Citropac® - darnitsa

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CYTROPAK®-DARNYTSIA (CitropaK-Darnitsa)

Composition:

Active ingredients: acetylsalicylic acid; paracetamol; caffeine;

One tablet contains: acetylsalicylic acid 240 mg, paracetamol 180 mg, caffeine 30 mg;

Excipients: citric acid monohydrate, potato starch, povidone, calcium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: tablets are white or white with creamish or pinkish tint, flat cylindrical in shape, with beveled edges and a score line.

Pharmacotherapeutic group. Analgesics and antipyretics. Acetylsalicylic acid combinations without psychotropic agents. ATC code N02BA51.

Pharmacological Properties.

Pharmacodynamics.

A combined medicinal product.

Due to the presence of acetylsalicylic acid and paracetamol in the tablet, the medicinal product has anti-inflammatory, antipyretic, and analgesic effects.

The components contained in the medicinal product enhance each other's effects.

Acetylsalicylic acid has analgesic, antipyretic, and anti-inflammatory actions, reduces pain—especially that caused by inflammatory processes—and moderately inhibits platelet aggregation and thrombosis, thereby improving microcirculation at the site of inflammation.

The antipyretic effect of acetylsalicylic acid is mediated through the central nervous system by suppressing PGF2 synthesis in the hypothalamus in response to endogenous pyrogens.

The analgesic effect has both peripheral and central origins: the peripheral effect results from inhibition of prostaglandin synthesis in inflamed tissues; the central effect involves action on hypothalamic centers.

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

Caffeine increases reflex excitability of the spinal cord, stimulates respiratory and vasomotor centers, dilates blood vessels in skeletal muscles, brain, heart, and kidneys, reduces platelet aggregation, decreases drowsiness and fatigue, and enhances mental and physical performance. Caffeine reduces the effects of sedatives and narcotic substances and enhances the effects of analgesics and antipyretics.

In this combination, caffeine in a low dose practically does not exert a stimulatory effect on the central nervous system, but promotes normalization of cerebral vascular tone and accelerates blood flow.

Pharmacokinetics.

Acetylsalicylic acid.

Rapidly and completely absorbed after oral administration. Primarily hydrolyzed in the gastrointestinal tract, liver, and blood to salicylate, which is then mainly metabolized in the liver.

Paracetamol.

After administration, absorbed in the gastrointestinal tract; peak plasma concentration of paracetamol is observed within 30–120 minutes. Paracetamol is metabolized in the liver and primarily excreted in urine as glucuronide and sulfate conjugates. Less than 5% is excreted unchanged. The elimination half-life is 1–4 hours. Plasma protein binding is negligible at normal therapeutic concentrations but increases proportionally with rising concentrations.

A minor hydroxylated metabolite, normally formed in very small amounts in the liver and detoxified mainly by conjugation with hepatic glutathione, may accumulate in cases of paracetamol overdose and cause liver damage.

Caffeine.

Maximum caffeine concentration is observed between 5 and 90 minutes after administration of Citropac**®** -Darnitsya on an empty stomach. Data on its presystemic metabolism are lacking. In adults, it is almost completely metabolized in the liver. Elimination rate in adults is individual. The mean elimination half-life from plasma is 4.9 hours, with a range of 1.9–12.2 hours. Caffeine is uniformly distributed in all body fluids. Plasma protein binding averages 35%.

Caffeine is almost entirely metabolized via oxidation, demethylation, and acetylation, and is excreted in urine. Its main metabolites are 1-methylxanthine, 7-methylxanthine, and 1,7-dimethylxanthine (paraxanthine). Minor metabolites include 1-methyluric acid and 5-acetylamino-6-formylamino-3-methyluracil (AMFU).

No cross-interaction occurs among the three active components, nor is there an increased risk of interaction with other medicinal products when the active components are used in combination. Due to the combination of three active substances, each is present in a low amount, thereby reducing the overall toxicity of the medicinal product.

Clinical characteristics.

Indications.

Treatment of mild to moderate pain: headache, toothache, primary dysmenorrhea, migraine, arthralgia, neuralgia, and conditions associated with hyperthermia of various etiologies (as an antipyretic agent).

Contraindications.

• Hypersensitivity to any component of the medicinal product, cross-sensitivity to other xanthine derivatives (theophylline, theobromine), or to other salicylates;
• History of bronchial asthma, urticaria, or rhinitis induced by acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs (NSAIDs);
• Erosive or ulcerative gastrointestinal lesions (in the acute phase), gastrointestinal bleeding or perforation, or history of peptic ulcer;
• Blood disorders: hemophilia, hemorrhagic diathesis, hypoprothrombinemia, anemia, leukopenia, increased tendency to bleeding, thrombosis, thrombophlebitis, hemorrhagic diseases;
• Severe renal or hepatic insufficiency, portal hypertension, congenital hyperbilirubinemia, Gilbert’s syndrome;
• Glucose-6-phosphate dehydrogenase deficiency;
• Organic cardiovascular diseases (particularly severe atherosclerosis), cardiac arrhythmias, conduction disorders, paroxysmal tachycardia, severe hypertension, severe course of ischemic heart disease, acute myocardial infarction, decompensated heart failure, predisposition to vascular spasm;
• Glaucoma, hyperthyroidism, acute pancreatitis, benign prostatic hyperplasia, severe forms of diabetes mellitus;
• Concomitant use with monoamine oxidase inhibitors (MAOIs) and within 2 weeks after discontinuation of MAOIs; simultaneous use with tricyclic antidepressants or beta-blockers;
• Alcoholism, epilepsy, increased excitability, sleep disorders;
• Combined use with methotrexate at doses of 15 mg or more per week;
• Surgical procedures associated with significant bleeding;
• Age over 60 years.

Special precautions.

For short-term use only. Do not exceed recommended doses. Do not use concurrently with other medicinal products containing acetylsalicylic acid or paracetamol.

It is not recommended to use Citropac**®** -Darnytsia for more than 5 days as an analgesic or for more than 3 days as an antipyretic without medical consultation.

Citropac**®** -Darnytsia should not be used in patients in whom >20% of migraine attacks are associated with vomiting or in whom >50% of migraine attacks require bed rest.

If no improvement occurs after taking the first 2 tablets of Citropac**®** -Darnytsia in a patient with migraine, the patient should seek medical advice.

This medicinal product should not be used in patients who have experienced headaches more than 10 days per month over the past 3 or more months.

This medicinal product should be used with caution in patients at risk of dehydration (e.g., due to vomiting, diarrhea, or before or after major surgery).

Due to its pharmacodynamic properties, Citropac**®** -Darnytsia may mask signs and symptoms of infection.

Citropac**®** -Darnytsia should be used with caution in patients with mild to moderate hepatic or renal insufficiency.

Due to acetylsalicylic acid content.

Since acetylsalicylic acid inhibits platelet aggregation, and this effect persists for several days after administration, the drug may increase the risk of bleeding during and after surgical procedures (including minor procedures such as tooth extraction). Patients should inform their physician in advance about the use of this medicinal product prior to surgery. The drug should be discontinued 5–7 days before elective surgical procedures.

Low-dose acetylsalicylic acid reduces the excretion of uric acid. In predisposed patients, this may in some cases trigger an attack of gout. The drug should be used with caution in patients with gout, renal or hepatic disease, dehydration, or diabetes mellitus.

Alcohol consumption should be avoided during treatment (increases the risk of gastrointestinal bleeding).

The drug should be used with particular caution in the following cases: history of gastrointestinal ulcers, chronic or recurrent peptic ulcer disease; concomitant anticoagulant therapy; worsening renal or hepatic function; inherited hyperbilirubinemias (Gilbert’s, Dubin-Johnson, and Rotor syndromes); elderly patients. Citropac**®** -Darnytsia should not be used without medical supervision concomitantly with anticoagulants or other medicinal products that inhibit platelet aggregation. Patients with coagulation disorders should be closely monitored. The drug should be used cautiously in cases of metrorrhagia or menorrhagia.

If gastrointestinal bleeding or ulceration occurs during therapy, Citropac**®** -Darnytsia should be discontinued immediately. The risk of bleeding may be increased by concomitant alcohol consumption, corticosteroids, and nonsteroidal anti-inflammatory drugs (NSAIDs).

In patients with hepatic or renal functional impairment, the dose should be reduced or the dosing interval increased. When renal or hepatic function is impaired, the dosing interval should be at least 8 hours.

Since acetylsalicylic acid, like all non-selective NSAIDs, irritates the gastrointestinal mucosa, the drug should be taken only after meals, with water, alkaline mineral water, 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 possible anticoagulant activity).

In cases of hyperthermia, the drug should preferably be prescribed only when other analgesic-antipyretic agents are ineffective, due to the risk of Reye’s syndrome. If vomiting occurs after taking the drug, Reye’s syndrome should be suspected.

The drug should be used cautiously in patients with allergic rhinitis, nasal polyps, or urticaria.

Bronchospasm or an attack of bronchial asthma may occur during treatment in patients with allergic conditions, including bronchial asthma, allergic rhinitis, urticaria, skin pruritus, mucosal edema, nasal polyposis, or in combination with chronic respiratory tract infections, especially in patients hypersensitive to NSAIDs.

Due to paracetamol content.

Citropac**®** -Darnytsia should be used with caution in patients with impaired renal or hepatic function or with alcohol dependence.

The risk of paracetamol toxicity increases in patients taking other potentially hepatotoxic medicinal products or agents that induce hepatic microsomal enzymes (e.g., rifampicin, isoniazid, chloramphenicol, sedatives, and antiepileptic drugs, including phenobarbital, phenytoin, and carbamazepine). Patients with a history of alcohol dependence are at particular risk of liver damage.

Due to caffeine content.

Citropac**®** -Darnytsia should be used with caution in patients with gout or hyperthyroidism.

During therapy with Citropac**®** -Darnytsia, the patient should limit consumption of products containing caffeine, as excessive caffeine concentrations may cause nervousness, irritability, insomnia, and periodic episodes of tachycardia.

Interaction with other medicinal products and other types of interactions.

Possible interactions of active substances.

Acetylsalicylic acid (ASA)

Use of acetylsalicylic acid in combination with	Possible consequence
Ibuprofen	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.
Other nonsteroidal anti-inflammatory drugs (NSAIDs)	Increased risk of gastrointestinal ulcers and bleeding due to synergistic effects. If concomitant use of these agents is necessary, consideration should be given to using gastroprotective agents. Therefore, use of this combination is not recommended.
Corticosteroids	Increased risk of gastrointestinal ulcers and bleeding due to synergistic effects. In patients receiving acetylsalicylic acid and corticosteroids, especially elderly patients, consideration should be given to prescribing gastroprotective agents. Systemic glucocorticoids reduce blood salicylate levels and increase the risk of overdose after discontinuation of treatment. Therefore, use of this combination is not recommended.
Oral anticoagulants (e.g., coumarin derivatives)	Acetylsalicylic acid may enhance the anticoagulant effect. Clinical and laboratory monitoring of bleeding time and prothrombin time is required. Therefore, use of this combination is not recommended.
Thrombolytics	Increased risk of hemorrhagic complications. In particular, in patients with acute stroke, acetylsalicylic acid therapy should not be initiated within the first 24 hours after administration of alteplase. Therefore, use of this combination is not recommended.
Heparin	Increased risk of hemorrhagic complications. Clinical and laboratory monitoring of bleeding time is required. Therefore, use of this combination is not recommended.
Platelet aggregation inhibitors (ticlopidine, clopidogrel, cilostazol)	Increased risk of hemorrhagic complications. Clinical and laboratory monitoring of bleeding time is required. Therefore, use of this combination is not recommended.
Selective serotonin reuptake inhibitors (SSRIs)	SSRIs, when used concomitantly with acetylsalicylic acid, may impair coagulation or platelet function, leading to hemorrhagic complications in general and particularly gastrointestinal bleeding. Therefore, concomitant use of these agents should be avoided.
Digoxin	When used concomitantly, plasma digoxin concentration increases due to reduced renal excretion.
Phenytoin	Serum phenytoin levels increase during acetylsalicylic acid therapy. Serum phenytoin levels should be closely monitored.
Valproate	Acetylsalicylic acid inhibits valproate metabolism, potentially increasing its toxicity. Serum valproate levels should be closely monitored.
Mineralocorticoid antagonists (spironolactone, canrenoate)	Acetylsalicylic acid may reduce their activity by inhibiting sodium excretion in urine. Arterial blood pressure should be closely monitored.
Loop diuretics (e.g., furosemide)	Acetylsalicylic acid may reduce their efficacy due to competition and inhibition of urinary prostaglandins. NSAIDs may cause acute renal failure, especially in dehydrated patients. When diuretics are used concomitantly with acetylsalicylic acid, measures should be taken to ensure adequate hydration and monitoring of renal function and blood pressure, particularly at the beginning of diuretic therapy.
Antihypertensive agents (ACE inhibitors, angiotensin II receptor antagonists, calcium channel blockers)	Acetylsalicylic acid may reduce their efficacy due to competition and inhibition of urinary prostaglandins. Use of this combination may lead to acute renal failure in elderly patients and in patients with dehydration. At the beginning of therapy, careful monitoring of blood pressure and renal function parameters is recommended, along with ensuring adequate hydration. When used concomitantly with verapamil, bleeding time should also be monitored.
Uricosuric agents (e.g., probenecid, sulfinpyrazone)	Acetylsalicylic acid may reduce their activity by inhibiting tubular reabsorption, leading to high plasma levels of acetylsalicylic acid and uric acid.
Methotrexate ≤ 15 mg/week	Use of methotrexate at doses of 15 mg/week and higher increases 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). Therefore, concomitant use of NSAIDs is contraindicated in patients receiving high-dose methotrexate. The risk of drug interactions between methotrexate and NSAIDs should also be considered in patients receiving low-dose methotrexate, especially those with impaired renal function. If combination therapy is necessary, complete blood count and monitoring of liver and kidney function should be performed, particularly during the first days of treatment.
Sulfonylurea derivatives and insulin	Acetylsalicylic acid potentiates their hypoglycemic effect; therefore, it may be advisable to slightly reduce the dose of the antidiabetic agent when high doses of salicylates are used. More careful monitoring of blood glucose levels is recommended.
Alcohol	Increased risk of gastrointestinal bleeding. Concomitant use of this combination should be avoided.

Paracetamol

Use of paracetamol in combination with medicinal products	Possible consequence
Enzyme inducers of the liver or substances with potential hepatotoxicity (e.g., alcohol, rifampicin, isoniazid, hypnotics and anticonvulsants, including phenobarbital, phenytoin and carbamazepine, salicylamide and other stimulators of microsomal oxidation)	Increased toxicity of paracetamol, which may lead to liver damage, even when using doses of paracetamol that are otherwise harmless. Therefore, liver function parameters should be monitored. Concomitant use is not recommended.
Chloramphenicol	Under the influence of paracetamol, the elimination time of chloramphenicol increases fivefold. During paracetamol therapy, the risk of increased plasma concentrations of chloramphenicol rises. Concomitant use is not recommended.
Zidovudine	During paracetamol therapy, the risk of developing neutropenia increases; therefore, haematopoietic system parameters should be monitored. Concomitant use is not recommended, except when such use is under medical supervision.
Probenecid	Probenecid reduces the clearance of paracetamol; therefore, the dose of paracetamol should be reduced when used concomitantly with this agent. Concomitant use is not recommended.
Oral anticoagulants	Repeated use of paracetamol for more than 1 week enhances anticoagulant effects. Occasional use of paracetamol does not significantly affect coagulation.
Propantheline or other agents causing delayed gastric emptying	These agents delay the absorption of paracetamol. Analgesic effect may be delayed and less pronounced.
Metoclopramide or other agents causing accelerated gastric emptying	These active substances accelerate the absorption of paracetamol, increasing its effectiveness and speeding up the onset of analgesic effect.
Cholestyramine	Cholestyramine reduces the absorption of paracetamol; therefore, to achieve maximum analgesic effect, cholestyramine should be taken no earlier than 1 hour after paracetamol.
Flucloxacillin	Caution is required when using paracetamol concomitantly with flucloxacillin, as co-administration is associated with high anion gap metabolic acidosis, particularly in patients with risk factors (see section "Special precautions")

Caffeine

Use of caffeine in combination with	Possible consequence
MAO inhibitors	Combination with caffeine may lead to a dangerous increase in blood pressure; therefore, this combination is contraindicated.
Sedatives (e.g., benzodiazepines, barbiturates, antihistamines)	The sedative effect may be reduced, or the anticonvulsant effect of barbiturates may be suppressed. Therefore, concomitant use is not recommended. If simultaneous use of these medicinal products is necessary, administration of such a combination in the morning may be more beneficial.
Lithium preparations	Caffeine decreases lithium blood concentration. After caffeine withdrawal, serum lithium levels increase, as caffeine may enhance renal clearance of lithium. Therefore, lithium dosage reduction may be required upon caffeine discontinuation. Concomitant use is not recommended.
Disulfiram	Patients with alcohol dependence receiving disulfiram therapy for this condition should be advised to avoid caffeine use to prevent exacerbation of alcohol withdrawal syndrome due to caffeine-induced cardiovascular and cerebral stimulation.
Substances similar to ephedrine	Use of such a combination increases the risk of dependence development. Therefore, concomitant use is not recommended.
Sympathomimetics or levothyroxine	When used in combination, tachycardic effects may be more pronounced due to synergistic actions. Therefore, concomitant use is not recommended.
Theophylline	Concomitant use may reduce theophylline excretion.
Quinolone antibacterial agents (ciprofloxacin, enoxacin, and pipemidic acid), terbinafine, cimetidine, fluvoxamine, and oral contraceptives	Increased caffeine half-life due to inhibition of the cytochrome P450 liver metabolic pathway. Therefore, patients with impaired liver function, cardiac arrhythmias, or latent epilepsy should avoid caffeine intake.
Nicotine, phenytoin, and phenylpropanolamine	These substances increase the elimination half-life of caffeine.
Clozapine	Concomitant use of caffeine increases serum clozapine levels—likely due to interactions mediated by both pharmacokinetic and pharmacodynamic mechanisms. Serum clozapine levels should be monitored. Therefore, concomitant use is not recommended.
Analgesic-antipyretics	Enhancement of their effect (improved bioavailability).
Ergotamine	Concomitant use of caffeine with ergotamine improves ergotamine absorption from the gastrointestinal tract.
Xanthine derivatives, alpha- and beta-adrenergic agonists, psychostimulants	Potentiates the effects of xanthine derivatives, alpha- and beta-adrenergic agonists, and psychostimulants.

Effect on laboratory test results:

• The use of high doses of acetylsalicylic acid may affect the results of several clinical chemical laboratory tests.
• The use of paracetamol may affect the results of uric acid measurement when the analysis is performed using phosphotungstic acid reagent, and the results of blood glucose measurement when the analysis is performed using the glucose oxidase/peroxidase method.
• Caffeine may counteract the effect of dipyridamole on myocardial blood flow and thus affect the results of this test. It is recommended to discontinue caffeine intake 8–12 hours before the start of this test.

Special precautions.

Regarding paracetamol: consult a physician before using the medicinal product if the patient is taking warfarin or similar medicinal products with anticoagulant effect, as well as in case of liver or kidney disorders.

The risk of overdose is highest in patients with non-cirrhotic alcoholic liver disease. The medicinal product may affect laboratory test results for blood glucose and uric acid levels.

Patients who take analgesics daily for mild forms of arthritis should consult a physician. In patients with severe infections such as sepsis, associated with reduced glutathione levels, the use of paracetamol increases the risk of metabolic acidosis. Symptoms of metabolic acidosis include deep, rapid, or labored breathing, nausea, vomiting, and loss of appetite. Immediate medical attention is required if these symptoms occur.

During treatment with this medicinal product, excessive consumption of beverages containing caffeine (such as coffee or tea) is not recommended. This may lead to sleep disturbances, tremor, or discomfort behind the sternum due to palpitations.

Caution is advised when using paracetamol concomitantly with flucloxacillin due to an increased risk of high anion gap metabolic acidosis, especially in patients with severe renal impairment, sepsis, malnutrition, and other sources of glutathione deficiency (e.g., chronic alcoholism), as well as those taking maximum daily doses of paracetamol. Close monitoring is recommended, including measurement of urinary 5-oxoproline.

Do not exceed the recommended doses.

Do not use this medicinal product with other products containing paracetamol.

If symptoms persist, consult a physician.

If headaches become persistent, consult a physician.

Regarding acetylsalicylic acid: use with caution in patients with impaired kidney function or cardiovascular disorders (e.g., renal vascular disease, congestive heart failure, hypovolemia, major surgery, sepsis, or severe bleeding), as acetylsalicylic acid may increase the risk of kidney dysfunction and acute renal failure.

Ibuprofen may reduce the inhibitory effect of acetylsalicylic acid on platelet aggregation. If this medicinal product is to be used before starting ibuprofen for pain relief, the patient should consult a physician.

Do not use medicinal products containing acetylsalicylic acid in children with acute respiratory viral infections (ARVI), with or without fever. In certain viral illnesses, particularly influenza A, influenza B, and varicella, there is a risk of Reye's syndrome, which requires urgent medical intervention. The risk may be increased if acetylsalicylic acid is used concomitantly, although a causal relationship has not been definitively established. If these conditions are accompanied by persistent vomiting, this may be a sign of Reye's syndrome.

Keep the medicinal product out of sight and reach of children.

Use during pregnancy or breastfeeding.

The medicinal product must not be used during pregnancy.

Acetylsalicylic acid has teratogenic effects; when used during the first trimester of pregnancy, it may cause developmental abnormalities such as cleft palate; during the third trimester, it may inhibit labor activity (by inhibiting prostaglandin synthesis), cause closure of the fetal arterial duct leading to pulmonary vascular hyperplasia and hypertension in the pulmonary circulation; impair kidney function with possible subsequent development of renal failure associated with oligohydramnios; and increase the risk of prolonged bleeding time due to antiplatelet (antiaggregant) effects, which may occur even after administration of very low doses.

Caffeine increases the risk of spontaneous abortion.

Breastfeeding should be discontinued during treatment. The medicinal product passes into breast milk, increasing the risk of bleeding in infants due to impaired platelet function.

Ability to influence reaction speed when driving or operating machinery.

When high doses of the medicinal product are used, patients should refrain from driving or operating machinery due to possible adverse reactions affecting the central nervous system (dizziness, psychomotor agitation, and disturbances in orientation and attention).

Method of Administration and Dosage.

Citropac**®** -Darnytsia should be taken 1 tablet 2–3 times daily after meals. The maximum daily dose is 6 tablets (2 tablets 3 times daily). Citropap**®** -Darnytsia tablets should not be used for more than 5 days as an analgesic or for more than 3 days as an antipyretic.

Do not exceed the recommended dose. Do not take together with other medicinal products containing paracetamol.

Each dose should be taken with a full glass of water.

Patients with hepatic or renal insufficiency should be aware that, although the effects of liver or kidney disease on the pharmacokinetics of Citropac**®** -Darnytsia have not been studied, due to the mechanism of action of acetylsalicylic acid and paracetamol, liver or kidney disorders may be exacerbated. Therefore, Citropac**®** -Darnytsia is contraindicated in patients with severe hepatic or renal insufficiency and should be used with caution in patients with mild to moderate hepatic or renal insufficiency.

Children.

The use of the medicinal product is contraindicated in children under 16 years of age unless there are specific indications (Kawasaki disease).

Overdose.

Symptoms of overdose may occur with prolonged use of the medicinal product or when used in doses many times higher than recommended.

Since Citropac**®** -Darnytsia is a combination medicinal product, overdose should be considered with respect to each active ingredient contained in its composition.

Acetylsalicylic acid.

Salicylate poisoning is usually observed at plasma concentrations > 350 mg/L (2.5 mmol/L). Most fatal outcomes have been observed at plasma concentrations of acetylsalicylic acid > 700 mg/L (5.1 mmol/L). A single dose of < 100 mg/kg body weight is unlikely to cause serious poisoning.

Symptoms of overdose. The following adverse reactions are very commonly observed: nausea, vomiting, dehydration, tinnitus, dizziness, hearing loss, increased sweating, feeling of warmth in the extremities, tachycardia, extrasystoles, and hyperventilation, disturbances in blood acid-base balance. A combination of respiratory alkalosis and metabolic acidosis with normal or elevated arterial blood pH is observed in both adults and children. Acidosis may promote increased transport of salicylates across the blood-brain barrier.

Less commonly observed adverse reactions include: vomiting with blood, hyperpyrexia, hypoglycemia, hypokalemia, thrombocytopenia, prolonged prothrombin time, intravascular coagulation, renal failure, non-cardiogenic pulmonary edema. Central nervous system adverse reactions are also possible: disorientation, psychomotor agitation or central nervous system depression, drowsiness, impaired consciousness, dizziness, tremor, hyperreflexia, seizures, and coma.

Symptoms of overdose caused by acetylsalicylic acid.

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

Chronic intoxication with salicylates may be asymptomatic, as it lacks specific symptoms. Moderate salicylate intoxication, or salicylism, usually develops only after repeated administration of high doses.

Symptoms: dizziness, tinnitus, hearing loss, sweating, nausea, vomiting, headache, and impaired consciousness may be controlled by reducing the dose. Tinnitus may occur at plasma concentrations of 150 to 300 µg/mL. More severe adverse effects occur at concentrations > 300 µg/mL. The hallmark of acute intoxication is severe disturbance of acid-base balance, which may vary with age and severity of intoxication. The most common symptom in children is metabolic acidosis. The severity of intoxication cannot be assessed using plasma concentration data alone. Absorption of acetylsalicylic acid may be delayed due to delayed gastric emptying, formation of gastric concretions, or use of enteric-coated medicinal products.

Emergency treatment for acetylsalicylic acid poisoning depends on the severity, stage, and clinical symptoms and follows standard emergency procedures for poisoning. Initial measures should focus on accelerating elimination of the drug and restoring electrolyte and acid-base balance.

Due to the complex pathophysiological effects of salicylate poisoning, certain symptoms and laboratory changes may occur.

Mild to moderate intoxication: tachypnea, hyperventilation, respiratory alkalosis, sweating, nausea, vomiting. Laboratory findings: alkalosis, alkaline urine reaction.

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

Neurological: toxic encephalopathy and CNS depression ranging from lethargy and impaired consciousness to coma and seizures.

Symptoms of overdose caused by paracetamol. Liver damage is possible in adults who have taken 10 g or more of paracetamol and in children who have ingested > 150 mg/kg body weight.

In patients with risk factors (long-term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John's wort, or other medicinal products inducing liver enzymes; regular excessive alcohol consumption; glutathione depletion (digestive disorders, cystic fibrosis, HIV infection, starvation, cachexia)), ingestion of 5 g or more of paracetamol may lead to liver damage.

Symptoms of overdose. During the first 24 hours: nausea, vomiting, loss of appetite, anorexia, abdominal pain, pallor of the skin. Within 12–48 hours: liver damage, impaired glucose metabolism, and metabolic acidosis may develop. With significant overdose, liver disturbances may lead to encephalopathy, hemorrhage, hypoglycemia, cerebral edema, coma, and fatal outcome. Acute renal failure with acute tubular necrosis may present as severe lumbar pain, hematuria, proteinuria, and may develop even in the absence of severe kidney damage.

With prolonged use of the medicinal product in high doses, the following may develop in the hematopoietic system: aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, thrombocytopenia.

Also reported are the following disorders: increased sweating, drowsiness, impaired consciousness, tachycardia, extrasystoles, tremor, hyperreflexia, seizures, cardiac arrhythmias, pancreatitis, psychomotor agitation or central nervous system depression. With large doses, urinary system: nephrotoxicity (renal colic, interstitial nephritis, capillary necrosis); central nervous system: dizziness, disorientation, psychomotor agitation.

Treatment. In case of overdose, prompt medical attention is required. The patient should be immediately taken to a hospital, even if early symptoms of overdose are absent. Symptoms may be limited to nausea and vomiting or may not reflect the severity of overdose or risk of organ damage. Plasma paracetamol concentration should be measured 4 hours or later after ingestion (earlier concentrations are unreliable). Treatment should begin with gastric lavage followed by activated charcoal (if the excessive dose was taken within 1 hour) and symptomatic therapy. The specific antidote for paracetamol overdose is N-acetylcysteine. In the absence of vomiting, oral methionine or intravenous N-acetylcysteine is effective within 24 hours, but maximum protective effect is achieved when administered within 8 hours after overdose. The effectiveness of the antidote sharply decreases after this time. General supportive measures should also be taken. If necessary, alpha-adrenoblockers should be used.

Symptoms of overdose caused by caffeine. Central and peripheral nervous system: increased irritability, nervousness, restlessness, insomnia, dizziness, increased emotional excitability, involuntary muscle contractions, seizures, rapid breathing. Gastrointestinal tract: stomach or abdominal pain. Cardiovascular system: tachycardia, arrhythmia. Others: facial flushing, frequent urination.

Treatment. Gastric lavage; if vomiting reflex is suppressed, ipecac preparations, activated charcoal, high cleansing enema, correction of acid-base balance and plasma electrolytes, forced diuresis, oxygen therapy, hemodialysis in severe cases. Symptomatic therapy. Diazepam is used in case of seizures.

In the first hours of acute poisoning, acetylcysteine should be administered; if possible orally – at a dose of 140 mg/kg, if oral administration is not possible – at a dose of 150 mg/kg for the first intravenous infusion, then the dose is increased to 300 mg/kg per day.

Adverse reactions.

When using the medicinal product, adverse reactions characteristic of medicinal products containing acetylsalicylic acid, paracetamol, or caffeine may occur in individual patients.

Most of the adverse reactions listed below are clearly dose-dependent and may manifest differently in each individual case.

Possible adverse reactions:

	Common from ≥ 1/100 to < 1/10	Uncommon from ≥ 1/1000 to < 1/100	Rare from ≥ 1/10000 to < 1/1000
Infections and infestations			Pharyngitis
Eye disorders			Eye pain; visual disturbance
Ear and labyrinth disorders		Sensation of noise/tinnitus
Respiratory, thoracic and mediastinal disorders			Nosebleed; pulmonary hypoventilation; rhinorrhea
Gastrointestinal disorders	Nausea; abdominal discomfort	Dry mouth; diarrhea; vomiting	Decreased appetite; belching; flatulence; dysphagia; oral paresthesia; hypersalivation
Nervous system disorders	Dizziness	Tremor; paresthesia; headache; feeling of uneasiness	Dysgeusia; attention disturbance; amnesia; coordination disorder; hyperesthesia; sinus headache
Psychiatric disorders	Nervousness	Insomnia	Anxiety; euphoric mood; tension
Cardiac disorders		Arrhythmia	Hyperemia; peripheral vascular disorders
Skin and subcutaneous tissue disorders			Hyperhidrosis; pruritus; urticaria
Musculoskeletal and connective tissue disorders			Musculoskeletal rigidity; neck pain; back pain; muscle spasms
General disorders		Increased fatigue;	General weakness; chest discomfort
Investigations		Increased heart rate

Data on adverse effects obtained from post-marketing surveillance (frequency unknown):

Ear and labyrinth disorders: deafness, disorientation.

Respiratory, thoracic and mediastinal disorders: rhinitis, nasal congestion, dry cough, dyspnea, shortness of breath, bronchial asthma, bronchospasm in patients sensitive to acetylsalicylic acid and other NSAIDs.

Gastrointestinal disorders: dyspeptic disorders including nausea, vomiting, discomfort and pain in the epigastrium, heartburn, abdominal pain, gastralgia; inflammation of the gastrointestinal tract, erosive-ulcerative lesions of the gastrointestinal tract which in isolated cases may lead to gastrointestinal hemorrhages and perforations with corresponding laboratory and clinical manifestations, oral mucosal ulcers.

Hepatobiliary disorders: hepatotoxicity, increased liver enzyme activity, usually without development of jaundice, hepatonecrosis (dose-dependent effect), transient hepatic insufficiency with elevated liver transaminase levels.

Renal and urinary disorders: nephrotoxicity, kidney damage with papillary necrosis, renal colic when high doses are used, interstitial nephritis.

Endocrine disorders: hypoglycemia, up to hypoglycemic coma.

Nervous system disorders: dizziness, headache, tremor, involuntary muscle contractions, psychomotor agitation and disturbances of orientation and attention, insomnia, sleep disturbances, nervousness, irritability, increased excitability, restlessness, anxiety, general weakness, paresthesia.

Psychiatric disorders: fear sensation, anxiety.

Cardiovascular disorders: tachycardia, palpitations, arterial hypertension, arterial hypotension, arrhythmia.

Blood and lymphatic system disorders: anemia, sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), hemolytic anemia, bruises or bleeding; with prolonged use in high doses – aplastic anemia, pancytopenia, neutropenia, leukopenia, thrombocytopenia, agranulocytosis. Due to the antiplatelet effect of acetylsalicylic acid, the risk of bleeding is increased, including reduced platelet aggregation, hypocoagulability, hemorrhagic syndrome, purpura. Bleeding events observed include intraoperative hemorrhages, hematomas, genitourinary tract bleeding, epistaxis, gingival bleeding, gastrointestinal hemorrhages, and cerebral hemorrhages (especially in patients with uncontrolled arterial hypertension and/or concomitant use of antihemostatic agents), which in rare cases were 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.

Immune system disorders: hypersensitivity reactions, including skin and mucous membrane rashes (e.g., generalized rash, erythematous, maculopapular-urticarial), urticaria, pruritus, swelling, angioneurotic edema, multiform exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome), anaphylaxis, anaphylactic shock, non-cardiogenic pulmonary edema.

In patients with individual hypersensitivity to salicylates, allergic reactions of the skin may occur, including symptoms such as skin hyperemia, sensation of warmth, rash, urticaria, swelling, pruritus, angioneurotic edema, rhinitis, nasal congestion. In patients with bronchial asthma, increased frequency of bronchospasm may occur; allergic reactions ranging from mild to moderate severity affecting the skin, respiratory tract, gastrointestinal tract, and cardiovascular system, manifesting as rashes, urticaria, edema, and pruritus.

Skin and subcutaneous tissue disorders: pruritus, skin and mucous membrane rashes (usually generalized, erythematous, urticaria), angioneurotic edema, multiform exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome).

General disorders: general weakness.

Additionally, when using medicinal products containing similar active substances, the following adverse reactions have been reported (frequency unknown): arterial hypertension, anemia, sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), hemolytic anemia, fear sensation, excitement, sleep disturbances, gastrointestinal inflammation, hypoglycemia up to hypoglycemic coma, hepatonecrosis (dose-dependent effect), hypoperfusion, non-cardiogenic pulmonary edema.

Currently, there are no data indicating that the severity of adverse events associated with the individual active substances of this medicinal product increases or that their spectrum broadens when the combined medicinal product is used according to the instructions.

The increased risk of hemorrhagic complications may persist for 4–8 days after the last dose of acetylsalicylic acid. Severe hemorrhagic complications (e.g., intracranial hemorrhage) have been very rarely observed, particularly in patients with untreated arterial hypertension and/or concomitant anticoagulant therapy. In individual cases, such complications may be life-threatening.

Reporting of suspected adverse reactions.

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

Shelf life. 2 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

6 or 10 tablets in a blister pack; 1 blister pack per carton; 6 or 10 tablets in blister packs.

Dispensing category. Over-the-counter.

Manufacturer. JSC "Pharmaceutical company "Darnytsia".

Manufacturer's address and location of its business activity.

13, Boryspilska Street, Kyiv, 02093, Ukraine.