack;

10 tablets in a blister; 1, 2, 5, or 10 blisters in a cardboard pack;

10 tablets in blisters or strips.

Availability.

Over-the-counter.

Manufacturer: JSC "Monfarm".

Manufacturer's address and location of business operations.

8, Zavodska St., Avramivka village, Uman district, Cherkasy region, 19161, Ukraine.