Acetylsalicylic acid-darnitsa

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ACETYLSALICYLIC ACID-DARNITSA (ACETYLSALICYLIC ACID-DARNITSA)

Composition:

active substance: acetylsalicylic acid;

1 tablet contains 500 mg of acetylsalicylic acid;

excipients: citric acid monohydrate, potato starch.

Pharmaceutical form. Tablets.

Main physico-chemical properties: white, round, biconvex tablets with bevelled edges.

Pharmacotherapeutic group. Analgesics and antipyretics.

Acetylsalicylic acid. ATC code N02BA01.

Pharmacological Properties.

Pharmacodynamics.

Acetylsalicylic acid is a non-steroidal anti-inflammatory drug (NSAID), a derivative of salicylate. The main mechanism of action of acetylsalicylic acid is inactivation of the enzyme COX (cyclooxygenase), resulting in reduced production of inflammatory mediators: prostaglandins, prostacyclins, and thromboxane. Decreased synthesis of prostaglandins leads to diminished influence on thermoregulatory centers, thereby reducing temperature elevated due to inflammation. It reduces the sensitizing effect of prostaglandins on pain-sensitive nerve endings, thereby decreasing their sensitivity to pain mediators. Irreversible inhibition of thromboxane A2 synthesis in platelets underlies the antiplatelet (antiaggregant) effect of acetylsalicylic acid.

The pharmacodynamics of acetylsalicylic acid depend on the daily dose:

• Low doses – 30−325 mg – cause inhibition of platelet aggregation;
• Medium doses – 1.5−2 g – exert analgesic and antipyretic effects;
• High doses – 4 g – exert anti-inflammatory effects.

At doses below 4 g, acetylsalicylic acid reduces the excretion of uric acid.

Pharmacokinetics.

After oral administration, acetylsalicylic acid is almost completely absorbed from the gastrointestinal tract (GI tract). Time to reach maximum plasma concentration (Tmax) is 10−20 minutes. Tmax of total salicylate formed as a result of metabolism ranges from 0.3 to 2 hours. Plasma protein binding ranges from 49% to 70%. Approximately 50% undergoes first-pass metabolism in the liver. Salicylic acid is metabolized to form glycine conjugates. It is excreted by the kidneys as metabolites. Elimination half-life (T1/2) is 20 minutes. The T1/2 of salicylic acid is approximately 2 hours. Acetylsalicylic acid penetrates into breast milk, synovial fluid, and cerebrospinal fluid.

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 colds.

Contraindications.

• Hypersensitivity to acetylsalicylic acid, other salicylates, or any excipient of the medicinal product.
• 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.
• Concomitant use with methotrexate at doses of 15 mg per week or higher (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Contraindications for concomitant use.

The use of acetylsalicylic acid and methotrexate at doses of 15 mg/week or higher increases hematological toxicity (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, 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 acetylsalicylic acid and 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/other platelet aggregation inhibitors/hemostatic agents increases the risk of bleeding.

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

Concomitant use of acetylsalicylic acid with selective serotonin reuptake inhibitors (SSRIs) increases the risk of gastrointestinal bleeding due to possible synergistic effects.

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

Concomitant use of high-dose acetylsalicylic acid with antidiabetic agents of the sulfonylurea group or insulin enhances the hypoglycemic effect of the latter due to displacement of protein-bound sulfonylureas by acetylsalicylic acid.

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

Systemic glucocorticosteroids (including hydrocortisone used as replacement therapy in Addison's disease) reduce blood salicylate levels and increase the risk of overdose after discontinuation of treatment, as well as increase the risk of gastrointestinal bleeding.

Angiotensin-converting enzyme (ACE) inhibitors in combination with high doses of acetylsalicylic acid cause reduced glomerular filtration due to inhibition of the vasodilatory effect of prostaglandins and reduced antihypertensive effect.

Concomitant use with valproic acid: acetylsalicylic acid displaces valproic acid from plasma protein binding, increasing its toxicity.

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

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

Special precautions for use.

Acetylsalicylic acid-Darnytsia should be used with special caution in the following cases:

• individual hypersensitivity to analgesic, anti-inflammatory, and antirheumatic agents, as well as presence of other types of allergies;
• history of gastrointestinal ulcers, as well as chronic or recurrent peptic ulcer disease or gastrointestinal bleeding;
• concomitant therapy with anticoagulants;
• impaired liver function.

The drug should also be used cautiously in patients with renal function impairment or those with circulatory disorders (e.g., renal vascular pathology, congestive heart failure, hypovolemia, major surgery, sepsis, or significant blood loss), since acetylsalicylic acid may increase the risk of renal function impairment and acute renal failure. In patients with severe glucose-6-phosphate dehydrogenase deficiency, acetylsalicylic acid may cause hemolysis or hemolytic anemia, especially in the presence of factors that may increase the risk of hemolysis, such as high drug doses, fever, or acute infectious processes.

In patients with allergic complications, including bronchial asthma, allergic rhinitis, urticaria, skin pruritus, mucosal edema, and nasal polyps, as well as in combination with chronic respiratory tract infections, and in patients with hypersensitivity to NSAIDs, administration of the drug may lead to the development of bronchospasm, asthma attack, or other hypersensitivity reactions.

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

In low doses, acetylsalicylic acid may reduce the excretion of uric acid. This may lead to the development of gout in patients with reduced uric acid excretion.

If used prior to starting ibuprofen as an analgesic, the patient should consult a physician.

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

Frequent use of analgesics may cause temporary impairment of kidney function with a risk of developing renal failure (analgesic nephropathy). The risk is higher when several different analgesics are used simultaneously.

Use during pregnancy or breastfeeding.

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 in early pregnancy. The risk increases with increasing dose and duration of therapy. Epidemiological data do not confirm an association between acetylsalicylic acid use and an increased risk of miscarriage. Data regarding congenital malformations are inconsistent; however, an increased risk of gastroschisis cannot be ruled out with drug use. Results of a prospective study on early pregnancy exposure (1st–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, drugs containing acetylsalicylic acid should not be prescribed without clear clinical necessity. In women who may be pregnant, or in pregnant women during the first and second trimesters, the dose of drugs containing acetylsalicylic acid should be as low as possible and the duration of treatment as short as possible.

During the third trimester of pregnancy, salicylates may affect the fetus as follows:

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

Salicylates may affect the mother and child at the end of pregnancy as follows:

• possible 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.

Use of acetylsalicylic acid in high doses shortly before delivery may lead to intracranial hemorrhage, especially in premature infants.

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

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

Since no harmful effects of the drug on the infant have been demonstrated after administration to women during lactation, breastfeeding need not be interrupted. However, in cases of regular use or use of high doses, breastfeeding should be discontinued at an early stage.

Ability to affect reaction rate while driving or operating machinery.

No effect on the ability to drive or operate machinery has been observed.

Dosage and Administration

The medicinal product should be taken orally after meals, with sufficient fluid. It should not be used for longer than 3–5 days without consulting a physician.

Adults and children aged 15 years and older

500–1000 mg as a single dose. Repeated administration may be performed every 4–8 hours. The maximum daily dose should not exceed 4 g.

Warning

For patients with concomitant hepatic or renal impairment, the dose should be reduced or the interval between doses increased.

Children

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

Acetylsalicylic acid-containing drugs should not be used in children with acute respiratory viral infections (ARVI), regardless of the presence or absence of fever. In certain viral diseases, particularly influenza A, influenza B, and varicella (chickenpox), there is a risk of Reye's syndrome—a very rare but life-threatening condition requiring immediate medical intervention. The risk may be increased if acetylsalicylic acid is administered 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 due to chronic intoxication resulting from prolonged therapy (administration of more than 100 mg/kg/day for over 2 days may cause toxic effects), or due to acute intoxication, which may be potentially life-threatening (overdose). Causes may include accidental ingestion by children or unintentional overdose.

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

Symptoms: impaired balance, dizziness, tinnitus, hearing loss, excessive sweating, tachypnea, nausea, vomiting, headache, confusion. These symptoms may be managed by reducing the dose. Tinnitus may occur at plasma concentrations of 150 to 300 µg/mL. More serious adverse reactions occur at concentrations exceeding 300 µg/mL.

Acute intoxication is characterized by significant 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 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 use of enteric-coated formulations.

Moderate to severe intoxication manifests as respiratory alkalosis accompanied by compensatory metabolic acidosis and hyperpyrexia. Respiratory system effects range from tachypnea and non-cardiogenic pulmonary edema to respiratory arrest and asphyxia. Cardiovascular effects range from arrhythmias and arterial hypotension to cardiac arrest. Dehydration, oliguria progressing to renal failure, disturbances in glucose metabolism, and ketosis may also occur. Gastrointestinal bleeding, hematological changes—from thrombocytopenia to coagulopathies—are observed. Neurologically, toxic encephalopathy and CNS depression may develop, presenting as drowsiness, depressed 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 abnormalities, hyperglycemia, hypoglycemia (especially in children), elevated ketone bodies, hypoprothrombinemia.

Treatment of intoxication caused by acetylsalicylic acid overdose depends on the severity and clinical symptoms and is based on standard management protocols for poisoning. All interventions should aim to accelerate drug elimination and restore electrolyte and acid-base balance. Administer activated charcoal, perform forced alkaline diuresis, and gastric lavage. Infusion of electrolyte solutions should be performed according to the patient's acid-base and electrolyte status. Hemodialysis is indicated in severe cases.

Manifestations, symptoms, and laboratory findings resulting from the complex pathophysiological effects of salicylate poisoning, and the necessary therapeutic measures:

Side effects.

From the auditory and vestibular system: tinnitus, hearing loss.

From the respiratory system, thoracic organs, and mediastinum: rhinitis, asthma, triad (eosinophilic rhinitis, recurrent nasal polyposis, hypertrophic sinusitis), non-cardiogenic pulmonary edema.

From the gastrointestinal tract: dyspepsia, heartburn, vomiting, nausea, epigastric pain, diarrhea, ulcerogenic effect, erosive and ulcerative lesions of the gastric and duodenal mucosa, gastrointestinal bleeding and gastrointestinal perforations with corresponding clinical symptoms and laboratory changes (microhemorrhages, melena).

From the liver and biliary system: liver function disorders, hepatogenic encephalopathy, transient liver failure with elevated liver transaminase levels.

From the kidneys and urinary system: renal damage and acute kidney injury have been reported.

From the metabolism and nutritional system: hypoglycemia.

From the nervous system: dizziness, tinnitus, headache, loss of consciousness, seizures, collapse, aseptic meningitis.

From the blood and lymphatic system: thrombocytopenia, anemia, leukopenia, eosinophilia, hemorrhagic syndrome, hypoprothrombinemia.

Due to the antiplatelet effect of acetylsalicylic acid, the risk of bleeding may be increased. Bleeding events observed include intraoperative hemorrhages, hematomas, bleeding from the genitourinary organs, epistaxis, gingival bleeding; rarely or very rarely – serious bleeding such as gastrointestinal bleeding and cerebral hemorrhage (especially in patients with uncontrolled arterial hypertension and/or concomitant use of antihemostatic agents), which in isolated cases could potentially 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, hypoperfusion.

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

From the immune system: hypersensitivity reactions, including urticaria and skin rashes, pruritus, angioneurotic edema, anaphylactic shock, hypotension, nasal congestion, asthma, bronchospasm; in patients with bronchial asthma, increased frequency and severity of attacks; toxic epidermal necrolysis; allergic reactions ranging from mild to moderate severity, potentially affecting the skin, respiratory system, gastrointestinal tract, and cardiovascular system.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after drug registration is an important procedure. It enables continuous monitoring of the benefit-risk balance for the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Shelf life. 4 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

10 tablets in a blister pack; 1, 2, or 5 blisters per carton; 10 tablets in blister packs.

Dispensing category.

Without prescription – packages of 10 and 20 tablets.

By prescription only – package of 50 tablets.

Manufacturer. JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and location of operations.

13, Boryspilska Street, Kyiv, 02093, Ukraine.