Citramon-forte

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CITRAMON-FORTE (Citramonum-forte)

Composition:

Active substances: 1 tablet contains acetylsalicylic acid 320 mg, paracetamol 240 mg, caffeine (calculated as dry substance) 40 mg;

Excipients: cocoa; citric acid monohydrate; povidone; sodium croscarmellose; talc; calcium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical characteristics: intact, regular, round cylindrical tablets with flat upper and lower surfaces, beveled edges, a dividing line on one side, light brown in color with specks, with a cocoa odor.

Pharmacotherapeutic group.

Analgesics and antipyretics. Acetylsalicylic acid, combinations without psychotropic agents.

ATC code N02B A51.

Pharmacological properties.

Pharmacodynamics.

A combined agent whose action is determined by the properties of its constituent components.

Acetylsalicylic acid exerts antipyretic and anti-inflammatory effects, relieves pain, especially that caused by inflammatory processes, and also moderately inhibits platelet aggregation and thrombosis, improving microcirculation at the site of inflammation.

Paracetamol exerts analgesic, antipyretic, and weak anti-inflammatory effects, which are related to its influence on the thermoregulatory center in the hypothalamus and its weak ability to inhibit prostaglandin synthesis in peripheral tissues.

Caffeine increases reflex excitability of the spinal cord, stimulates the respiratory and vasomotor centers, dilates blood vessels in skeletal muscles, brain, heart, and kidneys, reduces platelet aggregation, reduces drowsiness and fatigue, and enhances mental and physical performance. In this combination, caffeine in a low dose exerts almost no stimulatory effect on the central nervous system, but promotes normalization of cerebral vascular tone and accelerates blood flow.

The combination of acetylsalicylic acid and paracetamol potentiates the analgesic effect of the drug. Both the analgesic and antipyretic effects of acetylsalicylic acid and paracetamol are enhanced when administered concurrently with caffeine.

Pharmacokinetics.

Acetylsalicylic acid is rapidly absorbed after oral administration; sufficient blood concentration is observed within 30 minutes, and maximum concentration within 2 hours. A portion of the drug is absorbed in the stomach, but the majority is absorbed in the small intestine.

Paracetamol is well absorbed in the upper gastrointestinal tract and metabolized in the liver. It penetrates the blood-brain barrier, enters cerebrospinal fluid, synovial fluid, and passes into breast milk. Maximum therapeutic effect is achieved within 30–60 minutes after administration. Maximum plasma concentration is reached within 2–2.5 hours. The elimination half-life is 2–4 hours. In healthy volunteers, the drug is excreted from the body via urine within 4–4.5 hours; in patients with impaired renal function, excretion takes 8–12 hours.

Caffeine increases gastric secretion. The mechanism of action of caffeine is mediated by inhibition of the enzyme phosphodiesterase, leading to intracellular accumulation of cyclic adenosine monophosphate. Cyclic adenosine monophosphate stimulates metabolism in organs and tissues, including muscles and the central nervous system.

The components of the drug and their metabolites are excreted from the body via the kidneys.

Clinical characteristics.

Indications.

Mild to moderate pain: headache or toothache, pain associated with primary dysmenorrhea; migraine, arthralgia, myalgia, neuralgia, particularly inflammatory conditions (e.g., frontal sinusitis, maxillary sinusitis), rheumatic diseases, and conditions accompanied by hyperthermia of various etiologies (as an antipyretic agent).

Contraindications.

Hypersensitivity to the components of the drug or to other nonsteroidal anti-inflammatory drugs (NSAIDs).

Active peptic ulcers of the stomach or duodenum, history of gastrointestinal bleeding, acute pancreatitis, Gilbert's syndrome.

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

Coagulation disorders: hemorrhagic diseases (hemophilia, hemorrhagic diathesis), hypoprothrombinemia, severe anemia, increased tendency to bleeding.

Bone marrow suppression (leukopenia, anemia, including hemolytic anemia), acute hepatic porphyria.

Severe hepatic and/or renal insufficiency.

Glucose-6-phosphate dehydrogenase deficiency.

Surgical procedures associated with significant bleeding.

Combination with methotrexate at doses of 15 mg per week or higher (see "Interaction with other medicinal products and other forms of interaction").

Combination with monoamine oxidase inhibitors (MAOIs) and within 2 weeks after discontinuation of MAOIs (see "Interaction with other medicinal products and other forms of interaction").

Increased excitability, insomnia, thrombosis, thrombophlebitis, epilepsy, hyperthyroidism, arterial hypertension, atherosclerosis, organic cardiovascular diseases, decompensated heart failure, cardiac conduction disorders, paroxysmal tachycardia, ischemic heart disease, acute myocardial infarction, portal hypertension, predisposition to vascular spasm, benign prostatic hyperplasia, severe forms of diabetes mellitus, advanced age, glaucoma (due to the presence of caffeine in the tablet).

Interaction with other medicinal products and other forms of interaction.

Contraindicated combinations.

The use of methotrexate at doses of 15 mg per 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).

Concomitant use of caffeine with MAO inhibitors may cause a dangerous increase in blood pressure.

Combinations requiring caution.

Acetylsalicylic acid.

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.

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

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

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

Concomitant use with digoxin increases its plasma concentration due to reduced renal excretion.

Concomitant use of high doses of acetylsalicylic acid with oral antidiabetic sulfonylurea derivatives or insulin enhances the hypoglycemic effect of the latter 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 synthesis of renal prostaglandins.

Systemic glucocorticosteroids (excluding hydrocortisone) used for replacement therapy in Addison's disease reduce salicylate blood levels during corticosteroid treatment and increase the risk of overdose after discontinuation of therapy.

The risk of gastrointestinal bleeding increases when acetylsalicylic acid is used with corticosteroids.

Acetylsalicylic acid enhances the effect of phenytoin.

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

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

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

Enhances the effect of heparin, oral anticoagulants (dicoumarol derivatives), reserpine, steroid hormones, and hypoglycemic agents. Concomitant administration with other nonsteroidal anti-inflammatory drugs (e.g., ibuprofen), methotrexate, and triiodothyronine increases the risk of adverse effects. Reduces the effectiveness of spironolactone, furosemide, antihypertensive agents, and uricosuric anti-gout drugs.

Selective serotonin reuptake inhibitors (SSRIs): increase the risk of upper gastrointestinal bleeding due to possible synergistic effects.

The drug enhances the effect of agents that reduce blood coagulation and platelet aggregation, as well as the adverse effects of corticosteroids, sulfonylureas, and methotrexate.

Combinations with barbiturates, anticonvulsants, salicylates, rifampicin, and alcohol should be avoided.

Paracetamol.

The absorption rate of paracetamol may increase when used concomitantly with domperidone and decrease when used with cholestyramine. Paracetamol increases the elimination time of chloramphenicol fivefold. Repeated use of paracetamol may enhance the effect of indirect anticoagulants (dicoumarol derivatives). Antacid medicinal products may reduce the extent of absorption and slow down this process. Chronic alcohol consumption may increase the hepatotoxicity of paracetamol due to excessive formation of the toxic metabolite—phenacetin (induction of CYP 2E1)—and may also cause depletion of glutathione stores in liver cells. In addition, inducers of CYP 2E1 include carbamazepine, barbiturates, isoniazid, phenytoin, rifampin, ritonavir, etc., which produce the same effect as chronic alcohol consumption. Concomitant use with glucocorticoids (dexamethasone) increases the likelihood of ulcerogenic and hepatotoxic effects of the drug and enhances the risk of gastrointestinal bleeding. Sulfinpyrazone may induce increased formation of phenacetin. Paracetamol may reduce the clearance of busulfan. Long-term use of paracetamol together with NSAIDs or salicylates increases the risk of toxic nephropathy and malignancies of the kidneys and urinary bladder. Paracetamol may interact with coumarin and indandione anticoagulants, enhancing their hypoprothrombinemic response; therefore, dose modification may be necessary based on appropriate laboratory monitoring. In high concentrations, paracetamol may inhibit the action of insulin. Metoclopramide accelerates the absorption of paracetamol.

Antidepressants and other stimulators of microsomal oxidation increase the production of hydroxylated active metabolites, affecting liver function and increasing the risk of severe intoxication even with minor overdoses. Paracetamol reduces the effectiveness of diuretics. Coumarin derivatives (warfarin) with prolonged use of paracetamol increase the risk of bleeding.

Caution should be exercised when using paracetamol concomitantly with flucloxacillin, as this combination is associated with metabolic acidosis with a high anion gap, as a result of pyroglutamic acidosis, particularly in patients at risk (see section "Special precautions").

Caffeine.

Caffeine enhances the effect (improves bioavailability) of analgesic-antipyretic agents and potentiates the effects of xanthine derivatives, alpha- and beta-adrenergic agonists, and psychostimulants.

Cimetidine, hormonal contraceptives, and isoniazid enhance the effect of caffeine.

Caffeine reduces the effect of opioid analgesics, anxiolytics, hypnotics, and sedatives; it acts as an antagonist of anesthetic agents and other drugs that depress the central nervous system, and as a competitive antagonist of adenosine and adenosine triphosphate.

Concomitant use of caffeine with ergotamine improves the absorption of ergotamine in the gastrointestinal tract; with thyroid-stimulating agents, it enhances the thyroid effect.

Caffeine reduces blood lithium concentration.

Caffeine is intensively metabolized by liver microsomal enzymes, which is a key factor in caffeine interactions with other medicinal products, either reducing or increasing the metabolism of these compounds. Certain antibiotics reduce caffeine clearance, thereby increasing the risk of toxic effects. The most important representatives of such antibiotics are ciprofloxacin, enoxacin, norfloxacin, ofloxacin, and erythromycin. Concomitant use of caffeine with barbiturates may reduce their hypnotic and spasmolytic effects. Antiarrhythmic agents, such as mexiletine, reduce caffeine clearance by approximately 50%, thereby increasing the risk of toxic effects. Concomitant use of caffeine with β-adrenergic blockers may lead to mutual suppression of therapeutic effects. Concomitant use with lithium increases the excretion of lithium in urine, thereby reducing its therapeutic effect.

The effectiveness of the drug may be reduced when used concomitantly with cholestyramine, cholinolytics, antidepressants, and alkaline substances.

Special precautions for use

Before using the medication, consult a physician.

Do not use the drug in combination with other products containing paracetamol or acetylsalicylic acid.

Do not exceed the recommended dosage. For short-term use only.

Use with caution in patients with a history of peptic ulcers, including chronic or recurrent peptic ulcer disease or gastrointestinal bleeding; and when used concomitantly with anticoagulants.

Patients with impaired kidney or liver function should consult a physician regarding the possibility of using the medication.

In patients with hepatic or renal functional impairment, the dose of Citramon-Forte should be reduced or the dosing interval increased. The interval between doses should be no less than 8 hours in cases of impaired kidney or liver function.

Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported in patients with severe conditions such as severe renal insufficiency and sepsis, or in cases of malnutrition and other causes of glutathione deficiency (e.g., chronic alcoholism), who were treated with therapeutic doses of paracetamol over a prolonged period or in combination with paracetamol and flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol is recommended, along with careful monitoring. Measurement of 5-oxoproline levels in urine may be useful in identifying pyroglutamic acidosis as the underlying cause of HAGMA in patients with multiple risk factors.

Since acetylsalicylic acid, like all non-selective nonsteroidal anti-inflammatory drugs (NSAIDs), irritates the gastrointestinal mucosa, this medication should be taken only after meals, with water, alkaline mineral waters, sodium bicarbonate solution (preferably milk).

During prolonged use, fecal occult blood testing should be performed to detect ulcerogenic effects, and blood tests should be conducted (to monitor effects on platelet aggregation and potential anticoagulant activity).

In cases of hyperthermia, the medication should preferably be used only if other analgesic-antipyretic agents are ineffective, due to the risk of Reye’s syndrome. If vomiting occurs during treatment, Reye’s syndrome should be suspected.

It should be noted that in patients with alcoholic liver disease, the risk of hepatotoxic effects of paracetamol is increased. The drug may also affect laboratory test results for blood glucose and uric acid levels.

In surgical procedures (including dental surgery), the use of medications containing acetylsalicylic acid may increase the risk of bleeding or exacerbate existing bleeding due to the inhibition of platelet aggregation, which persists for some time after administration. The medication should be discontinued 5–7 days prior to surgery to reduce the risk of excessive bleeding.

The patient should inform the physician in advance about taking Citramon-Forte.

In patients with allergic complications, including bronchial asthma, allergic rhinitis, urticaria, skin pruritus, mucosal swelling, nasal polyposis, and especially in combination with chronic respiratory infections or in patients with hypersensitivity to NSAIDs, bronchospasm or an asthma attack may occur. Therefore, NSAIDs are contraindicated in these patient groups.

Acetylsalicylic acid, a component of the medication, even in small doses, may reduce the excretion of uric acid from the body, potentially triggering an acute gout attack in susceptible individuals.

Since acetylsalicylic acid causes irritation of the mucous membrane, the medication should not be used in children due to the risk of Reye’s syndrome. In patients with bronchial asthma, allergic diseases, or hypersensitivity to NSAIDs, allergic reactions or exacerbation of the underlying condition may occur.

During treatment with this medication, excessive consumption of beverages containing caffeine (e.g., coffee, tea) is not recommended, as this may cause sleep disturbances, tremor, feelings of tension, irritability, and discomfort behind the sternum due to palpitations.

Alcoholic beverages should not be consumed during treatment (increased risk of gastrointestinal bleeding).

Patients who take analgesics daily for mild forms of arthritis should consult a physician. Consultation with a physician is required before using the medication if the patient is taking warfarin or similar drugs with anticoagulant effects.

The drug should not be used in patients with hypersensitivity to analgesic, anti-inflammatory, or antirheumatic agents. Use with caution when used concomitantly with anticoagulants and in the presence of circulatory disorders (e.g., renal vascular disease, congestive heart failure, hypovolemia, major surgery, sepsis, or severe bleeding), as acetylsalicylic acid may also increase the risk of renal dysfunction and acute kidney injury. Ibuprofen may reduce the inhibitory effect of acetylsalicylic acid on platelet aggregation.

The medication may affect laboratory test results for blood glucose and uric acid levels.

The medication should not be used without medical consultation for more than 5 days as an analgesic or more than 3 days as an antipyretic.

If symptoms persist, consult a physician.

If headache becomes persistent, consult a physician.

Contraindicated in patients with bronchial asthma, increased bleeding tendency, and with particular caution during concomitant therapy with anticoagulants (coumarins and heparin), in cases of impaired liver function and kidney disease, as well as during concomitant anti-inflammatory therapy.

May alter results of doping tests in athletes. May complicate the diagnosis of "acute abdomen."

Use during pregnancy or breastfeeding.

The medication is contraindicated during pregnancy.

In the third trimester of pregnancy, high-dose salicylate intake (more than 300 mg/day) may lead to prolonged gestation and weakened labor contractions, as well as cardiopulmonary toxicity (premature closure of the ductus arteriosus) in newborns.

The use of high-dose acetylsalicylic acid shortly before delivery may result in intracranial hemorrhage, especially in premature infants.

If the medication must be used, breastfeeding should be discontinued.

Ability to affect reaction speed when driving or operating machinery.

The medication may affect neuromuscular transmission. Therefore, patients should refrain from driving vehicles or operating hazardous machinery during treatment.

Dosage and Administration.

The drug is taken orally during or after meals. It is prescribed to adults and children aged 16 years and older at a dose of 1 tablet 2–3 times daily. For relief of acute pain, a single dose of 2 tablets is recommended. The maximum daily dose is 6 tablets, divided into 3 doses. The drug should not be used for more than 5 days as an analgesic or for more than 3 days as an antipyretic without medical prescription and supervision.

Children.

Acetylsalicylic acid-containing drugs should not be administered to children with acute respiratory viral infection (ARVI), regardless of whether fever is present, 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, which requires urgent medical intervention. Persistent vomiting in such conditions may be a sign of Reye's syndrome.

Due to the above-mentioned risks, the use of this drug is contraindicated in children under 16 years of age.

Overdose.

Symptoms of overdose may occur with prolonged use or when doses many times higher than recommended are taken.

Symptoms of overdose caused by acetylsalicylic acid.

Salicylate toxicity may result from chronic intoxication due to prolonged use of therapeutic doses or from acute intoxication (after ingestion of >100 mg/kg/day for more than 2 days), which can be potentially life-threatening, either from accidental ingestion by children or accidental poisoning.

Chronic salicylate poisoning may be asymptomatic and lacks specific clinical signs. Moderate intoxication, or salicylism, usually develops only after repeated administration of high doses.

Symptoms: dizziness, tinnitus, hearing loss, increased sweating, nausea, vomiting, headache, and impaired consciousness, which may be managed by dose reduction. Tinnitus may occur at plasma concentrations of 150–300 mcg/mL. More severe adverse effects occur at concentrations exceeding 300 mcg/mL. The hallmark of acute poisoning is severe disturbance of acid-base balance, which may vary depending on the patient's age and severity of intoxication. The most common sign in children is metabolic acidosis. The severity of poisoning cannot be assessed based solely on plasma concentration. Absorption of acetylsalicylic acid may be delayed due to gastric emptying inhibition, formation of gastric concretions, or use of enteric-coated formulations. Emergency management of acetylsalicylic acid poisoning depends on the severity, stage, and clinical symptoms, and follows standard procedures for managing intoxications. Initial measures should focus on accelerating drug elimination and restoring electrolyte and acid-base balance. Due to the complex pathophysiological effects of salicylate poisoning, various symptoms and laboratory abnormalities may occur.

Poisoning of mild to moderate severity: tachypnea, hyperventilation, respiratory alkalosis, increased sweating, nausea, vomiting. Laboratory findings: alkalosis, alkaline urine reaction.

Severe poisoning: respiratory alkalosis with compensatory metabolic acidosis, hyperpyrexia, tinnitus, hearing loss. Respiratory system: from hyperventilation and non-cardiogenic pulmonary edema to respiratory arrest and asphyxia; laboratory findings – alkalosis, alkaline urine reaction. Cardiovascular system: from cardiac arrhythmias and arterial hypotension to cardiac arrest. Fluid and electrolyte loss: dehydration, oliguria, renal failure. Laboratory findings – hypokalemia, hypernatremia, hyponatremia, impaired renal function. Glucose metabolism disturbances and ketosis manifest as hyperglycemia, hypoglycemia (especially in children), and elevated ketone bodies. Gastrointestinal tract: gastrointestinal bleeding. Hematological changes: from platelet function suppression to coagulopathies.

Laboratory findings: prolonged prothrombin time, hypoprothrombinemia. Neurological: toxic encephalopathy and depression of the central nervous system ranging from lethargy and impaired consciousness to coma and seizures.

Symptoms of overdose within the first 24 hours caused by paracetamol.

Symptoms include pallor, loss of appetite, anorexia, nausea, vomiting, abdominal pain, hepatonecrosis, elevated liver transaminase activity, and increased prothrombin index.

Signs of liver damage typically appear 12–48 hours after overdose. Disturbances in glucose metabolism and metabolic acidosis may occur. In severe poisoning, liver failure may progress, leading to toxic encephalopathy with altered consciousness, hemorrhages, hypoglycemia, coma, and, in some cases, death. Acute renal failure with acute tubular necrosis may present with severe flank pain, hematuria, proteinuria, and may develop even in the absence of severe kidney damage. Cardiac arrhythmias and pancreatitis have also been reported.

With prolonged use of high doses, hematological side effects may include aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia. High doses may also cause central nervous system effects such as dizziness, psychomotor agitation, and disorientation. Urinary system effects may include nephrotoxicity (renal colic, interstitial nephritis, capillary necrosis).

Liver damage may occur in adults who ingest 10 g or more of paracetamol and in children who ingest more than 150 mg/kg body weight.

In patients with risk factors (chronic use of carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John’s wort, or other drugs that induce liver enzymes; chronic alcohol abuse; glutathione system deficiency, e.g., due to gastrointestinal disorders, HIV infection, fasting, cystic fibrosis, cachexia), ingestion of 5 g or more of paracetamol may lead to liver damage.

In case of overdose, prompt medical attention is required. The patient should be immediately transported to a hospital, even if early symptoms of overdose are absent.

Symptoms of overdose may include nausea, vomiting, excessive sweating, psychomotor agitation or central nervous system depression, drowsiness, impaired consciousness, cardiac arrhythmias, tachycardia, extrasystoles, tremor, hyperreflexia, and seizures, or the severity of overdose and risk of organ damage may not be immediately apparent. Plasma paracetamol concentration should be measured 4 hours or more after ingestion (earlier measurements are unreliable).

Treatment: gastric lavage followed by administration of activated charcoal (if the excessive dose was taken within 1 hour), symptomatic therapy. The specific antidote for paracetamol overdose is N-acetylcysteine. If vomiting is absent, oral methionine or intravenous N-acetylcysteine may be administered. N-acetylcysteine is effective within 24 hours of overdose, but maximum protective effect is achieved when administered within 8 hours. The efficacy of the antidote decreases sharply after this period. General supportive measures should also be implemented. If necessary, α-adrenergic blockers may be used.

Symptoms of overdose caused by caffeine.

Symptoms include restlessness, dizziness, rapid breathing, vomiting, tremors, seizures, and extrasystoles.

Treatment: gastric lavage, repeated administration of activated charcoal, forced alkaline diuresis, oxygen therapy, hemodialysis in severe cases, fluid and electrolyte infusion, and symptomatic therapy. Diazepam is used in case of seizures. The specific antidote for paracetamol overdose is N-acetylcysteine.

Side effects.

When using the drug, adverse reactions characteristic of acetylsalicylic acid, paracetamol, or caffeine may occur in individual patients.

Gastrointestinal tract: gastrointestinal disorders: dyspepsia, heartburn, epigastric pain and abdominal pain, nausea, vomiting; in individual cases – inflammation and erosive-ulcerative lesions of the gastrointestinal tract, which in rare instances may lead to gastrointestinal hemorrhages and perforations, with corresponding laboratory findings and clinical manifestations; rarely – transient hepatic insufficiency with increased liver enzyme activity, usually without development of jaundice, hepatonecrosis (a dose-dependent effect); liver function disorders.

Blood-forming system: leukopenia, agranulocytosis, hemolytic anemia, methemoglobinemia, sulfhemoglobinemia; with prolonged use in high doses – aplastic anemia, pancytopenia, neutropenia, leukopenia, thrombocytopenia; hemorrhages may lead to acute and chronic post-hemorrhagic anemia/iron-deficiency anemia (due to so-called hidden microbleeding), with corresponding laboratory findings and clinical symptoms such as asthenia, pallor of the skin, hypoperfusion.

Allergic reactions: in patients with individual hypersensitivity to salicylates, allergic skin reactions may develop, including symptoms such as skin hyperemia, sensation of warmth, skin and mucous membrane rashes, including generalized and erythematous eruptions; urticaria, edema, pruritus, angioneurotic edema. In patients with bronchial asthma, increased frequency of bronchospasm may occur; allergic reactions ranging from mild to moderate severity, potentially affecting the skin, respiratory tract, gastrointestinal tract, and cardiovascular system, manifesting as rashes, urticaria, swelling, itching, non-cardiogenic pulmonary edema. Very rarely, severe reactions including anaphylactic shock have been observed.

Dermatological reactions: erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome).

Central and peripheral nervous system: tremor, nervousness, restlessness, dizziness and tinnitus, visual disturbances which may indicate overdose, insomnia, increased excitability, disorientation.

Urinary and reproductive system: when taking high doses – nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis).

Cardiovascular system: transient tachycardia and increased blood pressure, arrhythmia, palpitations.

Endocrine system: hypoglycemia, up to hypoglycemic coma.

Coagulation system: due to the antiplatelet and anticoagulant effects of acetylsalicylic acid, the risk of bleeding may be increased. Bleeding events observed include intraoperative hemorrhages, hematomas, bleeding from organs of the urinary and reproductive system, nosebleeds, bleeding from gums, purpura; rarely or very rarely – serious bleeding such as gastrointestinal hemorrhages, cerebral hemorrhages (especially in patients with uncontrolled arterial hypertension and/or concomitant use of antihemostatic agents), which in isolated cases could potentially be life-threatening.

Metabolism and nutrition disorders: metabolic acidosis with high anion gap with frequency "unknown" (cannot be estimated from available data).

Description of individual adverse reactions

Metabolic acidosis with high anion gap

Cases of metabolic acidosis with high anion gap as a result of pyroglutamic acidosis have been observed in patients with risk factors who used paracetamol (see section "Special precautions for use"). Pyroglutamic acidosis may occur as a consequence of low glutathione levels in these patients.

Reporting suspected adverse reactions.

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

Shelf life.

3 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.

10 tablets per blister; 10 blisters per carton.

Prescription status.

Over-the-counter: tablets pack size № 10.

By prescription: tablets pack size № 100 (10×10).

Manufacturer.

JSC "Lubnifarm".

Manufacturer's address and location of business activity.

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