Ascofen-extra

INSTRUCTIONS FOR MEDICINAL USE OF THE MEDICINAL PRODUCT ASKOFEN-EXTRA

Composition:

Active substances: Each tablet contains 300 mg of acetylsalicylic acid, 100 mg of paracetamol, and 50 mg of caffeine (calculated as dry substance);

Excipients: citric acid monohydrate; potato starch; colloidal anhydrous silicon dioxide; calcium stearate; stearic acid.

Pharmaceutical form. Tablets.

Main physicochemical properties: Intact, regular, round cylindrical tablets with flat upper and lower surfaces, beveled edges, and a score line for division, 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 via 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 action on hypothalamic centers. Acetylsalicylic acid also reduces platelet aggregation.

Paracetamol exerts 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 action of analgesics and antipyretic agents.

Pharmacokinetics.

Not studied.

Clinical characteristics.

Indications.

Mild to moderate pain (headache, migraine, toothache, neuralgia, primary dysmenorrhea). The drug is also used 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, marked arterial hypertension, portal hypertension, tendency 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 such agents. 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 per week or higher, hematological toxicity of methotrexate increases due to reduced renal clearance of methotrexate by anti-inflammatory agents and its displacement from plasma protein binding; therefore, this combination is contraindicated.

MAO inhibitors – when used concomitantly with caffeine, a dangerous increase in blood pressure may occur; therefore, this combination is contraindicated.

Combinations requiring caution.

Paracetamol. Anticonvulsants (including phenytoin, barbiturates, carbamazepine), antidepressants, and other stimulators of microsomal oxidation – these drugs increase the production of hydroxylated active metabolites affecting liver function, potentially leading to severe intoxication even with small overdoses of the drug.

Concomitant use with hepatotoxic agents increases the hepatotoxic effects of drugs. Concurrent 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 is associated with metabolic acidosis with a high anion gap due to pyroglutamic acidosis, particularly in patients with risk factors (see section "Special precautions").

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

Under the influence of paracetamol, the 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 suppress the central nervous system (CNS), and as a competitive antagonist of CNS depressants and adenosine and adenosine triphosphate (ATP) preparations. When used concomitantly with ergotamine, caffeine improves the absorption of ergotamine from the gastrointestinal tract; when used with thyroid-stimulating agents, it enhances the thyroid effect. Caffeine reduces lithium concentration in blood. Caffeine enhances the effect (improves bioavailability) of analgesic-antipyretic drugs and potentiates the effects of xanthine derivatives, alpha- and beta-adrenergic agonists, and psychostimulants.

Acetylsalicylic acid. Concomitant use with uricosuric agents such as benzbromarone or 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 reduced glomerular filtration due to inhibition of vasodilatory prostaglandins and reduced antihypertensive effect. Selective serotonin reuptake inhibitors: increased 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 drug enhances the effects 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 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 the medication 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 insufficiency, the dose should be reduced or the dosing interval increased. The interval between doses should be at least 8 hours in patients with impaired kidney or liver function.

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

During prolonged treatment, 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 medication should preferably be prescribed only if other analgesic-antipyretic agents are ineffective, due to the risk of Reye's syndrome. Vomiting during treatment should raise suspicion of Reye's syndrome.

Note that patients with alcoholic liver disease 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 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. Seek immediate medical attention if these symptoms occur. Cases of high anion gap metabolic acidosis (HAGMA) due to 5-oxoproline (pyroglutamic) acidosis have been reported in patients with severe conditions such as severe renal failure and sepsis, as well as in patients with inadequate nutrition 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, paracetamol should be discontinued immediately and the patient should be closely monitored. Measurement of 5-oxoproline levels in urine may be useful in identifying pyroglutamic acidosis as the underlying cause of high anion gap metabolic acidosis in patients with multiple risk factors.

The use of medications containing acetylsalicylic acid during surgical procedures (including dental surgery) may increase the likelihood or severity of bleeding due to the inhibition of platelet aggregation for some time after administration. The medication 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-Extra.

Bronchospasm or an asthma attack may occur in patients with allergic complications, including bronchial asthma, allergic rhinitis, urticaria, skin itching, mucosal swelling, nasal polyps, especially when combined with chronic respiratory infections, or in patients with hypersensitivity to NSAIDs. Therefore, NSAIDs are contraindicated in these patients.

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.

Due to the mucosal irritation caused by acetylsalicylic acid, the medication should not be used in children because of the risk of Reye's syndrome. Allergic reactions or exacerbation of the underlying disease may occur in patients with bronchial asthma, allergic conditions, or hypersensitivity to NSAIDs.

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

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

Patients who take analgesics daily for mild arthritis should consult a physician. This also applies to patients taking warfarin or similar anticoagulant drugs, and when using Ascofen-Extra prior to starting ibuprofen as an analgesic.

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 disease, congestive heart failure, hypovolemia, major surgery, sepsis, or severe bleeding), as acetylsalicylic acid may increase the risk of impaired kidney function and acute renal failure. 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 for more than 5 days as an analgesic or more than 3 days as an antipyretic without consulting a physician.

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 medication should not be used during pregnancy or breastfeeding.

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

Caffeine increases the risk of spontaneous abortion.

The medication 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.

Due to possible adverse reactions affecting the nervous system (dizziness, increased excitability, impaired orientation and attention), potentially hazardous activities, including driving a vehicle or operating machinery requiring high attention and rapid psychomotor responses, should be avoided during treatment with Ascofen-Extra.

Method of Administration and Dosage.

The product is intended for oral administration.

Adults: 1 tablet 2–3 times daily after meals. The maximum daily dose 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 the drug is used as an analgesic, or 3 days when used as an antipyretic.

Children.

The drug must not be administered to 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.

Symptoms of paracetamol overdose.

Hepatic injury is possible in adults who have ingested 10 g or more of paracetamol, and in children who have ingested more than 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 alcohol consumption; glutathione depletion (digestive disorders, cystic fibrosis, HIV infection, fasting, cachexia)], ingestion of 5 g or more of paracetamol may lead to hepatic injury.

Liver damage may become apparent 12–48 hours after ingestion of excessive doses. During the first 24 hours, symptoms may include 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 lumbar pain, hematuria, proteinuria, and may develop even in the absence of severe kidney damage. Disturbances in glucose metabolism and metabolic acidosis may occur. Cardiac arrhythmias and pancreatitis have also been reported. With prolonged use of high doses, blood-forming organs may be affected, leading to aplastic anemia, thrombocytopenia, pancytopenia, agranulocytosis, neutropenia, and leukopenia. High-dose intake may cause central nervous system (CNS) disturbances such as dizziness, psychomotor agitation, and disorientation; urinary system effects may include nephrotoxicity (renal colic, interstitial nephritis, papillary 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 may be beneficial if the excessive dose of paracetamol was ingested within 1 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 sharply 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 appropriate alternative in remote areas outside hospital settings. General supportive measures should also be implemented.

Symptoms of acetylsalicylic acid overdose.

Salicylate overdose may occur due to chronic intoxication resulting from prolonged therapy (administration of more than 100 mg/kg/day for over 2 days may cause toxic effects), or due to acute, life-threatening intoxication (overdose), which may result from accidental ingestion or unintentional overdose.

Chronic salicylate poisoning may have an insidious onset, as its signs are nonspecific. Moderate chronic intoxication, or salicylism, typically occurs only after repeated ingestion of large doses. Main symptoms include loss of balance, dizziness, tinnitus, deafness, excessive sweating, nausea, vomiting, headache, and confusion. These symptoms may be controlled by reducing the dose. Tinnitus may occur at plasma salicylate concentrations above 150–300 µg/mL. More serious adverse reactions occur at plasma concentrations exceeding 300 µg/mL. Acute intoxication is characterized by significant disturbances in acid-base balance, which may vary depending on the patient's 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 delayed gastric emptying or formation of concretions in the stomach.

Treatment: Intoxication caused by acetylsalicylic acid overdose is managed according to severity and clinical symptoms, using standard poisoning treatment methods. All measures should aim to accelerate drug elimination and restore electrolyte and acid-base balance. Activated charcoal and forced alkaline diuresis are used. Infusion of electrolyte solutions is administered depending 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, attention deficits, insomnia, tremor, nervousness, restlessness) and urinary system effects – nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis). In case of overdose, symptoms may include increased sweating, psychomotor agitation or CNS depression, drowsiness, impaired consciousness, cardiac arrhythmias, tachycardia, extrasystoles, tremor, hyperreflexia, and seizures.

Symptoms of caffeine overdose.

Large 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 antagonists to counteract cardiotoxic effects. No specific antidote is available.

Adverse Reactions

When using Ascofen-Ekstra, adverse reactions typical for drugs containing acetylsalicylic acid, paracetamol, or caffeine may occur in some patients.

Eye disorders: Visual disturbances indicating overdose.

Ear and labyrinth disorders: Tinnitus, ear noise, 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 antiplatelet effect of acetylsalicylic acid, the risk of bleeding is increased. Bleeding events observed include intraoperative hemorrhages, hematomas, genitourinary bleeding, epistaxis, gingival bleeding, gastrointestinal bleeding, and cerebral hemorrhages (especially in patients with uncontrolled arterial hypertension and/or concomitant use of antihemostatic agents), which in rare cases were 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-ulcerative lesions of the gastrointestinal tract, which in rare cases may lead to gastrointestinal bleeding and perforations, 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, anaphylactic shock.

In patients with individual hypersensitivity to salicylates, allergic skin reactions may occur, 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, and cardiovascular system, manifesting as rashes, urticaria, swelling, and pruritus.

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 liver failure with elevated liver transaminases.

Skin and subcutaneous tissue disorders: Pruritus, 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 due to 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 drug registration is important. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

2 years. Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

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

Keep out of the reach of children.

Packaging.

10 tablets per blister; 1 blister per carton.

Supply category. Over-the-counter.

Manufacturer: JSC "Lubnipharm".

Manufacturer's address and location of business activity.

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