Theophedrine ic®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT THEOFEDRIN IS® (Theophedrin IS)

Composition:

Active substances: anhydrous theophylline, anhydrous caffeine, phenobarbital, ephedrine hydrochloride, paracetamol, dry extract of belladonna (Atropa belladonna) (5–9:1, extraction solvent: 70% ethanol), cytisine;

One tablet contains: anhydrous theophylline 100 mg (0.1 g), anhydrous caffeine (calculated as monohydrate) 50 mg (0.05 g), phenobarbital 20 mg (0.02 g), ephedrine hydrochloride 20 mg (0.02 g), paracetamol 200 mg (0.2 g), dry extract of belladonna (Atropa belladonna) (5–9:1, extraction solvent: 70% ethanol) 3 mg (0.003 g), cytisine 0.1 mg (0.0001 g);

Excipients: potato starch, calcium stearate, microcrystalline cellulose, sodium croscarmellose, copovidone, anhydrous colloidal silicon dioxide, talc.

Pharmaceutical form. Tablets.

Main physicochemical properties: white tablets with a creamy shade and slightly noticeable specks, flat cylindrical in shape with beveled edges; a commercial trademark is imprinted on one side of the tablet, and a dividing line on the other side.

Pharmacotherapeutic group. Agents for systemic use in obstructive respiratory diseases. Xanthines. Theophylline combinations with psycholeptics.

ATC code R03DA74.

Pharmacological properties.

Pharmacodynamics.

A combined medicinal product that causes relaxation of bronchial smooth muscles. The medicinal product increases bronchial lumen and reduces respiratory resistance, dilates pulmonary vessels, increases heart rate and force of cardiac contractions, enhances cardiac output; exerts a moderate diuretic effect, exhibits M-cholinolytic activity and anti-inflammatory action.

Theophylline belongs to the methylxanthine group. Its mechanism of action is mediated by blockade of adenosine receptors, inhibition of phosphodiesterase, increased intracellular cAMP levels, and decreased intracellular calcium ion concentration, resulting in relaxation of bronchial smooth muscle and development of a pronounced bronchodilator effect. It stimulates the respiratory center and exhibits a moderate diuretic effect.

Caffeine stimulates the psychomotor centers of the brain, exhibits analeptic activity, enhances the effect of analgesics, and relieves drowsiness and sensations of increased fatigue.

Phenobarbital is a derivative of barbituric acid. It exerts spasmolytic and myorelaxant effects. In the composition of the medicinal product, it provides mild and prolonged sedative action and contributes to correction of the psychoemotional state in patients with bronchoobstructive syndrome of various origins.

Ephedrine is a mixed-action sympathomimetic. It exerts a spasmolytic effect on bronchial smooth muscle due to pronounced stimulation of β2-adrenergic receptors. Facilitation of sputum expectoration and bronchial deobstruction are due to ephedrine's bronchodilating effect. It stimulates the respiratory center.

Paracetamol is a non-narcotic analgesic that blocks cyclooxygenase, primarily in the central nervous system (CNS), affecting pain and thermoregulatory centers in the hypothalamus.

Belladonna extract contains a complex of alkaloids exhibiting anticholinergic (cholinolytic) effects. It exerts analgesic and spasmolytic actions.

The alkaloid cytisine acts as a respiratory analeptic, promoting stimulation of respiration through reflex activation of the respiratory center by enhanced impulses from carotid bodies.

Pharmacokinetics.

All active ingredients of the medicinal product are readily and almost completely absorbed in the gastrointestinal tract.

After oral administration, the therapeutic plasma concentration of theophylline is reached within 1–1.5 hours and maintained for 6–12 hours. Theophylline is metabolized in the liver into inactive metabolites and is primarily excreted by the kidneys.

Caffeine is well absorbed in the stomach and small intestine. It is metabolized in the liver into three metabolites: paraxanthine, theobromine, and theophylline. The elimination half-life ranges from 3.5 to 6 hours. It is excreted in urine, with approximately 10% excreted unchanged.

Phenobarbital is approximately 45% plasma protein-bound and only partially metabolized by hepatic microsomal enzymes. Maximum plasma concentration is achieved within 1–2 hours after administration. The sedative effect of phenobarbital appears 20–60 minutes after taking the medicinal product and lasts for 6–10 hours. Phenobarbital is uniformly distributed in organs and tissues. It crosses histohematogenous barriers, enters breast milk, and readily crosses the placenta. It is slowly excreted from the body, creating conditions for drug accumulation. The elimination half-life in adults is 2–4 days. It is excreted by the kidneys both unchanged (up to 25% of the dose is excreted in urine) and as metabolites. Renal excretion of unchanged phenobarbital depends on urine pH and may increase in alkaline conditions.

Ephedrine hydrochloride is well absorbed. After oral administration, maximum effect is achieved within 1 hour and lasts approximately 4 hours (2–8 hours). Ephedrine is almost completely excreted unchanged in urine, along with a small amount of metabolites formed in the liver. The elimination half-life of ephedrine is 3–6 hours.

Paracetamol is bound to plasma proteins. Its elimination half-life is 1–4 hours. It is metabolized in the liver into glucuronide and sulfate conjugates of paracetamol. It is excreted primarily by the kidneys as conjugation products, with less than 5% excreted unchanged.

Clinical characteristics.

Indications.

Respiratory diseases associated with bronchospasm (chronic bronchitis, bronchial asthma, chronic obstructive pulmonary disease (COPD)).

Contraindications.

Hypersensitivity to the components of the drug, other xanthine derivatives (theobromine, pentoxifylline, etc.), congenital hyperbilirubinemias (including Gilbert's syndrome), congenital glucose-6-phosphate dehydrogenase deficiency, porphyria, sepsis, blood disorders (including leukopenia, severe anemia), recent cerebrovascular events, severe cardiovascular diseases including cardiac arrhythmias (including extrasystole), severe atherosclerosis, severe forms of ischemic heart disease (including unstable angina, acute myocardial infarction), severe arterial hypertension, severe arterial hypotension; history of bleeding, peptic ulcer of the stomach and duodenum (in the stage of exacerbation), gastroesophageal reflux, acute pancreatitis, severe hepatic or renal dysfunction, prostatic hypertrophy with urinary retention, diabetes mellitus, hyperthyroidism, pheochromocytoma, retinal hemorrhage, glaucoma, epilepsy, increased seizure susceptibility, myasthenia gravis, severe respiratory depression, pulmonary edema, conditions of increased excitation, sleep disorders, alcoholism, drug and narcotic dependence, depressive disorders with patient's tendency toward suicidal behavior.

Do not use together with monoamine oxidase inhibitors (MAOIs) or within 2 weeks after discontinuation of their use.

Interaction with other medicinal products and other types of interactions.

During treatment with Theofedrin ISÒ, consumption of alcoholic beverages, as well as food and drinks containing methylxanthines (chocolate, coffee, tea, cocoa, Coca-Cola and similar tonic drinks), and use of drugs stimulating the CNS (theobromine, pentoxifylline), may enhance the stimulatory effects of theophylline, caffeine, and ephedrine on the CNS.

Interactions related to theophylline

The effect of theophylline may be enhanced when used concomitantly with zafirlukast, paracetamol, phenylbutazone, allopurinol, probenecid, cimetidine, nizatidine, ranitidine, fluoroquinolones (including ciprofloxacin, enoxacin), macrolides, imipenem, lincomycin, furosemide, calcium antagonists, isoprenaline, amiodarone, propafenone, mexiletine, propranolol (pharmacokinetic interaction – theophylline metabolic clearance decreases by 30–50%), pentoxifylline (oxpentifylline), ticlopidine, oral contraceptives, carbimazole, fluconazole, vilazodone, tacrine, disulfiram, thiabendazole, isoniazid, methotrexate, α-interferons, influenza vaccine. When these drugs are used concomitantly with Theofedrin ISÒ, serum theophylline concentration should be monitored and the dose reduced if necessary. Combination of theophylline with fluvoxamine should be avoided. Ephedrine enhances the effect of theophylline.

Due to increased theophylline clearance, the drug's effect may be reduced when used concomitantly with isoproterenol, antiepileptic agents (e.g., phenytoin, carbamazepine, primidone), barbiturates (especially phenobarbital and pentobarbital), aminoglutethimide, magnesium hydroxide, moricizine, rifampicin, ritonavir, sulfinpyrazone. When these drugs are used concomitantly with Theofedrin ISÒ, serum theophylline concentration should be monitored and the dose increased if necessary. The effect of the drug may be lower in smokers. Concomitant use of theophylline with adrenergic receptor antagonists should be avoided, as theophylline may lose its bronchodilating effect.

Theophylline may enhance the effects of β-adrenergic agonists, diuretics, and reserpine. Theophylline may reduce the effectiveness of adenosine, lithium carbonate, and β-adrenergic antagonists. Hypokalemia may occur during theophylline treatment, especially when used concomitantly with α-adrenergic agonists, thiazide diuretics, furosemide, corticosteroids, and also in the presence of hypoxemia; therefore, periodic monitoring of serum potassium levels is recommended.

Concomitant use of theophylline with herbal preparations containing St. John’s wort (Hypericum perforatum) should be avoided. Combinations with benzodiazepines or lomustine should be used with particular caution. Halothane may cause serious cardiac arrhythmias in patients taking theophylline.

Concomitant use of theophylline with ketamine or quinolones reduces the seizure threshold; with doxapram – may cause CNS stimulation. Such combinations should be avoided.

Interactions related to caffeine

Caffeine reduces the effect of opioid analgesics, anxiolytics, hypnotics, and sedatives; it acts as an antagonist of anesthetic agents and other CNS depressants, and as a competitive antagonist of adenosine agents. Caffeine reduces lithium blood concentration. Caffeine enhances the effect of analgesic-antipyretics and potentiates the effects of xanthine derivatives, α- and β-adrenergic agonists, and psychostimulants. Concomitant use of caffeine with MAO inhibitors may cause a dangerous increase in blood pressure. When caffeine is used concomitantly with ergotamine, absorption of ergotamine from the gastrointestinal tract improves; with thyroid agents – thyroid effect is enhanced. Hormonal contraceptives, cimetidine, isoniazid enhance the effect of caffeine. Concurrent intake of certain hydrolase inhibitors (including ciprofloxacin) may prolong elimination of caffeine and its metabolite paraxanthine.

Interactions related to phenobarbital

Phenobarbital induces liver enzymes and thus may accelerate the metabolism of certain drugs metabolized by these enzymes (including paracetamol, salicylates, indirect anticoagulants, cardiac glycosides (digoxin), antimicrobials (chloramphenicol, doxycycline, metronidazole, rifampicin), antivirals, antifungals (griseofulvin, itraconazole), antiepileptics (anticonvulsants), psychotropics (tricyclic antidepressants), hormones (estrogens, progestogens, corticosteroids, thyroid hormones), immunosuppressants (glucocorticoids, cyclosporine, cytostatics), antiarrhythmics, antihypertensives (β-blockers, calcium channel blockers), oral hypoglycemic agents, etc.). Phenobarbital may accelerate the metabolism of oral contraceptives, leading to loss of their efficacy. Phenobarbital enhances the effect of analgesics, anesthetics, and drugs that depress the CNS. Concomitant use of phenobarbital with drugs exhibiting sedative effects leads to enhanced sedative-hypnotic effect and may be accompanied by respiratory depression. Possible influence of phenobarbital on blood concentrations of phenytoin, carbamazepine, clonazepam. Drugs with acidic properties (ascorbic acid, ammonium chloride) enhance the effect of barbiturates and shorten the elimination half-life of ephedrine. Patients receiving concomitant treatment with valproate and phenobarbital should be monitored for signs of hyperammonemia. In half of reported cases, hyperammonemia was asymptomatic and did not necessarily lead to encephalopathy. MAO inhibitors (including furazolidone, procarbazine, selegiline) prolong the action of phenobarbital and potentiate the pressor effect of ephedrine and caffeine (risk of hypertensive crisis). Rifampicin may reduce the effect of phenobarbital. When used together with gold preparations, the risk of kidney damage increases. With prolonged use in combination with nonsteroidal anti-inflammatory drugs (NSAIDs), there is a risk of gastric ulceration and bleeding. Concomitant use of phenobarbital with zidovudine enhances the toxicity of both drugs.

Interactions related to ephedrine

Concomitant use of Theofedrin ISÒ with drugs that, when used together with ephedrine, increase the risk of intoxication, dangerous arrhythmias, severe and acute arterial hypertension, should be avoided, namely: cardiac glycosides, quinidine, oxytocin, tricyclic antidepressants, non-selective adrenergic blockers (propranolol), antihypertensive drugs (guanethidine, reserpine), ergot alkaloids (ergometrine, ergotamine, methylergometrine), antiparkinsonian agents (levodopa, bromocriptine), and vasodilators (tolazoline).

Interactions related to paracetamol

The rate of paracetamol absorption may be increased when used with metoclopramide and domperidone, and decreased when used with cholestyramine. Anticonvulsant drugs (including phenytoin, barbiturates, carbamazepine), which stimulate hepatic microsomal enzyme activity, may enhance the hepatotoxic effect of paracetamol due to increased formation of hepatotoxic metabolites. Barbiturates reduce the antipyretic effect of paracetamol. Concomitant use of tricyclic antidepressants may increase the elimination half-life of paracetamol and increase the risk of hepatotoxic effects. Use of paracetamol in combination with hepatotoxic agents increases the toxic effects of the drugs on the liver. Concomitant use of high doses of paracetamol with isoniazid increases the risk of hepatotoxic syndrome. The frequency of neutropenia increases when paracetamol and zidovudine are used concomitantly. The anticoagulant effect of warfarin and other coumarins may be enhanced, increasing the risk of bleeding, with long-term, regular daily use of paracetamol; occasional use does not show significant effect. Paracetamol reduces the effectiveness of diuretics. Paracetamol should be used cautiously in combination with flucloxacillin, as this concomitant use is associated with metabolic acidosis with a high anion gap due to pyroglutamic acidemia, especially in patients with risk factors (see section "Special precautions"). Do not use simultaneously with alcohol.

Interactions related to belladonna extract

Belladonna extract weakens or neutralizes the effect of m-cholinomimetics, anticholinesterase drugs, and weakens the effect of morphine. Belladonna extract potentiates the arrhythmogenic effect of MAO inhibitors, cardiac glycosides, clonidine, the cholinolytic properties of quinidine and procainamide, and the effects of barbiturates, ganglion blockers, β-adrenergic agonists, antihistamines, tranquilizers, tricyclic antidepressants. Concomitant use with digitalis preparations causes cardiac arrhythmias.

Interactions related to cytisine

Cytisine should not be used concomitantly with antituberculosis drugs due to the risk of enhanced adverse effects. Concomitant use of cytisine with cholinomimetics and anticholinesterase drugs may enhance cholinomimetic adverse effects. Concomitant use with lipid-lowering agents (statins) increases the risk of myalgia. Concomitant use of cytisine with antihypertensive drugs may reduce their efficacy.

Special precautions for use.

Prior to administration of the medicinal product, patients with hepatic or renal disorders should consult a physician. It should be noted that in patients with alcoholic non-cirrhotic liver damage, the risk of hepatotoxic effects of paracetamol is increased. The medicinal product should be administered with caution and only in cases of acute necessity to patients with certain forms of schizophrenia, history of peptic ulcer of the stomach and duodenum (see section "Contraindications"), patients with occlusive vascular diseases who have an increased risk of peripheral ischemia (see section "Contraindications"); patients with prostate disorders who have an increased risk of urinary retention (see section "Contraindications"); patients with mild to moderate renal and hepatic impairment (see section "Contraindications"); patients with hyperkinesia, adrenal insufficiency, acute and persistent pain, acute intoxication with medicinal products. The dosage of the medicinal product should be carefully monitored.

The use of theophylline may worsen the condition of patients with gastroesophageal reflux (exacerbate reflux) due to its effect on smooth muscles of the cardioesophageal sphincter (see section "Contraindications").

During treatment, the dose of the medicinal product should be reduced and the condition of patients with reduced oxygen concentration in blood (hypoxemia), persistent fever, pneumonia, viral infections (especially influenza), and acute life-threatening conditions should be carefully monitored.

In patients with severe infections such as sepsis, associated with reduced glutathione levels, administration of paracetamol increases the risk of metabolic acidosis (for information on sepsis, see section "Contraindications"). Symptoms of metabolic acidosis include deep, rapid, or labored breathing, nausea, vomiting, and loss of appetite. Immediate medical attention should be sought if these symptoms occur.

Cases of high anion gap metabolic acidosis caused by pyroglutamic acidemia have been reported in critically ill patients, such as those with renal failure and sepsis, or in patients with malnutrition or other conditions associated with glutathione deficiency (e.g., alcoholism), who received paracetamol at therapeutic doses for prolonged periods or received combined treatment with paracetamol and flucloxacillin. In suspected cases of high anion gap metabolic acidosis due to pyroglutamic acidemia, immediate discontinuation of paracetamol is recommended, along with close monitoring of the patient. Monitoring urinary 5-oxoproline levels may be helpful in identifying pyroglutamic acidemia as the underlying cause of high anion gap metabolic acidosis in patients with multiple risk factors.

Patients with mild forms of arthritis who take analgesics daily, and patients receiving warfarin or similar anticoagulant agents, should consult a physician before using the medicinal product Theofedrin IS®.

Do not use concomitantly with ethanol or with other medicinal products containing ethanol. Do not take the medicinal product with other medications containing paracetamol to avoid exceeding the maximum daily dose of paracetamol.

Theophylline may increase levels of fatty acids and catecholamines in urine.

Ephedrine may affect doping test results in athletes.

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

Due to the presence of cytisine, smoking during treatment with Theofedrin IS® may lead to increased adverse effects of nicotine (nicotine intoxication).

Patients aged 60 years and older are more sensitive to the effects of medicinal products; therefore, the medicinal product should be used with caution in this age group.

The risk of developing Stevens-Johnson syndrome or Lyell's syndrome is highest during the first weeks of treatment.

Do not exceed the recommended doses. In case of overdose, seek immediate medical attention due to the risk of liver damage, even if the patient feels well.

Prolonged use of the medicinal product without consulting a physician may be hazardous. Avoid prolonged use due to the potential for phenobarbital accumulation and development of drug dependence. Phenobarbital is associated with withdrawal syndrome; therefore, discontinuation of the medicinal product should be gradual.

If symptoms persist, consult a physician.

Use during pregnancy or breastfeeding.

Active ingredients of the medicinal product cross the placental barrier and may have harmful effects on the fetus. Do not use the medicinal product during pregnancy.

Active ingredients of the medicinal product pass into breast milk. Do not use the medicinal product during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

During treatment, patients should refrain from driving or operating machinery.

Dosage and Administration

Administer orally after meals. To prevent disruption of nighttime sleep, it is advisable to take the medication in the first half of the day.

For adults, the recommended dose is ½–1 tablet once daily. In severe cases, the daily dose may be increased up to the maximum dose of 5 tablets, divided into 2–3 doses.

The duration of treatment is determined individually by a physician, depending on the nature, characteristics of the disease course, and the therapeutic effect of the medication.

Children

Do not use.

Overdose

Possible intensification of adverse reactions.

Symptoms: nausea, vomiting, hematemesis, dehydration, epigastric pain, diarrhea, pancreatitis, acute heart failure, cardiovascular depression including arrhythmias; decreased arterial blood pressure, up to collapse; arterial hypertension, extrasystoles, tachycardia, respiratory depression with risk of respiratory arrest, rapid breathing, hyperventilation, psychomotor agitation or central nervous system (CNS) depression up to coma; dementia, seizures, hyperreflexia, dizziness, insomnia, nervous excitement, anxiety, irritability, affective disturbances, muscle hypertonia, tremor, toxic psychosis, delirium, metabolic acidosis, hypokalemia, hypomagnesemia, hypophosphatemia, hypercalcemia, hyperglycemia, respiratory alkalosis, rhabdomyolysis, decreased urine output, acute renal failure, weakness, decreased body temperature.

If a patient has taken a dose exceeding the recommended dose, immediate medical attention is required due to the risk of liver damage! Liver 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 of paracetamol. Ingestion of 5 g or more of paracetamol may lead to liver injury in patients with the following risk factors: long-term use of carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John’s wort, or other drugs that induce liver enzymes; chronic excessive alcohol consumption; glutathione deficiency, for example, due to eating disorders, HIV infection, fasting, cystic fibrosis, or cachexia.

Symptoms of paracetamol overdose within the first 24 hours: pallor, nausea, vomiting, loss of appetite, abdominal pain. Liver damage may become evident 12–48 hours after overdose. Glucose metabolism disturbances and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, hemorrhage, hypoglycemia, coma, and fatal outcome. Acute renal failure with acute tubular necrosis may present as severe flank pain, hematuria, proteinuria, and may develop even in the absence of severe liver injury. Cases of cardiac arrhythmias and pancreatitis have been reported.

With prolonged use of high-dose paracetamol, hematological disorders such as pancytopenia, aplastic anemia, thrombocytopenia, leukopenia, agranulocytosis, and neutropenia may develop. High-dose intake may cause CNS-related symptoms such as dizziness, psychomotor agitation, and disorientation; urinary system-related effects may include nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis).

Treatment. In most cases, reducing the dose or temporarily discontinuing the medication is sufficient. In severe cases of overdose and intoxication, gastric lavage, administration of activated charcoal, and symptomatic therapy should be performed [primarily monitoring of vital functions (respiration, pulse, blood pressure)].

In theophylline overdose, osmotic laxatives may be used. In severe cases, theophylline elimination can be accelerated by hemoperfusion or hemodialysis. If severe overdose is suspected, plasma theophylline levels should be monitored until normalization. Serum potassium levels should be urgently determined and monitored until hypokalemia is corrected. In case of low serum potassium, serum magnesium levels should be determined as soon as possible.

In caffeine overdose, β-adrenergic receptor antagonists may help alleviate cardiotoxic effects.

In paracetamol overdose, prompt medical intervention is required. The patient should be immediately transported to a hospital, even if early symptoms 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 within 1 hour after ingestion of an excessive paracetamol dose. Plasma paracetamol concentration should be measured 4 hours or later after overdose (earlier concentrations are unreliable). Treatment with N-acetylcysteine may be administered within 24 hours after paracetamol overdose, but maximum protective effect is achieved when administered within 8 hours of ingestion. The efficacy of the antidote declines 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.

Adverse Reactions

When the medicinal product is used at recommended doses, adverse reactions occur very rarely and are dose- and duration-dependent.

The following adverse reactions are associated with the active substances of the medicinal product.

Psychiatric disorders: paradoxical excitation, restlessness, irritability, anxiety, fear, sleep disturbances (including insomnia, drowsiness), increased fatigue, cognitive disorders (including hallucinations, decreased attention concentration, confusion, delirium), delirium, depression.

Nervous system disorders: headache, dizziness, slowed reaction time, impaired motor coordination, ataxia, tremor, seizures, nystagmus, mydriasis, weakness. Cases of paraesthesia associated with ephedrine use have been reported.

Skin and mucous membranes: facial skin hyperemia, exfoliative dermatitis, photosensitization.

Musculoskeletal system: muscle spasms, myalgia, rhabdomyolysis; with prolonged use, there is a risk of impaired osteogenesis and rickets development.

Urinary and reproductive system: increased urine volume, urinary retention, aseptic pyuria.

Cardiovascular system: rapid heartbeat or uncomfortable awareness of heartbeat (palpitations), arrhythmia (including tachycardia, bradycardia, extrasystoles), fluctuations in blood pressure (including sudden drop in blood pressure), circulatory disturbances in extremities, angina pectoris, cardialgia, chest pain, heart failure, dyspnea.

Blood and lymphatic system disorders: agranulocytosis, thrombocytopenia, anemia, hemolytic anemia, sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), bleeding, bruising; if concentrations of the active substances in blood serum exceed therapeutic levels, leukocytosis and leukopenia are possible.

Immune system disorders: hypersensitivity reactions, including anaphylactic reactions, angioneurotic edema, skin itching, skin and mucous membrane rashes (usually generalized rash, erythematous, urticaria), erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome), bronchospasm, collapse.

Antiepileptic hypersensitivity syndrome (AHS): elevated body temperature, skin rash, lymphadenopathy, lymphocytosis.

Gastrointestinal disorders: feeling of heaviness or pain in the epigastric region, nausea, vomiting, diarrhea, constipation, heartburn, stimulation of gastric acid secretion; with prolonged use – decreased appetite / anorexia, exacerbation of peptic ulcer disease.

Hepatobiliary system: liver function abnormalities, elevated liver enzyme activity, usually without development of jaundice; hepatitis.

Metabolic and nutritional disorders: if concentrations of the active substances in blood serum exceed therapeutic levels, metabolic acidosis, hyperuricemia, hypokalemia, hyperkalemia, hypercalcemia, hyperglycemia, hypoglycemia up to hypoglycemic coma may occur; frequency unknown (cannot be estimated based on available data) – metabolic acidosis with high anion gap.

Respiratory system: dyspnea, bronchospasm in patients sensitive to acetylsalicylic acid and other NSAIDs.

General disorders: dry mouth, altered taste sensations, loss of appetite, weight loss, excessive sweating, asthenia, sensation of warmth and facial hyperemia, elevated body temperature.

Laboratory findings: disturbances in blood acid-base balance.

Other: with prolonged use – folate deficiency, impotence, drug dependence, withdrawal syndrome, which usually may occur upon abrupt discontinuation of the medicinal product and is accompanied by the occurrence of nightmares and nervousness.

Description of selected adverse reactions

Metabolic acidosis with high anion gap

Cases of metabolic acidosis with high anion gap, caused by pyroglutamic acidemia, have been observed in patients with risk factors who used paracetamol (see section "Special precautions for use"). Pyroglutamic acidemia may be caused by low glutathione levels in these patients.

Reporting suspected adverse reactions

Healthcare and pharmacy professionals, as well as patients or their legal representatives, are requested to report all cases of suspected adverse reactions and lack of therapeutic effect via the Automated Pharmacovigilance Information System at the link https://aisf.dec.gov.ua to monitor the benefit-risk balance of the medicinal product.

Shelf life

3 years.

Storage conditions

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

Keep out of reach of children.

Packaging

10 tablets in a blister; 1 blister per carton.

Prescription status

Prescription only.

Manufacturer

Limited liability company "INTERKHIM".

Manufacturer's address and place of business

40-A, 21st km, Starokyivska Road, Odesa, 65025, Ukraine