Helpex® anticold dx

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT HELPEX® ANTICOLD DX (HELPEX® ANTICOLD DX)

Composition:

Active substances: paracetamol, caffeine, phenylephrine hydrochloride, chlorpheniramine maleate, dextromethorphan hydrobromide;

1 tablet contains paracetamol 500 mg, caffeine 30 mg, phenylephrine hydrochloride 10 mg, chlorpheniramine maleate 2 mg, dextromethorphan hydrobromide 10 mg;

Excipients: corn starch, microcrystalline cellulose, povidone, tartrazine (E 102), magnesium stearate, talc, sodium starch glycolate (type A), brilliant blue (E 133).

Pharmaceutical form. Tablets.

Main physico-chemical properties: green speckled, oval-shaped tablets with a score line, imprinted with “M” and “H” on the side with the score line, uncoated.

Pharmacotherapeutic group. Analgesics and antipyretics. Anilides. Paracetamol combinations without psychotropic agents.

ATC code N02BE51.

Pharmacological properties.

Pharmacodynamics

A combined medicinal product for the treatment of influenza and colds. Has antitussive, antipyretic, analgesic, antiallergic, and mild anti-inflammatory properties. Relieves dry, non-productive cough. Eliminates symptoms of nasal congestion, rhinorrhea, lacrimation, sneezing, headache, and improves general well-being.

Paracetamol acts as an antipyretic, analgesic, and anti-inflammatory agent. The analgesic and antipyretic effects of paracetamol are associated with its influence on the thermoregulatory center and its ability to inhibit prostaglandin synthesis.

Phenylephrine hydrochloride acts as a vasoconstrictor, reducing swelling of the nasal mucosa and paranasal sinuses.

Chlorpheniramine maleate has antiallergic effects and relieves lacrimation and nasal itching.

Caffeine exerts a stimulant effect on the central nervous system, primarily on the cerebral cortex, respiratory, and vasomotor centers. It enhances mental and physical performance, reduces drowsiness and fatigue, and diminishes the effects of central nervous system depressants.

Dextromethorphan hydrobromide is a centrally-acting antitussive agent. It reduces receptor sensitivity and increases the threshold sensitivity of the cough center to stimuli from the respiratory tract. Therapeutically alleviates symptoms of dry cough and reduces irritation of the respiratory tract.

Pharmacokinetics

Dextromethorphan undergoes rapid and extensive first-pass metabolism in the liver following oral administration. Genetically controlled O-demethylation (CYP2D6) is the primary mechanism of dextromethorphan pharmacokinetics in volunteers.

There are different phenotypes of this oxidation process, leading to significant variability in pharmacokinetics among individuals. Unmetabolized dextromethorphan, together with three demethylated morphinan metabolites—dextrorphan (also known as 3-hydroxy-N-methylmorphinan), 3-hydroxymorphinan, and 3-methoxymorphinan—are identified as conjugated products in urine.

Dextrorphan, which also possesses antitussive activity, is the main metabolite. If metabolism is slower, dextromethorphan predominates in blood and urine in unchanged form.

Clinical characteristics.

Indications.

Symptomatic treatment of acute respiratory viral infections and influenza (relief of dry, persistent cough; reduction of elevated body temperature; alleviation of rhinorrhea; reduction of nasal mucosa edema; relief of body aches; relief of headache).

Contraindications.

Hypersensitivity to any component of the medicinal product or to other xanthine derivatives (theophylline, theobromine). Decompensated heart failure, ventricular tachycardia, acute myocardial infarction, conduction disorders, severe form of ischemic heart disease, severe arterial hypertension, marked atherosclerosis, peripheral arterial thrombosis. Pheochromocytoma. Bronchial asthma, emphysema, chronic obstructive pulmonary diseases; risk of developing respiratory failure. Stenosing ulcers of the stomach and duodenum, pyloroduodenal obstruction. Severe hepatic or renal dysfunction, acute pancreatitis, hepatitis. Prostate adenoma with impaired urination, bladder neck obstruction. Blood disorders (including severe anemia, leukopenia). Glucose-6-phosphate dehydrogenase deficiency, congenital hyperbilirubinemia. Epilepsy, increased excitability, sleep disturbances. Hyperthyroidism, diabetes mellitus, alcoholism. Advanced age (60 years and older). Closed-angle glaucoma. Concomitant use with tricyclic antidepressants, β-blockers, serotonin reuptake inhibitors; concurrent use with monoamine oxidase inhibitors (MAOIs) or within 2 weeks after discontinuation of MAOIs.

Interaction with other medicinal products and other forms of interaction.

When used concomitantly with paracetamol, the following interactions may occur:

• May slow down elimination of antibiotics from the body;
• Barbiturates reduce the antipyretic effect of paracetamol;
• Concurrent use of paracetamol with hepatotoxic agents increases hepatotoxic effects;
• Inducers of hepatic microsomal enzymes (anticonvulsants (phenytoin, barbiturates, carbamazepine), rifampicin), alcohol, and isoniazid enhance the hepatotoxicity of paracetamol;
• Metoclopramide and domperidone increase, while cholestyramine decreases, the rate of paracetamol absorption;
• Tetracycline increases the risk of anemia and methemoglobinemia caused by paracetamol;
• Paracetamol reduces the efficacy of diuretics.

The anticoagulant effect of warfarin and other coumarins, with an increased risk of bleeding, may be enhanced by prolonged regular use of paracetamol. Single doses do not show significant effects.

Concomitant use with flucloxacillin may result in metabolic acidosis with a high anion gap due to pyroglutamic acidosis, especially in patients with risk factors (see section "Special precautions for use").

Use of phenylephrine hydrochloride with MAO inhibitors, tricyclic antidepressants, indomethacin, and bromocriptine may cause severe arterial hypertension; may reduce the effectiveness of β-blockers and other antihypertensive agents (reserpine, methyldopa), increasing the risk of arterial hypertension and cardiovascular side effects; when used with sympathomimetic amines, digoxin, and cardiac glycosides, increases the risk of arrhythmias and myocardial infarction.

Alkaloids of Rauwolfia reduce the therapeutic effect of phenylephrine hydrochloride.

Chlorpheniramine maleate enhances the anticholinergic effects of atropine, spasmolytics, tricyclic antidepressants, and agents that depress the central nervous system (tranquilizers, barbiturates), as well as antiparkinsonian drugs. Do not use concurrently with alcohol. Chlorpheniramine maleate, when used concomitantly with alcohol, potentiates the effects of each other. Concurrent use with hypnotics, barbiturates, sedatives, neuroleptics, tranquilizers, anesthetics, narcotic analgesics, and alcohol enhances the effect of chlorpheniramine maleate.

Maprotiline (a tetracyclic antidepressant) and other anticholinergic agents: the anticholinergic effect of these drugs or antihistamines such as chlorpheniramine may be intensified.

Caffeine enhances the effect (improves bioavailability) of analgesic-antipyretic agents, potentiates the action of xanthine derivatives, α- and β-adrenergic agonists, and psychostimulants.

Caffeine reduces the effect of opioid analgesics, anxiolytics, hypnotics, and sedatives; acts as an antagonist of anesthetic agents and other drugs that depress the central nervous system; acts as a competitive antagonist of adenosine and adenosine triphosphate. When used concomitantly with ergotamine, caffeine improves the absorption of ergotamine in the gastrointestinal tract; when used with thyroid-stimulating agents, it enhances the thyroid effect. Caffeine reduces lithium concentration in blood.

Dextromethorphan hydrobromide is metabolized by cytochrome CYP2D6 and undergoes extensive first-pass metabolism. Concurrent use of potent inhibitors of the CYP2D6 enzyme (fluoxetine, paroxetine, quinidine, and terbinafine) may increase dextromethorphan concentrations in the body to levels many times higher than normal, increasing the risk of its toxic effects (excitation, confusion, tremor, insomnia, diarrhea, respiratory depression) and the possibility of serotonin syndrome. When used concomitantly with quinidine, plasma concentrations of dextromethorphan increased up to 20-fold, intensifying CNS-related adverse reactions. Amiodarone, flecainide, propafenone, sertraline, bupropion, methadone, cinacalcet, haloperidol, perphenazine, and thioridazine demonstrate similar effects on dextromethorphan metabolism. If concomitant use of CYP2D6 inhibitors and dextromethorphan is necessary, patients should be closely monitored and the dose of dextromethorphan may need to be reduced.

Special precautions for use.

Do not exceed the recommended dose or duration of treatment.

Avoid concomitant use with other medicinal products containing paracetamol, as this may lead to paracetamol overdose, potentially causing hepatic failure. Prolonged use of high doses may result in liver and kidney damage. Patients with pre-existing liver disease are at increased risk of hepatotoxic effects of paracetamol. 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. If these symptoms occur, seek immediate medical attention.

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

Consult a physician regarding the possibility of using the medicine in patients with mild to moderate renal or hepatic impairment.

The risk of hepatotoxicity from therapeutic doses of paracetamol (acetaminophen) is increased by polypharmacy, alcoholism, alcoholic liver disease, sepsis, or diabetes mellitus.

Concomitant use with sedatives, hypnotics, or alcohol is not recommended (this may enhance the sedative effect of chlorpheniramine and increase the risk of paracetamol hepatotoxicity). If symptoms persist, consult a physician. If headache becomes persistent, seek medical advice. In case of high or prolonged fever lasting more than 3 days despite treatment, or if signs of superinfection appear, consult a physician.

Very rarely, severe skin reactions have been reported. If skin redness, rash, blisters, or peeling occur, discontinue paracetamol use immediately and seek urgent medical help.

When using this medicine, avoid excessive consumption of coffee, strong tea, other caffeinated beverages, and medicinal products containing caffeine. This may cause sleep disturbances, tremor, tension, irritability, or palpitations.

Consult a physician before using the medicine if you are taking warfarin or similar anticoagulant agents.

Use with caution in patients with persistent or chronic cough due to smoking, especially when cough is associated with excessive sputum production. Ensure the underlying cause of cough has been identified and that cough suppression does not increase the risk of clinical or physiological complications. Use with caution in patients with compensated heart failure, in those at risk of seizures, or in patients with congenital long QT syndrome or with prolonged use of drugs that may prolong the QT interval.

The medicine may interfere with laboratory tests for blood glucose and uric acid levels. Chlorpheniramine may mask symptoms of hypersensitivity and affect the results of skin tests; therefore, discontinue the medicine several days before such procedures.

Cases of abuse and dependence have been reported with the use of dextromethorphan. Use with particular caution in adolescents and young adults, as well as in patients with a history of substance or psychotropic drug abuse.

Dextromethorphan is metabolized in the liver by cytochrome P450 2D6. The activity of this enzyme is genetically determined. Approximately 10% of the general population are poor metabolizers of CYP2D6. Caution is advised in such individuals and in patients taking concomitant CYP2D6 inhibitors, as this may lead to enhanced and/or prolonged effects of dextromethorphan (see section "Interaction with other medicinal products and other forms of interaction").

Serotonin syndrome

Serotonergic effects of dextromethorphan, including potentially life-threatening serotonin syndrome, have been reported when used concomitantly with serotonergic agents such as selective serotonin reuptake inhibitors (SSRIs), drugs affecting serotonin metabolism (including MAO inhibitors), and CYP2D6 inhibitors. Serotonin syndrome may include mental status changes, autonomic instability, neuromuscular abnormalities, and/or gastrointestinal symptoms. If serotonin syndrome is suspected, discontinue treatment immediately.

The dye tartrazine (E 102) may cause allergic reactions.

Use during pregnancy or breastfeeding.

Do not use.

Ability to influence reaction speed when driving or operating machinery.

During treatment, avoid driving, operating machinery, or engaging in other potentially hazardous activities.

Dosage and Administration.

For adults and children aged 12 years and older, the recommended dose is 1 tablet up to 4 times daily. The interval between doses should be no less than 4 hours. The treatment duration should not exceed 5 days. The maximum duration of use without medical consultation is 3 days. The medication should be taken 1 hour after food intake, with a large amount of water.

Do not exceed the recommended dose.

Children.

The drug is indicated for use in children aged 12 years and older.

Overdose.

In patients with risk factors, therapeutic doses of paracetamol may cause symptoms of overdose when used concomitantly with certain medications or in conditions that increase oxidative stress and deplete hepatic glutathione stores (prolonged fasting, sepsis, diabetes mellitus).

In paracetamol overdose, symptoms develop within the first 24 hours: pallor, nausea, vomiting, anorexia, and abdominal pain. Psychomotor agitation or central nervous system depression, increased sweating, dizziness, sleep disturbances, somnolence, cardiac arrhythmias, tachycardia, extrasystoles, tremor, hyperreflexia, seizures, and pancreatitis may occur.

Renal toxicity has occasionally been observed, including renal colic, interstitial nephritis, and acute renal failure with acute tubular necrosis, which may manifest as severe lumbar pain, hematuria, proteinuria, and may develop even in the absence of severe liver damage.

In severe cases, liver injury (hepatocellular necrosis) and impaired liver function may occur, potentially progressing to hepatic encephalopathy, hepatic coma, cerebral edema, and may be fatal. The first clinical and biochemical signs of liver damage may appear 12–48 hours after overdose. Glucose metabolism disturbances, hypokalemia, metabolic acidosis (including lactic acidosis), elevated liver transaminase activity, increased bilirubin levels, prolonged prothrombin index, and hemorrhages may occur. In children, liver injury may develop after ingestion of more than 150 mg/kg body weight; in adults, after ingestion of 10 g of paracetamol.

In patients with risk factors (long-term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John's wort, or other drugs inducing liver enzymes; alcoholism; glutathione depletion due to malnutrition, cystic fibrosis, HIV infection, fasting, cachexia), ingestion of 5 g or more of paracetamol may lead to liver injury.

Arrhythmias and pancreatitis have also been reported. With high-dose ingestion, disturbances in orientation may occur due to central nervous system effects.

With prolonged use of high doses, aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia are possible.

In case of overdose, immediate medical assistance is required. The patient should be taken to hospital immediately, 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. Activated charcoal should be considered if the excessive dose of paracetamol was taken within the last hour. Gastric lavage should be performed within the first hours after suspected overdose. 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 after ingestion. 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 appropriate alternative in remote areas outside hospital settings.

In case of caffeine overdose, symptoms of central nervous system stimulation occur: dizziness, insomnia, nervous excitation, irritability, affective state, anxiety, tremor, seizures, increased diuresis, rapid breathing, tachycardia or cardiac arrhythmia, extrasystoles, vomiting, epigastric pain. Clinically significant symptoms of caffeine overdose may also be associated with paracetamol-induced liver injury. There is no specific antidote, but supportive measures such as beta-adrenergic antagonists may alleviate cardiotoxic effects. Gastric lavage is required; oxygen therapy is recommended, and diazepam should be administered in case of seizures. Symptomatic therapy is indicated.

In case of phenylephrine hydrochloride overdose, symptoms include headache, hyperhidrosis, somnolence, insomnia, behavioral changes, arrhythmias, tremor, seizures, hyperreflexia, dizziness, nausea, vomiting, irritability, restlessness, impaired consciousness, tachycardia, extrasystoles, and arterial hypertension.

In chlorpheniramine maleate overdose, the clinical picture may range from depression to excitation (restlessness and seizures). Anticholinergic-like symptoms may occur, including mydriasis, photophobia, dryness of skin and mucous membranes, elevated body temperature, intestinal atony; central nervous system depression may be accompanied by respiratory depression and cardiovascular disturbances (decreased pulse rate, decreased arterial pressure up to circulatory failure).

Symptoms of dextromethorphan hydrobromide overdose: nausea, vomiting, dystonia, excitation, confusion, somnolence, stupor, nystagmus, cardiotoxicity (tachycardia, ECG abnormalities including QTc interval prolongation), ataxia, toxic psychosis with visual hallucinations, and increased excitability.

Very high doses may cause coma, respiratory depression, and seizures.

Treatment: Patients who have ingested an excessive dose of dextromethorphan within the previous hour and who are asymptomatic may be given activated charcoal. For patients who have ingested dextromethorphan and are in a sedated or comatose state, naloxone may be considered at standard doses used for opioid overdose. In case of seizures, benzodiazepines may be administered; in case of hyperthermia due to serotonin syndrome, benzodiazepines and external cooling measures should be used.

Side effects.

Immune system side effects: hypersensitivity reactions, including pruritus, skin and mucous membrane rashes (usually generalized rash (erythematous, urticaria)), anaphylactic shock, angioneurotic edema, erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis.

Central nervous system side effects: psychomotor agitation and disorientation, restlessness, fear, anxiety, irritability, sleep disturbances, insomnia, drowsiness, dizziness, confusion, hallucinations, depressive states, tremor, sensations of tingling and heaviness in the extremities, tinnitus, headache; in individual cases – coma, seizures, dyskinesia, behavioral changes, general weakness, increased sweating.

Respiratory system side effects: bronchospasm in patients sensitive to aspirin and other nonsteroidal anti-inflammatory drugs.

Eye disorders: visual disturbances and accommodation disorders, mydriasis, increased intraocular pressure, dry eyes.

Gastrointestinal side effects: nausea, vomiting, heartburn, dry mouth, epigastric discomfort and pain, diarrhea, hypersalivation, loss of appetite, exacerbation of peptic ulcer disease, flatulence, constipation.

Hepatobiliary side effects: liver function disturbances, increased liver enzyme activity, usually without development of jaundice, hepatonecrosis (with high-dose administration).

Endocrine system side effects: hypoglycemia, up to hypoglycemic coma.

Blood and lymphatic system side effects: anemia, including hemolytic anemia, bruising or bleeding; sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain).

With prolonged use at high doses – aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, thrombocytopenia.

Renal and urinary system side effects: with high-dose administration – nephrotoxicity (including papillary necrosis), urinary disturbances, urinary retention and difficulty in urination, dysuria, interstitial nephritis, increased creatinine clearance, increased excretion of sodium and calcium, sterile pyuria, renal colic.

Cardiovascular side effects: arterial hypertension, tachycardia or reflex bradycardia, arrhythmia, dyspnea, chest pain.

Metabolism and nutrition side effects: metabolic acidosis with a high anion gap.

Description of individual side effects

Metabolic acidosis with a high anion gap as a result of pyroglutamic acidosis has been observed in patients with risk factors who used paracetamol (see section "Special precautions"). Pyroglutamic acidosis may occur due to low glutathione levels in these patients.

Concomitant use of the drug at recommended doses with products containing caffeine may enhance caffeine-related side effects such as dizziness, increased excitability, insomnia, restlessness, anxiety, irritability, headache, gastrointestinal disturbances, and tachycardia.

Reporting suspected adverse reactions

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

Shelf life. 4 years.

Storage conditions.

Store in a place inaccessible to children, in the original packaging, at a temperature not exceeding 25 °C.

Packaging. 4 or 10 tablets per blister, 1 blister per cardboard pack; 10 packs of 4 tablets per group cardboard pack (No. 40), 20 packs of 4 tablets per group cardboard pack (No. 80), 10 packs of 10 tablets per group cardboard pack (No. 100).

Dispensing category. Over-the-counter.

Manufacturer.

Sava Helskea Ltd.

Manufacturer's location and address of business site.

India, GIDC Estate, 507-B-512, Vadodwan City - 363 035, Surendranagar.

Marketing Authorization Holder. LLC "Movі Health"

Address of the Marketing Authorization Holder.

162 A, Shevchenka Street, Shevchenkove, Kyiv-Sviatoshynskyi district, Kyiv Oblast, 08140, Ukraine

Date of last review.

APPROVED Order of the Ministry of Health of Ukraine 04.2019 No 858 Registration Certificate No UA/9825/01/01

INSTRUCTION

for medical use of the medicinal product

HELPEX® ANTICOLD DX

(HELPEX® ANTICOLD DX)

Composition:

Active ingredients: paracetamol, caffeine, phenylephrine hydrochloride, chlorpheniramine maleate, dextromethorphan hydrobromide;

1 tablet contains 500 mg of paracetamol, 30 mg of caffeine, 10 mg of phenylephrine hydrochloride, 2 mg of chlorpheniramine maleate, and 10 mg of dextromethorphan hydrobromide;

Excipients: maize starch, microcrystalline cellulose, povidone, tartrazine (E 102), magnesium stearate, talc, sodium starch glycolate (type A), brilliant blue (E 133).

Pharmaceutical form. Tablets.

Main physicochemical properties: green mottled oval-shaped tablets with a score line, imprinted with “M” and “H” on the side with the score line, uncoated.

Pharmacotherapeutic group. Analgesics and antipyretics. Anilides. Paracetamol combinations without psycholeptics.

ATC code N02BE51.

Pharmacological properties.

Pharmacodynamics

A combined medicinal product for the treatment of influenza and colds. Has antitussive, antipyretic, analgesic, antiallergic, and weak anti-inflammatory properties. Relieves dry, non-productive cough. Eliminates symptoms of nasal congestion, rhinorrhea, lacrimation, sneezing, headache, and improves general well-being.

Paracetamol acts as an antipyretic, analgesic, and anti-inflammatory agent. The analgesic and antipyretic effects of paracetamol are associated with its influence on the thermoregulatory center and its ability to inhibit prostaglandin synthesis.

Phenylephrine hydrochloride acts as a vasoconstrictor, reducing swelling of the nasal mucosa and paranasal sinuses.

Chlorpheniramine maleate has antiallergic effects and relieves lacrimation and nasal itching.

Caffeine exerts a stimulatory effect on the central nervous system, primarily on the cerebral cortex, respiratory and vasomotor centers, increases mental and physical performance, reduces drowsiness and fatigue, and diminishes the effects of central nervous system depressants.

Dextromethorphan hydrobromide is a centrally-acting antitussive agent. It reduces receptor sensitivity and raises the sensitivity threshold of the cough center to stimuli from the respiratory tract. Therapeutically alleviates symptoms of dry cough and reduces irritation of the respiratory tract.

Pharmacokinetics

Dextromethorphan undergoes rapid and extensive first-pass metabolism in the liver following oral administration. Genetically controlled O-demethylation (CYP2D6) is the primary mechanism of dextromethorphan pharmacokinetics in volunteers.

There are different phenotypes of this oxidation process, leading to significant variability in pharmacokinetics among individuals. Unmetabolized dextromethorphan, together with three demethylated morphinan metabolites—dextrorphan (also known as 3-hydroxy-N-methylmorphinan), 3-hydroxymorphinan, and 3-methoxymorphinan—are identified as conjugated products in urine.

Dextrorphan, which also exerts antitussive activity, is the major metabolite. If metabolism is slower, dextromethorphan predominates in blood and urine in unchanged form.

Clinical characteristics.

Indications.

For symptomatic treatment of acute viral respiratory infections and influenza (relief of dry persistent cough, reduction of elevated body temperature, alleviation of rhinorrhea, reduction of nasal mucosa edema, relief of malaise, relief of headache).

Contraindications.

Hypersensitivity to any component of the medicinal product or to other xanthine derivatives (theophylline, theobromine). Decompensated heart failure, ventricular tachycardia, acute myocardial infarction, cardiac conduction disorders, severe form of ischemic heart disease, severe arterial hypertension, marked atherosclerosis, peripheral arterial thrombosis. Pheochromocytoma. Bronchial asthma, emphysema, chronic obstructive pulmonary diseases; risk of respiratory failure development. Stenosing gastric and duodenal ulcers, pyloroduodenal obstruction. Severe hepatic and renal function impairment, acute pancreatitis, hepatitis. Benign prostatic hyperplasia with urinary retention, bladder neck obstruction. Blood disorders (including severe anemia, leukopenia). Glucose-6-phosphate dehydrogenase deficiency, congenital hyperbilirubinemia. Epilepsy, increased excitability, sleep disturbances. Hyperthyroidism, diabetes mellitus, alcoholism. Advanced age (60 years and older). Closed-angle glaucoma. Concurrent use with tricyclic antidepressants, β-blockers, serotonin reuptake inhibitors; concurrent use with monoamine oxidase inhibitors or within 2 weeks after their discontinuation.

Interaction with other medicinal products and other forms of interaction.

When used concomitantly with paracetamol, the following interactions may occur:

• May slow down elimination of antibiotics from the body;
• Barbiturates reduce the antipyretic effect of paracetamol;
• Concomitant use of paracetamol with hepatotoxic agents increases hepatotoxic effects;
• Hepatic microsomal enzyme inducers (anticonvulsants (phenytoin, barbiturates, carbamazepine), rifampicin), alcohol, and isoniazid enhance the hepatotoxicity of paracetamol;
• Metoclopramide and domperidone increase, while cholestyramine decreases, the absorption rate of paracetamol;
• Tetracycline increases the risk of anemia and methemoglobinemia caused by paracetamol;
• Paracetamol reduces the efficacy of diuretics.

The anticoagulant effect of warfarin and other coumarins, with an increased risk of bleeding, may be enhanced by prolonged regular use of paracetamol. Single-dose administration does not show a significant effect.

Concomitant use with flucloxacillin may result in metabolic acidosis with a high anion gap due to pyroglutamic acidosis, especially in patients with risk factors (see section "Special precautions").

Use of phenylephrine hydrochloride with monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants, indomethacin, and bromocriptine may cause severe arterial hypertension; may reduce the effectiveness of β-blockers and other antihypertensive agents (reserpine, methyldopa), increasing the risk of arterial hypertension and cardiovascular adverse reactions; when used with sympathomimetic amines, digoxin, and cardiac glycosides, increases the risk of arrhythmias and myocardial infarction.

Alkaloids of Rauwolfia reduce the therapeutic effect of phenylephrine hydrochloride.

Chlorpheniramine maleate enhances the anticholinergic effects of atropine, spasmolytics, tricyclic antidepressants, and agents that depress the central nervous system (CNS) (tranquilizers, barbiturates), antiparkinsonian drugs. Do not use concurrently with alcohol. Chlorpheniramine maleate, when used concomitantly with alcohol, potentiates the effects of both substances. Concurrent use with hypnotics, barbiturates, sedatives, neuroleptics, tranquilizers, anesthetics, narcotic analgesics, and alcohol enhances the effect of chlorpheniramine maleate.

Maprotiline (a tetracyclic antidepressant) and other anticholinergic agents: the anticholinergic effects of these agents or antihistamines such as chlorpheniramine may be intensified.

Caffeine enhances the effect (improves bioavailability) of analgesic-antipyretic agents, potentiates the action of xanthine derivatives, α- and β-adrenomimetics, and psychostimulants.

Caffeine reduces the effect of opioid analgesics, anxiolytics, hypnotics, and sedatives; acts as an antagonist of anesthetic agents and other drugs that depress the CNS; acts as a competitive antagonist of adenosine and adenosine triphosphate preparations. Concomitant use of caffeine with ergotamine improves ergotamine absorption in the gastrointestinal tract; with thyrotropic agents – increases thyroid effect. Caffeine reduces lithium concentration in blood.

Dextromethorphan hydrobromide is metabolized by cytochrome CYP2D6 and undergoes extensive first-pass metabolism. Concurrent use of potent inhibitors of CYP2D6 enzyme (fluoxetine, paroxetine, quinidine, and terbinafine) may increase dextromethorphan concentration in the body to levels many times higher than normal, increasing the risk of its toxic effects (excitation, confusion, tremor, insomnia, diarrhea, respiratory depression) and the possibility of serotonin syndrome. Concomitant use with quinidine increases plasma concentrations of dextromethorphan up to 20-fold, increasing CNS-related adverse reactions. Amiodarone, flecainide, propafenone, sertraline, bupropion, methadone, cinacalcet, haloperidol, perphenazine, and thioridazine demonstrate similar effects on dextromethorphan metabolism. If concomitant use of CYP2D6 inhibitors and dextromethorphan is necessary, the patient should be closely monitored and the dose of dextromethorphan possibly reduced.

Special precautions for use.

Do not exceed the recommended dose or duration of treatment.

Avoid concomitant use with other medicinal products containing paracetamol, as this may lead to paracetamol overdose, potentially causing liver failure. Prolonged use of high doses may result in liver and kidney damage. Patients with pre-existing liver disease have an increased risk of hepatotoxic effects of paracetamol. In patients with severe infections such as sepsis, which are associated with reduced glutathione levels, the use of paracetamol increases the risk of developing metabolic acidosis. Symptoms of metabolic acidosis include deep, rapid, or labored breathing, nausea, vomiting, and loss of appetite. If these symptoms occur, seek immediate medical attention.

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

Consult a physician regarding the possibility of using the medicinal product in patients with mild to moderate renal or hepatic impairment.

The concomitant use of multiple drugs, alcoholism, alcoholic liver disease, sepsis, or diabetes mellitus increases the risk of hepatotoxicity associated with therapeutic doses of paracetamol (acetaminophen).

Concomitant use with sedatives, hypnotics, or alcohol is not recommended (this may enhance the sedative effect of chlorpheniramine and increase the risk of paracetamol-induced hepatotoxicity). If symptoms persist, consult a physician. If headache becomes persistent, seek medical advice. In case of high or prolonged fever lasting more than 3 days despite treatment, or if signs of superinfection appear, consult a physician.

Very rarely, severe skin reactions have been reported. If skin redness, rash, blisters, or peeling occur, discontinue paracetamol and seek immediate medical assistance.

When using this medicinal product, avoid excessive consumption of coffee, strong tea, other stimulant beverages, and medicinal products containing caffeine, as this may cause sleep disturbances, tremor, tension, irritability, or palpitations.

Consult a physician before using this product if you are taking warfarin or similar anticoagulant agents.

Use with caution in patients with persistent or chronic cough due to smoking, especially when cough is associated with excessive sputum production. Ensure the underlying cause of cough has been identified and that suppression of cough does not increase the risk of clinical or physiological complications. Use with caution in patients with compensated heart failure, those at risk of seizures, or in patients with congenital long QT syndrome or prolonged use of drugs that may prolong the QT interval.

The medicinal product may interfere with laboratory tests for blood glucose and uric acid levels. Chlorpheniramine may mask symptoms of hypersensitivity and affect the results of skin tests; therefore, discontinue the medicinal product several days before such procedures.

Cases of abuse and dependence have been reported with the use of dextromethorphan. Particular caution is advised when using in adolescents and young adults, as well as in patients with a history of substance or psychotropic drug abuse.

Dextromethorphan is metabolized in the liver by cytochrome P450 2D6. The activity of this enzyme is genetically determined. Approximately 10% of the general population are poor metabolizers of CYP2D6. Caution is advised in such individuals and in patients concurrently taking CYP2D6 inhibitors, as this may lead to enhanced and/or prolonged effects of dextromethorphan (see section "Interaction with other medicinal products and other forms of interaction").

Serotonin syndrome

Serotonergic effects of dextromethorphan, including potentially life-threatening serotonin syndrome, have been reported when used concomitantly with serotonergic agents such as selective serotonin reuptake inhibitors (SSRIs), drugs that interfere with serotonin metabolism (including MAO inhibitors), and CYP2D6 inhibitors. Serotonin syndrome may include changes in mental status, autonomic instability, neuromuscular abnormalities, and/or gastrointestinal symptoms. If serotonin syndrome is suspected, treatment with this medicinal product should be discontinued immediately.

The dye tartrazine (E 102) may cause allergic reactions.

Use during pregnancy or breastfeeding.

Do not use.

Ability to influence reaction speed when driving or operating machinery.

During treatment, avoid driving vehicles, operating machinery, or engaging in other potentially hazardous activities.

Dosage and Administration

For adults and children aged 12 years and older, the recommended dose is 1 tablet up to 4 times daily. The interval between doses should be no less than 4 hours. The treatment duration should not exceed 5 days. The maximum duration of use without medical consultation is 3 days. The medication should be taken 1 hour after eating, with a large amount of water.

Do not exceed the recommended dose.

Children.

The medication is indicated for treatment in children aged 12 years and older.

Overdose.

In patients with risk factors, therapeutic doses of paracetamol may cause symptoms of overdose when used concomitantly with certain medications or in conditions that increase oxidative stress and deplete hepatic glutathione stores (prolonged fasting, sepsis, diabetes mellitus).

In paracetamol overdose, symptoms develop within the first 24 hours: pallor, nausea, vomiting, anorexia, and abdominal pain. Psychomotor agitation or central nervous system depression may occur, along with excessive sweating, dizziness, sleep disturbances, somnolence, cardiac arrhythmias, tachycardia, extrasystoles, tremor, hyperreflexia, seizures, and pancreatitis.

Occasionally, nephrotoxicity may occur, including renal colic, interstitial nephritis, and acute renal failure with acute tubular necrosis, which may present as severe lumbar pain, hematuria, proteinuria, and may develop even in the absence of severe liver damage.

In severe cases, liver injury (hepatocellular necrosis) and impaired liver function may occur, potentially progressing to hepatic encephalopathy, hepatic coma, cerebral edema, and may be fatal. The first clinical and biochemical signs of liver damage may appear 12–48 hours after overdose. Disturbances in glucose metabolism, hypokalemia, metabolic acidosis (including lactic acidosis), elevated liver transaminase activity, increased bilirubin levels, prolonged prothrombin time, and hemorrhages may occur. Liver injury in children may develop after ingestion of more than 150 mg/kg body weight, and in adults after ingestion of 10 g of paracetamol.

In patients with risk factors (long-term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John's wort, or other drugs inducing liver enzymes; alcoholism; glutathione deficiency due to malnutrition, cystic fibrosis, HIV infection, fasting, cachexia), ingestion of 5 g or more of paracetamol may lead to liver injury.

Arrhythmias (disturbances in cardiac rhythm) and pancreatitis have also been reported. After ingestion of large doses, disturbances in orientation may occur in the central nervous system.

With prolonged use of high doses, aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia are possible.

In case of overdose, prompt medical assistance is required. The patient should be immediately hospitalized, 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. Activated charcoal should be considered if the excessive dose of paracetamol was ingested within the last hour. Gastric lavage should be performed within the first hours after suspected overdose. 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 the maximum protective effect is achieved when administered within 8 hours after ingestion. 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 the hospital setting.

In case of caffeine overdose, symptoms of central nervous system stimulation occur: dizziness, insomnia, nervous excitement, irritability, affective state, anxiety, tremor, seizures, increased frequency of diuresis, rapid breathing, tachycardia or cardiac arrhythmia, extrasystoles, vomiting, and epigastric pain. Clinically significant symptoms of caffeine overdose are also associated with liver injury caused by paracetamol. There is no specific antidote, but supportive measures such as beta-adrenergic antagonists may alleviate cardiotoxic effects. Gastric lavage is required, oxygen therapy is recommended, and diazepam may be administered in case of seizures. Symptomatic therapy is indicated.

In case of phenylephrine hydrochloride overdose, symptoms include headache, hyperhidrosis, somnolence, insomnia, behavioral changes, arrhythmias, tremor, seizures, hyperreflexia, dizziness, nausea, vomiting, irritability, restlessness, impaired consciousness, tachycardia, extrasystoles, and arterial hypertension.

In case of chlorpheniramine maleate overdose, the condition may range from depression to excitation (restlessness and seizures). Anticholinergic-like symptoms may occur, including mydriasis, photophobia, dry skin and mucous membranes, elevated body temperature, and intestinal atony; central nervous system depression may be accompanied by respiratory depression and cardiovascular disturbances (reduced pulse rate, decreased blood pressure up to circulatory failure).

Symptoms of dextromethorphan hydrobromide overdose: nausea, vomiting, dystonia, excitation, confusion, somnolence, stupor, nystagmus, cardiotoxicity (tachycardia, ECG abnormalities, including QTc interval prolongation), ataxia, toxic psychosis with visual hallucinations, and increased excitability.

Very high doses may cause coma, respiratory depression, and seizures.

Treatment: Patients who have ingested an excessive dose of dextromethorphan within the previous hour and who do not exhibit symptoms may be given activated charcoal. For patients who have ingested dextromethorphan and are in a sedative or comatose state, naloxone may be considered at standard doses used for opioid overdose. Benzodiazepines may be used in case of seizures, and in case of hyperthermia due to serotonin syndrome, benzodiazepines and external cooling measures are recommended.

Side effects

Immune system disorders: hypersensitivity reactions including pruritus, skin and mucous membrane rashes (usually generalized rash (erythematous, urticaria)), anaphylactic shock, angioneurotic edema, erythema multiforme (including Stevens–Johnson syndrome), toxic epidermal necrolysis.

Central nervous system disorders: psychomotor agitation and disorientation, restlessness, fear, anxiety, irritability, sleep disturbances, insomnia, drowsiness, dizziness, confusion, hallucinations, depressive states, tremor, sensations of tingling and heaviness in the extremities, tinnitus, headache; in individual cases – coma, seizures, dyskinesia, behavioral changes, general weakness, increased sweating.

Respiratory system disorders: bronchospasm in patients sensitive to aspirin and other nonsteroidal anti-inflammatory drugs.

Eye disorders: visual disturbances and accommodation disorders, mydriasis, increased intraocular pressure, dry eyes.

Gastrointestinal disorders: nausea, vomiting, heartburn, dry mouth, epigastric discomfort and pain, diarrhea, hypersalivation, decreased appetite, exacerbation of peptic ulcer, flatulence, constipation.

Hepatobiliary disorders: liver function abnormalities, elevated liver enzyme activity, usually without development of jaundice, hepatonecrosis (with high-dose administration).

Endocrine system disorders: hypoglycemia, up to hypoglycemic coma.

Blood and lymphatic system disorders: anemia, including hemolytic anemia, bruising or bleeding; sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain).

With prolonged use at high doses – aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, thrombocytopenia.

Renal and urinary system disorders: with high-dose administration – nephrotoxicity (including papillary necrosis), urinary disturbances, urinary retention and difficulty in urination, dysuria, interstitial nephritis, increased creatinine clearance, increased excretion of sodium and calcium, sterile pyuria, renal colic.

Cardiovascular disorders: arterial hypertension, tachycardia or reflex bradycardia, arrhythmia, dyspnea, chest pain.

Metabolism and nutrition disorders: metabolic acidosis with a high anion gap.

Description of individual side effects

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

Concomitant use of the medicinal product at recommended doses with caffeine-containing products may enhance caffeine-related side effects such as dizziness, increased excitability, insomnia, restlessness, anxiety, irritability, headache, gastrointestinal disturbances, and tachycardia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 4 years.

Storage conditions.

Store in the original packaging, out of reach of children, at a temperature not exceeding 25 °C.

Packaging.

4 or 10 tablets per blister, 1 blister per cardboard pack; 10 packs of 4 tablets per group cardboard package (No. 40), 20 packs of 4 tablets per group cardboard package (No. 80), 10 packs of 10 tablets per group cardboard package (No. 100).

Availability category. Over-the-counter.

Manufacturer.

Meditop Pharmaceutical Ltd.

Manufacturer's address and place of business.

Edi Endre u. 1., Pilisborosjenő, 2097, Hungary.

Marketing Authorization Holder. TOV "Movi Health"

Address of the Marketing Authorization Holder.

162 A, Shevchenka St., Shevchenkove village, Kyiv-Sviatoshyn district, Kyiv region, 08140, Ukraine