Ascofen l

INSTRUCTION for medical use of the medicinal product ASCOFEN L

Composition:

Active substances: 1 tablet contains acetylsalicylic acid 200 mg, paracetamol 200 mg, caffeine 40 mg;

Excipients: citric acid monohydrate; potato starch; calcium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: intact, regular round cylinders, with flat upper and lower surfaces, beveled edges, with a division mark on one side, white in color. Marbling on the tablet surface is permissible.

Pharmacotherapeutic group.

Analgesics. Other analgesics and antipyretics. Acetylsalicylic acid, combinations without psychotropic agents. ATC code N02BA51.

Pharmacological Properties.

Pharmacodynamics.

The drug exerts analgesic, antipyretic, and anti-inflammatory effects. The components contained in the drug enhance each other's effects.

The antipyretic effect of acetylsalicylic acid is mediated through the central nervous system by inhibition of prostaglandin PGE2 synthesis in the hypothalamus in response to the action of 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 is due to its action on hypothalamic centers. Acetylsalicylic acid also reduces platelet aggregation.

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

Caffeine stimulates the central nervous system. It also enhances positive conditioned reflexes, increases motor activity, reduces the effects of sedatives and narcotic substances, and potentiates the effects of analgesics and antipyretic agents.

Pharmacokinetics.

Not studied.

Clinical characteristics.

Indications.

Treatment of mild to moderate pain: headache, toothache, neuralgia, myalgia, arthralgia, and primary dysmenorrhea. As an antipyretic in diseases accompanied by fever.

Contraindications.

Hypersensitivity to components of the drug, hypersensitivity to other xanthine derivatives (theophylline, theobromine), or other salicylates;

• bronchial asthma, urticaria, or rhinitis induced by salicylates or other nonsteroidal anti-inflammatory drugs (NSAIDs) in medical history;
• congenital hyperbilirubinemia, severe renal or hepatic insufficiency, congenital glucose-6-phosphate dehydrogenase deficiency, Gilbert’s syndrome;
• blood disorders, hemorrhagic diathesis, hemophilia, hypoprothrombinemia, leukopenia, anemia, increased tendency to bleeding, thrombosis, thrombophlebitis, hemorrhagic diseases;
• acute gastrointestinal ulcers; gastrointestinal bleeding; surgical procedures associated with significant blood loss;
• severe cardiovascular diseases, including arrhythmias, paroxysmal tachycardia, marked atherosclerosis, severe form of ischemic heart disease, severe heart failure, acute myocardial infarction, severe arterial hypertension, portal hypertension, predisposition to vascular spasm;
• states of increased excitation, sleep disorders, elderly age, glaucoma, alcoholism, hyperthyroidism, acute pancreatitis, prostate hypertrophy, severe forms of diabetes mellitus.

Concomitant use with monoamine oxidase inhibitors (MAOIs), as well as within 2 weeks after discontinuation of MAOIs. Combination with methotrexate at doses of 15 mg per week or higher.

Concomitant use with tricyclic antidepressants or β-blockers.

Interaction with other medicinal products and other types of interactions.

Contraindicated combinations.

Methotrexate – when used concomitantly with salicylates at doses of 15 mg/week or higher, hematological toxicity of methotrexate increases due to reduced renal clearance of methotrexate caused by anti-inflammatory agents and displacement from plasma protein binding; therefore, this combination is contraindicated.

MAO inhibitors – concomitant use with caffeine may lead to dangerous elevation of blood pressure; therefore, this combination is contraindicated.

Combinations requiring caution.

Paracetamol. Anticonvulsant medicinal products (including phenytoin, barbiturates, carbamazepine), antidepressants, and other microsomal oxidation stimulants – these drugs increase the production of hydroxylated active metabolites affecting liver function, increasing the risk of severe intoxication even with minor overdoses of the drug.

Concomitant use with hepatotoxic agents increases the hepatotoxic effects of drugs. Simultaneous use of high-dose paracetamol with isoniazid increases the risk of hepatotoxic syndrome.

Caution should be exercised when using paracetamol concomitantly with flucloxacillin, as this combination has been associated with metabolic acidosis with a high anion gap due to pyroglutamic acidosis, especially in patients with risk factors (see section "Special precautions").

The absorption rate of paracetamol may be increased when used concomitantly with metoclopramide and domperidone, and decreased when used with cholestyramine. Paracetamol reduces the effectiveness of diuretics. Long-term use of paracetamol with coumarin derivatives (warfarin) increases the risk of bleeding. Do not use concomitantly with alcohol.

Under the influence of paracetamol, the elimination half-life of chloramphenicol increases fivefold.

Caffeine. 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 (CNS), as a competitive antagonist of CNS depressants, and as a competitive antagonist of adenosine, ATP preparations. When used concomitantly with ergotamine, caffeine improves the absorption of ergotamine from the gastrointestinal tract; when used with thyrotropic agents, it enhances the thyroid effect. Caffeine reduces lithium concentration in blood. Caffeine enhances the effect (improves bioavailability) of analgesic-antipyretic agents and potentiates the effects of xanthine derivatives, α- and β-adrenomimetics, and psychostimulants.

Acetylsalicylic acid. Concomitant use with uricosuric agents such as benzbromarone and probenecid reduces the uric acid excretion effect (due to competition for renal tubular excretion of uric acid). When used concomitantly with digoxin, its plasma concentration increases due to reduced renal excretion. ACE inhibitors in combination with high doses of acetylsalicylic acid cause decreased glomerular filtration due to inhibition of vasodilatory prostaglandins and reduced antihypertensive effect. Selective serotonin reuptake inhibitors: increase the risk of upper gastrointestinal bleeding due to possible synergistic effect. When used concomitantly with valproic acid, acetylsalicylic acid displaces it from plasma protein binding, increasing its toxicity.

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

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

Special precautions for use.

Before using the medicinal product, consult a physician.

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

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

Use the drug with caution in patients with a history of gastrointestinal 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 drug.

In patients with hepatic or renal functional impairment, the dose of the medicinal product should be reduced or the interval between doses increased. The interval between doses in patients with impaired kidney or liver function should be at least 8 hours.

Since acetylsalicylic acid, like all non-selective nonsteroidal anti-inflammatory drugs (NSAIDs), causes irritation of the gastrointestinal mucosa, the drug should be taken only after food, with water, alkaline mineral water, sodium bicarbonate solution (preferably milk).

During prolonged use of the drug, 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 be prescribed only if 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.

Note that patients with alcoholic liver damage have an increased risk of hepatotoxic effects from paracetamol. The drug may affect laboratory test results for blood glucose and uric acid levels.

Liver diseases increase the risk of liver damage from paracetamol. The risk of overdose is higher in patients with non-cirrhotic alcoholic liver disease.

In patients with severe infections such as sepsis, which are associated with reduced glutathione levels, the risk of metabolic acidosis increases during paracetamol use. 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.

Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported in patients with severe conditions such as severe renal failure and sepsis, as well as in patients with malnutrition or other causes of glutathione deficiency (e.g., chronic alcoholism) who were treated with paracetamol at therapeutic doses for prolonged periods or in combination with flucloxacillin. If high anion gap metabolic acidosis due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol is recommended, and careful monitoring of the patient's condition should be initiated. Measuring 5-oxoproline levels in urine may be helpful in identifying pyroglutamic acidosis as the underlying cause of high anion gap metabolic acidosis in patients with multiple risk factors.

During surgical procedures (including dental surgery), the use of drugs containing acetylsalicylic acid increases the likelihood of bleeding or increased bleeding due to inhibition of platelet aggregation for some time after administration of acetylsalicylic acid. The drug should be discontinued 5–7 days before surgery (to reduce the risk of excessive bleeding).

The patient should inform the physician in advance about taking Ascofen L.

Bronchospasm or an asthma attack may occur in patients with allergic complications, including bronchial asthma, allergic rhinitis, urticaria, skin itching, mucosal edema, nasal polyposis, or combinations thereof with chronic respiratory infections, as well as in patients with hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs); therefore, NSAIDs are contraindicated in these patients.

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

Since acetylsalicylic acid causes irritation of the mucosa, the drug should not be used in children due to the risk of Reye's syndrome. Allergic reactions or exacerbation of the underlying disease may occur in patients with bronchial asthma, allergic diseases, or hypersensitivity to NSAIDs.

During treatment with the drug, excessive consumption of beverages containing caffeine (e.g., coffee, tea) is not recommended. 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 (increases the risk of gastrointestinal bleeding).

Patients should consult a physician if they take analgesics daily for mild forms of arthritis; if they are taking warfarin or similar anticoagulant drugs; or before starting ibuprofen as an analgesic while using Ascofen L.

Do not use in patients with hypersensitivity to analgesic, anti-inflammatory, or antirheumatic agents. Use with caution when co-administered with anticoagulants, and in patients with circulatory disorders (e.g., renal vascular pathology, congestive heart failure, hypovolemia, major surgery, sepsis, or severe bleeding), as acetylsalicylic acid may also increase the risk of impaired kidney function and acute renal failure. Ibuprofen may reduce the inhibitory effect of acetylsalicylic acid on platelet aggregation.

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

Ascofen L 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 or increased bleeding tendency. Use with particular caution when used concomitantly with anticoagulants (coumarins and heparin), in patients with impaired liver function or kidney disease, and during concomitant anti-inflammatory therapy.

Use during pregnancy or breastfeeding.

The medicinal product should not be used during pregnancy or breastfeeding.

Acetylsalicylic acid has teratogenic effects; when used during the first trimester of pregnancy, it may cause cleft palate; in the third trimester, it may inhibit labor activity (by inhibiting prostaglandin synthesis), lead to closure of the fetal arterial duct, resulting in pulmonary vascular hyperplasia and pulmonary hypertension in the pulmonary circulation, impair kidney function with possible subsequent development of renal failure and oligohydramnios, and prolong bleeding time due to antiplatelet (anti-aggregatory) effects, which may occur even after very low doses.

Caffeine increases the risk of spontaneous abortion.

The drug passes into breast milk, increasing the risk of bleeding in infants due to impaired platelet function.

Ability to affect reaction speed when driving or operating machinery.

Since adverse reactions affecting the nervous system (dizziness, increased excitability, impaired orientation and attention) may occur, patients should avoid driving vehicles or performing tasks requiring high attention and rapid psychomotor reactions while using Ascofen L.

Dosage and Administration.

The medicinal product is intended for oral administration.

Adults: 1 tablet 2–3 times daily after meals. The maximum daily dose of the medicinal product is 6 tablets (in 3 divided doses).

The duration of treatment depends on the course and severity of the disease and should not exceed 5 days when used as an analgesic and 3 days as an antipyretic.

Do not take together with other medicinal products containing paracetamol.

Children.

The drug is contraindicated in children due to the risk of developing Reye's syndrome (hyperpyrexia, metabolic acidosis, neurological and psychiatric disturbances, vomiting, liver dysfunction) associated with hyperthermia during viral infections.

Overdose.

Paracetamol overdose symptoms.

Hepatic injury is possible in adults who have ingested 10 g or more of paracetamol and in children who have received a dose exceeding 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 drugs inducing liver enzymes; chronic excessive ethanol consumption; glutathione depletion (digestive disorders, cystic fibrosis, HIV infection, fasting, cachexia)), ingestion of 5 g or more of paracetamol may result in hepatic injury.

Hepatic injury may become evident 12–48 hours after ingestion of excessive doses. Within the first 24 hours, the following symptoms may occur: pallor, nausea, vomiting, anorexia, and abdominal pain. In severe poisoning, hepatic failure may progress to encephalopathy, hypoglycemia, coma, and death. Acute renal failure with acute tubular necrosis may present as severe flank pain, hematuria, proteinuria, and may develop even in the absence of severe kidney damage. Glucose metabolism disturbances and metabolic acidosis may also occur. Cardiac arrhythmias and pancreatitis have also been reported. With prolonged use of high doses, hematopoietic system disorders such as aplastic anemia, thrombocytopenia, pancytopenia, agranulocytosis, neutropenia, and leukopenia may develop. High-dose intake may cause central nervous system (CNS) effects such as dizziness, psychomotor agitation, and disorientation; and urinary system effects such as nephrotoxicity (renal colic, interstitial nephritis, capillary necrosis).

In case of overdose, prompt medical assistance is required. The patient should be immediately transported 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. Administration of activated charcoal should be considered if the excessive dose of paracetamol was ingested within the past hour. Plasma paracetamol concentration should be measured 4 hours or later after ingestion (earlier concentrations are unreliable). Treatment with N-acetylcysteine may be administered within 24 hours after paracetamol ingestion, but maximum protective effect is achieved when administered within 8 hours. The efficacy of the antidote decreases significantly after this time. If necessary, intravenous N-acetylcysteine should be administered according to current guidelines. In the absence of vomiting, oral methionine may be used as an alternative in remote areas outside hospital settings. General supportive measures should also be implemented.

Acetylsalicylic acid overdose symptoms.

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 acute intoxication, which is life-threatening (overdose), potentially caused by accidental ingestion (especially in children) or unintentional overdose.

Chronic salicylate poisoning may have an insidious onset, as its symptoms are nonspecific. Moderate chronic intoxication, or salicylism, typically occurs only after repeated intake of large doses. Main symptoms include: loss of balance, dizziness, tinnitus, hearing loss, excessive sweating, nausea and vomiting, headache, and confusion. These symptoms may be managed by dose reduction. Tinnitus may occur at plasma salicylate concentrations exceeding 150–300 µg/mL. More serious adverse reactions occur at plasma concentrations above 300 µg/mL.

Acute intoxication is characterized by marked acid-base imbalance, which may vary depending on age and severity of intoxication. The severity of the condition cannot be determined solely by plasma salicylate concentration.

Absorption of acetylsalicylic acid may be delayed due to prolonged gastric emptying or formation of gastric concretions.

Treatment: Intoxication caused by acetylsalicylic acid overdose is managed according to severity and clinical symptoms using standard poisoning treatment protocols. All measures should aim to accelerate drug elimination and restore electrolyte and acid-base balance. Activated charcoal and forced alkaline diuresis are recommended. Infusion of electrolyte solutions should be administered based on acid-base and electrolyte status. Hemodialysis is indicated in severe cases. Long-term use of high doses may lead to aplastic anemia, thrombocytopenia, pancytopenia, agranulocytosis, neutropenia, and leukopenia. High-dose intake may cause central nervous system disturbances (dizziness, psychomotor agitation, disorientation, insomnia, tremor, nervousness, anxiety), and urinary system effects – nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis). In case of overdose, symptoms may include excessive sweating, psychomotor agitation or CNS depression, somnolence, impaired consciousness, cardiac arrhythmias, tachycardia, extrasystoles, tremor, hyperreflexia, and seizures.

Caffeine overdose symptoms.

High doses of caffeine may cause epigastric pain, vomiting, diuresis, rapid breathing, extrasystoles, tachycardia, or cardiac arrhythmia, and effects on the central nervous system (dizziness, insomnia, nervousness, nervous excitation, syndrome of increased neuromuscular excitability, headache, irritability, affective state, anxiety, restlessness, tremor, seizures). Clinically significant symptoms of caffeine overdose may also be associated with liver injury caused by paracetamol.

Treatment. Prompt medical assistance is required in case of overdose, even if symptoms are absent. Administration of oral methionine or intravenous acetylcysteine may be beneficial within 48 hours after overdose. General supportive measures and symptomatic therapy should also be implemented, including use of β-adrenergic receptor antagonists to counteract cardiotoxic effects. No specific antidote is available.

Adverse Reactions

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

Eye disorders: Visual disturbances indicating overdose.

Ear and labyrinth disorders: Tinnitus, ringing in the ears, disorientation.

Respiratory system disorders: Rhinitis, nasal congestion, bronchospasm in patients sensitive to acetylsalicylic acid and other NSAIDs.

Cardiovascular system disorders: Tachycardia, palpitations, arterial hypertension, arrhythmia.

Blood and lymphatic system disorders: Anemia, sulfhemoglobinemia, and methemoglobinemia (cyanosis, dyspnea, chest pain), hemolytic anemia, bruising or bleeding. With prolonged use in high doses – aplastic anemia, pancytopenia, neutropenia, thrombocytopenia, agranulocytosis. Due to the anti-aggregant effect of acetylsalicylic acid on platelets, the risk of bleeding is increased. Bleeding events observed include intraoperative hemorrhages, hematomas, genitourinary tract bleeding, epistaxis, gingival bleeding, gastrointestinal bleeding, and cerebral hemorrhages (especially in patients with uncontrolled arterial hypertension and/or concomitant use of anticoagulant agents), which in rare cases may be life-threatening.

Nervous system disorders: Headache, nervousness, restlessness, dizziness, tremor, paresthesia, increased excitability, irritability, sleep disturbances, insomnia, general weakness, agitation.

Psychiatric disorders: Feelings of fear, restlessness, anxiety.

Gastrointestinal disorders: Dyspeptic symptoms including nausea, vomiting, epigastric discomfort and pain, heartburn, abdominal pain; inflammation of the gastrointestinal tract, erosive and ulcerative lesions of the gastrointestinal tract, which in rare cases may lead to gastrointestinal bleeding and perforation with corresponding laboratory and clinical manifestations; oral mucosal ulcers.

Metabolism and nutrition disorders: Metabolic acidosis with high anion gap (frequency unknown).

Immune system disorders: Hypersensitivity reactions, including anaphylaxis and anaphylactic shock.

In patients with individual hypersensitivity to salicylates, skin allergic reactions may develop, including symptoms such as skin hyperemia, sensation of warmth, rash, urticaria, swelling, itching, angioedema, 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, cardiovascular system, and manifesting as rashes, urticaria, swelling, and itching.

Endocrine system disorders: Hypoglycemia, up to hypoglycemic coma.

Renal and urinary system disorders: Nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis).

Hepatobiliary system disorders: Liver function abnormalities, increased liver enzyme activity (usually without jaundice), hepatonecrosis (dose-dependent effect), transient hepatic failure with elevated liver transaminase levels.

Skin and subcutaneous tissue disorders: Skin itching, skin and mucosal rashes (usually generalized, erythematous rash, urticaria), angioedema, erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome).

General disorders: General weakness.

Other: Bleeding may lead to acute and chronic post-hemorrhagic/iron-deficiency anemia (due to so-called occult microbleeding) with corresponding laboratory findings and clinical symptoms such as asthenia, pallor of the skin, hypoperfusion, non-cardiogenic pulmonary edema.

Description of selected 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 taking paracetamol (see section "Special precautions for use"). Pyroglutamic acidosis may occur due to low glutathione levels in these patients.

Reporting suspected adverse reactions.

Reporting of adverse reactions after medicinal product registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through 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.

6 tablets in blisters;

6 tablets per blister, 10 blisters per pack;

10 tablets in blisters;

10 tablets per blister, 1, 5, or 10 blisters per pack.

Availability classification.

Over-the-counter: tablets No. 6, No. 10.

By prescription only: tablets No. 50 (5×10), No. 60 (6×10), No. 100 (10×10).

Manufacturer.

PJSC "Lubnifarm".

Manufacturer's address and location of business activity.

16, Barvinkova Street, Lubny, Poltava region, 37500, Ukraine.