Coldrex blitz

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT COLDREX BLITZ (COLDREX BLITZ)

Composition:

Active substances: paracetamol, ascorbic acid, caffeine, chlorpheniramine maleate;

1 stick pack contains: paracetamol 400 mg, ascorbic acid 300 mg, caffeine 50 mg, chlorpheniramine maleate 5 mg;

Excipients: citric acid, sodium bicarbonate, sodium cyclamate, sodium saccharin, povidone, sodium riboflavin phosphate, talc, lemon flavoring "Evogran".

Pharmaceutical form. Granules for oral solution.

Main physicochemical properties: white or almost white granules, free-flowing without formation of agglomerates or lumps.

Pharmacotherapeutic group. Combined cold remedies. Paracetamol combinations. ATC code R05XA01.

Pharmacological Properties.

Pharmacodynamics.

Paracetamol.

Paracetamol has analgesic, antipyretic, and very weak anti-inflammatory effects. The mechanism of action of paracetamol has not been fully established. Significant inhibition of cerebral prostaglandin synthesis has been confirmed, while inhibition of peripheral prostaglandin synthesis is weaker. In addition, paracetamol inhibits the effect of endogenous pyrogens on the hypothalamic temperature-regulating center.

Chlorpheniramine maleate.

Chlorpheniramine is a classical H1-antihistamine that suppresses the effects of histamine occurring during immune reactions. In influenza infections, these include increased capillary permeability near venules and contractile effects on smooth muscles, particularly bronchial muscles. Chlorpheniramine inhibits these histamine-dependent processes. As a result, reduction of nasal mucosal edema and decreased mucus production restore the ability to breathe through the nose.

Caffeine.

Caffeine is a xanthine derivative and enhances the analgesic properties of paracetamol.

Ascorbic acid.

Ascorbic acid is one of the essential substances for humans. Ascorbic acid and dehydroascorbic acid (formed in the body) are components of the redox system, which plays a significant physiological role.

Due to its redox potential, ascorbic acid acts as a cofactor for many enzymatic systems (collagen formation, catecholamine synthesis, hydroxylation of steroids, tyrosine and exogenous substances, carnitine biosynthesis, regeneration of tetrahydrofolic acid, and alpha-amidation of peptides such as adrenocorticotropic hormone (ACTH) and gastrin). Furthermore, vitamin C deficiency affects immune defense system responses, including chemotaxis, complement activation, and interferon production. The molecular biological functions of vitamin C have not yet been fully defined.

Ascorbic acid—due to iron ion reduction and iron chelate formation—improves the resorption of iron salts. It blocks radical oxygen-induced chain reactions in aqueous environments of the body. Antioxidant functions are in close biochemical interaction with the functions of vitamin E, vitamin A, and carotenoids. The reduction of potentially carcinogenic substances in the gastrointestinal tract under the influence of ascorbic acid has not been sufficiently confirmed.

Since the combination of active components in the medicinal product COLDREX BLITZ is fixed, it is not possible to adjust doses so that the effect is primarily directed at one of the symptoms. In such a case, preference should be given to monocomponent medicinal products.

Pharmacokinetics.

Paracetamol.

Absorption. After oral administration, paracetamol is rapidly and almost completely absorbed, reaching peak plasma concentration within 30 to 60 minutes after ingestion.

Distribution. Paracetamol is rapidly distributed in all tissues. Concentrations in blood, plasma, and saliva are approximately equal. Protein binding in plasma is weak.

Biological transformation. Paracetamol is primarily metabolized in the liver. The main metabolic pathway is conjugation, forming glucuronic acid and sulfuric acid. This pathway becomes saturated when doses exceeding therapeutic limits are administered. A minor metabolic pathway, catalyzed by cytochrome P450, leads to the formation of the intermediate substance N-acetylbenzoquinoneimine, which under normal conditions is rapidly detoxified by reduced glutathione and excreted in urine after conjugation with cysteine and mercapturic acid. However, in severe poisoning, the amount of this toxic metabolite increases.

Elimination (excretion). The drug is primarily excreted in urine. 90% of the administered dose is eliminated by the kidneys within 24 hours, primarily as glucuronide conjugates (60–80%) and sulfate conjugates (20–30%). Less than 5% is excreted unchanged. The elimination half-life is approximately 2 hours. The half-life is prolonged in patients with impaired liver or kidney function, after overdose, and in newborns. The maximum effect and average duration of action (4–6 hours) approximately correspond to plasma concentration.

Patients with impaired renal function. In patients with severe renal insufficiency (creatinine clearance < 10 mL/min), elimination of paracetamol and its metabolites is delayed.

Elderly patients. Conjugation is not altered in this patient group.

Chlorpheniramine maleate.

The highest plasma concentration of chlorpheniramine is reached approximately 1–2 hours after administration. The duration of action of the drug lasts from 3 to 6 hours. Metabolism occurs primarily in the liver via hydroxylation and conjugation, as well as demethylation and formation of N- and S-oxides.

Chlorpheniramine undergoes metabolism during "first-pass" in the liver, which is reduced in patients with hepatic insufficiency; bioavailability after oral administration reaches 25–50%. Plasma protein binding is approximately 69–72%. The apparent volume of distribution is relatively high, ranging from 3 to 7 L per kg of body weight. In adults, the plasma half-life of chlorpheniramine ranges from 15 to 36 hours and is about 10–13 hours in children. In cases of renal insufficiency, prolonged half-life of metabolites should be expected. Depending on the pH reaction level (from alkaline to acidic), 0–34% of the dose is excreted in urine as unchanged chlorpheniramine. Accumulation may occur with prolonged administration.

Caffeine.

After oral intake, caffeine is rapidly and almost completely absorbed (t½ = 2–13 min) and is practically fully bioavailable. When administered at 5 mg/kg, Cmax is reached within 30–40 minutes. Plasma protein binding ranges from 30% to 40%; the volume of distribution reaches 0.52–1.06 L/kg. Caffeine distributes rapidly in all body tissues and fluids, quickly crosses the blood-brain barrier and placental barrier, and also enters breast milk.

The plasma half-life is mainly approximately 4.1 to 5.7 hours; however, in some patients, it may reach 9 or 10 hours.

Caffeine and its metabolites are primarily excreted by the kidneys. In urine collected over more than 48 hours, up to 86% of the administered dose was found, of which only up to 1.8% was unchanged caffeine. 1-methyluric acid (12–38%), 1-methylxanthine (8–19%), and 5-acetylamino-6-amino-3-methyluracil (15%) are the main metabolites. Feces contained only 2–5% of the total dose. The primary metabolite 1,7-dimethyluric acid, accounting for 44% of the total amount, has been identified.

Ascorbic acid.

Ascorbic acid is absorbed in the proximal part of the small intestine. With increasing single doses, bioavailability decreases to 60–75% after intake of 1 g, approximately 40% after intake of 3 g, and less than 16% after intake of 12 g. The unabsorbed portion is primarily degraded by colonic flora into CO2 and organic acids.

In healthy adults, the maximum metabolic rate of 40–50 mg/day is achieved at plasma concentrations of 0.8–1.0 mg/dL. The daily total turnover reaches approximately 1 mg/kg body weight. After administration of very high oral doses, plasma concentrations up to 4.2 mg/dL can be achieved approximately 3 hours after intake.

Under these conditions, more than 80% of ascorbic acid is excreted unchanged in urine. The average elimination half-life is 2.9 hours. Renal excretion occurs via glomerular filtration and subsequent reabsorption in the proximal tubules. In healthy adult males, the upper limit of ascorbic acid concentration in plasma reaches 1.34 ± 0.21 mg/dL, in females—1.46 ± 0.22 mg/dL.

After intake of large doses, approximately 180 mg per day, the total content of ascorbic acid will be no less than 1.5 g. Ascorbic acid accumulates in the pituitary gland, adrenal glands, eye lens, and white blood cells.

Indications.

For relief of cold symptoms such as headache and body aches, nasal congestion, and irritating cough, elevated body temperature.

Contraindications.

• Hypersensitivity to paracetamol or to any other component of the medicinal product;
• severe renal insufficiency;
• pediatric age (under 18 years);
• age over 60 years;
• pregnancy;
• breastfeeding;
• hepatic insufficiency;
• Gilbert's syndrome (Möller–Græmer disease);
• congenital hyperbilirubinemia;
• Dubin–Johnson syndrome;
• glucose-6-phosphate dehydrogenase deficiency;
• diabetes mellitus;
• blood disorders (including severe anemia, leukopenia);
• predisposition to thrombosis, thrombosis, thrombophlebitis;
• oxalate-induced urolithiasis;
• diseases associated with iron accumulation (thalassemia, hemochromatosis, sideroblastic anemia);
• chronic alcohol abuse;
• pyloroduodenal obstruction and urinary bladder neck obstruction;
• closed-angle glaucoma;
• benign prostatic hyperplasia;
• gastric or duodenal ulcer in the acute phase;
• acute pancreatitis;
• hyperthyroidism;
• epilepsy;
• severe forms of arterial hypertension, ischemic heart disease (myocardial infarction), predisposition to vascular spasm in organic cardiovascular diseases (including atherosclerosis), decompensated heart failure;
• severe cardiac conduction disorders and arrhythmias, including paroxysmal tachycardia (risk of increased pulse rate in tachycardia and extrasystoles);
• states of increased excitation, including anxiety disorders;
• sleep disorders.

Do not use concomitantly with monoamine oxidase inhibitors (MAOIs) and within 2 weeks after discontinuation of their use; do not use with tricyclic antidepressants, β-blockers.

Interaction with other medicinal products and other forms of interaction.

Known interactions of individual components of the medicinal product COLDREX BLITZ with other medicinal products:

Paracetamol.

The absorption rate of paracetamol may be increased when used with metoclopramide and domperidone and decreased when used with cholestyramine.

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

Barbiturates reduce the antipyretic effect of paracetamol.

Anticonvulsants (including phenytoin, barbiturates, carbamazepine), which stimulate hepatic microsomal enzyme activity, may enhance the hepatotoxic effect of paracetamol due to increased conversion of the drug into hepatotoxic metabolites. Special caution is required when used concomitantly with enzyme inducers.

Concomitant use of paracetamol with hepatotoxic agents increases the hepatotoxic effect of drugs. Concurrent use of high doses of paracetamol with isoniazid increases the risk of hepatotoxic syndrome. Paracetamol reduces the effectiveness of diuretics.

Concomitant use of medicinal products that delay gastric emptying, such as propantheline, may delay the absorption and onset of action of paracetamol. Concurrent use of paracetamol and zidovudine increases the risk of neutropenia. Therefore, the medicinal product COLDREX BLITZ and zidovudine may be used concomitantly only upon physician's recommendation.

The use of probenecid inhibits glucuronidation of paracetamol and thus reduces the clearance of paracetamol by approximately two-fold. When used concomitantly with probenecid, the dose of paracetamol should be reduced. Salicylates (e.g., salicylamide) may prolong the half-life of paracetamol. Do not use concomitantly with alcohol.

Caution is advised when using paracetamol concomitantly with flucloxacillin, as this concomitant intake has been associated with metabolic acidosis with a high anion gap due to pyroglutamic acidosis, especially in patients with risk factors (see section "Special warnings and precautions for use").

Chlorpheniramine maleate.

Chlorpheniramine enhances the anticholinergic effect of atropine, spasmolytics, tricyclic antidepressants, and antiparkinsonian agents.

Concomitant use of chlorpheniramine maleate with medicinal products that depress central nervous system (CNS) activity, particularly sedatives, neuroleptics, tranquilizers, or alcohol, enhances the sedative (calming) effect.

Caffeine.

Concomitant use of caffeine with monoamine oxidase inhibitors (MAOIs) may cause a dangerous increase in blood pressure.

Caffeine has a synergistic effect with sympathomimetics and thyroxine (increases heart rate).

Caffeine enhances the effect (improves bioavailability) of analgesic-antipyretic agents, potentiates the effects of xanthine derivatives, alpha- and beta-adrenomimetics, and psychostimulants. Oral contraceptives, isoniazid, cimetidine, and disulfiram reduce caffeine breakdown in the liver and enhance its effect; barbiturates and nicotine enhance caffeine breakdown in the liver. Caffeine reduces the effect of opioid analgesics, anxiolytics, hypnotics, and sedatives (including barbiturates), and it is an antagonist of anesthetic agents and other CNS depressants, as well as a competitive antagonist of adenosine and adenosine triphosphate (ATP) preparations.

When used concomitantly with ergotamine, absorption of ergotamine from the gastrointestinal tract improves; when used with thyroid-stimulating agents, the thyroid effect is enhanced. Caffeine reduces blood lithium concentration.

Concomitant intake of theophylline may reduce theophylline excretion.

Caffeine increases the potential for dependence on ephedrine-type substances.

In cases of combination of caffeine with broad-spectrum agents (e.g., benzodiazepines), various and unpredictable types of interactions may occur in individual cases. Concomitant use of inhibitors of hydrolase of quinolone-carboxylic acid type may slow the excretion of caffeine and its breakdown product paraxanthine.

Ascorbic acid.

Oral administration of ascorbic acid increases the absorption of penicillin, tetracycline, and iron; promotes intestinal absorption of aluminum, which should be considered when treating concomitantly with aluminum-containing antacids.

Concomitant use of vitamin C and deferoxamine increases tissue iron toxicity, especially in the myocardium, which may lead to circulatory decompensation. Vitamin C may be used only 2 hours after deferoxamine injection. Long-term use of high doses by individuals treated with disulfiram inhibits the disulfiram-alcohol reaction.

High doses of the drug reduce the effectiveness of tricyclic antidepressants, neuroleptics—phenothiazine derivatives, tubular reabsorption of amphetamine, impair renal excretion of mexiletine, and affect vitamin B12 resorption.

Ascorbic acid increases the total clearance of ethanol.

The medicinal product reduces the toxicity of sulfonamide drugs, reduces the effectiveness of heparin and indirect anticoagulants.

Vitamin C enhances oxalate excretion in urine, thereby increasing the risk of oxalate stone formation in urine, and increases the risk of crystalluria during treatment with salicylates. Quinolone drugs, calcium chloride, salicylates, and corticosteroids, with prolonged use, reduce ascorbic acid reserves in the body. Absorption of ascorbic acid is reduced when used concomitantly with oral contraceptives, consumption of fruit or vegetable juices, and alkaline beverages.

Due to the stimulatory effect of ascorbic acid on corticosteroid hormone production, when the drug is used in high doses, monitoring of kidney function and blood pressure is required.

Special precautions for use.

Medicinal product COLDCREX BLITZ should be used only with extreme caution after consultation with a physician.

Consult a physician if high fever, symptoms of secondary infection, or other complications occur.

Prolonged use of analgesic medicinal products at high doses may cause headaches, which should not be treated with even higher doses of medicinal products. Paracetamol.

The medicinal product contains paracetamol; therefore, it should not be used together with other products containing paracetamol, such as those used for fever reduction, pain relief, flu and cold symptoms, or insomnia. Concurrent use with other medicinal products containing paracetamol may lead to overdose. Paracetamol overdose can cause liver failure, which may necessitate liver transplantation or result in death.

In patients with liver or kidney disease, consult a physician before using this medicinal product.

Patients with liver disease, particularly alcoholic liver damage, have an increased risk of hepatotoxic effects of paracetamol. The medicinal product may affect laboratory test results for blood glucose and uric acid levels. Patients who take analgesics daily for mild forms of arthritis should consult a physician before use.

Cases of impaired liver function and liver failure have been reported in patients with reduced glutathione levels, such as those with severe malnutrition, anorexia, low body mass index, or chronic alcoholism.

In patients with reduced glutathione levels, for example during severe infections such as sepsis, 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. To avoid overdose, ensure that the maximum daily dose of paracetamol (4000 mg paracetamol for body weight over 43 kg) is not exceeded, even when other paracetamol-containing medicines are used.

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

Ascorbic acid.

When using high doses or prolonged treatment, kidney function, blood pressure, and pancreatic function should be monitored. Treatment of patients with mild to moderate kidney or liver dysfunction or urinary disorders should be conducted with caution after consultation with a physician. There is a risk of calcium oxalate stone formation when high doses of ascorbic acid are used in patients predisposed to kidney stone formation. In patients with urolithiasis, the daily dose of ascorbic acid should not exceed 1 g.

Large doses of the medicinal product should not be prescribed to patients with increased blood coagulation. Since ascorbic acid enhances iron absorption, its use in high doses may be dangerous for patients with hemochromatosis, thalassemia, polycythemia, leukemia, or sideroblastic anemia. Patients with high iron levels in the body should use the medicinal product at the lowest possible doses.

Concurrent use of the medicinal product with alkaline drinks reduces the absorption of ascorbic acid; therefore, it should not be taken with alkaline mineral water. Absorption of ascorbic acid may also be impaired in intestinal dyskinesia, enteritis, and achylia.

Due to the stimulatory effect of ascorbic acid on corticosteroid hormone production, kidney function and blood pressure should be monitored when the medicinal product is used in high doses.

Ascorbic acid may affect the results of various laboratory tests, for example, blood glucose, bilirubin, transaminase activity, lactate dehydrogenase activity, etc.

Caffeine.

During treatment with the medicinal product, excessive consumption of caffeine-containing beverages (such as coffee, tea, and certain other drinks) is not recommended. This may cause dizziness, increased excitability, insomnia, tremor, restlessness, anxiety, irritability, headache, gastrointestinal disturbances, and rapid heartbeat.

Do not exceed the recommended doses.

If headaches become persistent, consult a physician.

Avoid concomitant use of other products intended for symptomatic treatment of colds and flu, vasoconstrictor agents for rhinitis treatment, and medicinal products containing paracetamol.

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

If symptoms of illness do not begin to improve within 3 days of treatment or if the condition worsens, medical advice should be sought.

Important information about excipients.

Sodium. This medicinal product contains 63.8 mg of sodium per stick-pack. Use with caution in patients on a sodium-controlled diet.

Use during pregnancy or breastfeeding.

Pregnancy.

Use of the medicinal product is contraindicated during pregnancy, as epidemiological studies have shown an increased risk of central nervous system developmental disorders, craniofacial abnormalities, and childhood tumors associated with chlorphenamine. Furthermore, one study reports an increased risk of retrolental fibroplasia in premature infants exposed to antihistamine medicinal products during the last two weeks of pregnancy.

Breastfeeding.

Since it is unknown whether chlorphenamine maleate is excreted in breast milk, breastfeeding mothers should not breastfeed while being treated with this medicinal product.

Reproductive function.

Data on reproductive function are lacking.

Ability to affect reaction speed when driving or operating machinery.

During treatment, activities requiring high attention, and rapid mental and motor reactions should be avoided.

Method of Administration and Dosage.

Adults should take 1 sachet 3 times a day.

Patients with hepatic and/or renal impairment.

When treating patients with impaired liver and/or kidney function, the daily dose should be reduced or the interval between doses increased. The use of COLDREX BLITZ is contraindicated in cases of severe hepatic and/or renal insufficiency.

The contents of 1 sachet should be poured into a glass of drinking water — the powder will dissolve within one minute, even without stirring; the solution should then be consumed.

The duration of treatment should be determined after consultation with a physician.

Children.

Not recommended for use in children (under 18 years of age).

Overdose.

Symptoms of overdose correspond to those of intoxication caused by individual components of the medication.

Paracetamol.

In patients with risk factors [prolonged treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John's wort, or other drugs that induce liver enzymes; chronic excessive ethanol intake; glutathione depletion (due to malnutrition, cystic fibrosis, HIV infection, fasting, or cachexia)], ingestion of 5 g or more of paracetamol may lead to liver damage.

In case of overdose, immediate medical assistance is required. Treatment should be initiated without delay. The patient should be taken to a hospital, even if early symptoms of overdose are absent.

Symptoms within the first 24 hours: pallor, nausea, vomiting, loss of appetite, and 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 may be fatal. Elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase, and bilirubin levels, along with prolonged prothrombin time, may appear 12–48 hours after ingestion. Acute renal failure with acute tubular necrosis may present with severe flank pain, hematuria, proteinuria, and may develop even in the absence of severe liver injury. Cardiac arrhythmias and pancreatitis have also been reported.

With prolonged use of the medication in high doses, hematological side effects may include aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia. High doses may also cause central nervous system effects such as dizziness, psychomotor agitation, and disorientation. Urinary system effects may include nephrotoxicity (renal colic, interstitial nephritis, capillary necrosis). Symptoms may be limited to nausea and vomiting or may not reflect the severity of overdose or risk of organ damage. Administration of activated charcoal should be considered if the excessive dose was taken within the last hour. Plasma paracetamol concentration should be measured at least 4 hours after ingestion (earlier measurements are unreliable). Treatment with N-acetylcysteine may be administered within 24 hours of paracetamol ingestion, but maximum protective effect is achieved when given within 8 hours of ingestion. The efficacy of the antidote decreases significantly after this time. If required, N-acetylcysteine should be administered intravenously according to the recommended dosage. In the absence of vomiting, oral methionine may be used as an alternative, particularly in remote areas outside hospital settings.

The risk of intoxication is particularly high in elderly patients.

Chlorpheniramine maleate.

In case of overdose, anticholinergic syndrome may occur, characterized by facial flushing, ataxia, excitation, hallucinations, muscle tremors, convulsions, fixed dilated pupils, dry mouth, constipation, and abnormally high body temperature. Additionally, signs of central nervous system intoxication (hallucinations, coordination disturbances, convulsions) may appear. The clinical state may range from depression to excitation: restlessness and seizures, photophobia, dryness of skin and mucous membranes, intestinal atony. In severe cases, coma, respiratory arrest, and cardiovascular collapse may occur.

Caffeine.

Large doses of caffeine (≥ 1 g) taken within a short period may cause intoxication symptoms: epigastric pain, vomiting, diuresis, tachypnea, cardiovascular disturbances (tachycardia, myocardial injury, or cardiac arrhythmia), and effects on the central nervous system (insomnia, restlessness, nervous excitation, anxiety, dizziness, irritability, affective disturbances, tremor, seizures). Clinically significant symptoms of caffeine overdose may also be associated with liver damage caused by paracetamol. There is no specific antidote, but supportive measures such as beta-adrenergic antagonists may help alleviate cardiotoxic effects. Gastric lavage is required; oxygen therapy is recommended. Diazepam is indicated in case of seizures. Symptomatic therapy should be administered.

Ascorbic acid.

Ascorbic acid is well tolerated. It is a water-soluble vitamin, and excess amounts are excreted in urine.

Symptoms. Prolonged use of high doses of vitamin C may suppress the function of the islet apparatus of the pancreas, requiring monitoring of pancreatic status. Overdose may alter renal excretion of ascorbic and uric acids during urine acidification, increasing the risk of oxalate stone precipitation. After administration of high doses, the following may occur: epigastric pain, nausea, vomiting, diarrhea, itching, skin rashes, and increased excitability. There is a risk of hemolysis and kidney stone formation. A single dose of ≥ 3 g may cause transient osmotic diarrhea and gastrointestinal disturbances.

High-dose ascorbic acid intake (4 g per day) in patients with glucose-6-phosphate dehydrogenase deficiency has been associated with isolated cases of erythrocyte hemolysis.

Treatment. Symptomatic therapy; gastric lavage, administration of alkaline drinks, activated charcoal, or other absorbents.

Adverse Reactions

Classification of adverse effects by frequency: very common (≥ 1/10), common (from ≥ 1/100 to < 1/10), uncommon (from ≥ 1/1000 to < 1/100), rare (from ≥ 1/10000 to < 1/1000), very rare (< 1/10000), not known (frequency cannot be estimated from available data).

Blood and lymphatic system disorders. Very rare: changes in hemogram such as leukopenia, neutropenia, agranulocytosis, thrombocytopenia, thrombocytopenic purpura, pancytopenia, aplastic anemia, sulfhemoglobinemia, hemolytic anemia; with high-dose administration — slight formation of methemoglobin, thrombocytopenic purpura, methemoglobinopathy, bruising and bleeding.

Immune system disorders. Very rare: anaphylaxis, hypersensitivity reactions including skin pruritus, skin and mucous membrane rashes (usually generalized, erythematous rash, urticaria). Severe hypersensitivity reactions have been reported during administration of the active substance paracetamol (Quincke's edema, respiratory distress, sweating, nausea, drop in arterial pressure, sometimes leading to circulatory failure, and anaphylactic shock). Not known: in isolated cases, multiform exudative erythema (including Stevens-Johnson syndrome) and toxic epidermal necrolysis (Lyell's syndrome) temporally associated with the use of the medicinal product have been observed.

Metabolism and nutrition disorders: Very rare: increased appetite; frequency not known: metabolic acidosis with high anion gap.

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 during paracetamol use in patients with risk factors (see section "Special precautions"). Pyroglutamic acidosis may occur as a result of low glutathione levels in these patients.

Endocrine system disorders: Rare: hypoglycemia, up to hypoglycemic coma.

Psychiatric disorders. Very rare: psychotic reactions. Not known: restlessness, insomnia.

Nervous system disorders. Very rare: dyskinesia. Not known: headache, dizziness, psychomotor agitation and disorientation, restlessness, sedation, somnolence, insomnia, fear sensations, sleep disorders, confusion, in isolated cases — coma, convulsions, behavioral changes.

Eye disorders. Very rare: glaucoma (closed-angle glaucoma), visual and accommodation disturbances, dry eyes, mydriasis.

Cardiac disorders. Not known: arrhythmia, e.g. tachycardia, reflex bradycardia, dyspnea, chest pain, arterial hypertension, palpitations.

Respiratory, thoracic and mediastinal disorders. Very rare: respiratory hypersensitivity reactions; bronchospasm in patients sensitive to acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs (NSAIDs).

Gastrointestinal disorders. Common: dry mouth. Very rare: nausea, vomiting, gastrointestinal disturbances, gastrointestinal discomfort and epigastric pain, hypersalivation, decreased appetite, heartburn, diarrhea.

Hepatobiliary disorders. Rare: liver function abnormalities, increased levels of liver transaminases (aspartate aminotransferase, alanine aminotransferase), usually without development of jaundice, hepatonecrosis (a dose-dependent effect). Very rare: prolonged use of high doses or overdose may cause liver damage.

Skin and subcutaneous tissue disorders. Uncommon: allergic skin reactions (erythematous reactions or urticaria), sometimes accompanied by fever (drug fever) and mucous membrane involvement, localized drug dermatitis. Very rare: serious skin reactions.

Renal and urinary disorders. Very rare: renal colic, interstitial nephritis, urinary disorders, difficult urination. Renal damage may develop during prolonged use of high doses.

Investigations. Not known: paracetamol use may affect the results of uric acid analysis performed by the phosphotungstic acid method, as well as blood glucose determination by the glucose oxidase-peroxidase method. High doses of ascorbic acid may affect the results of certain laboratory tests: determination of glucose, uric acid, creatinine, and inorganic phosphate in urine. In addition, with high-dose use, false-negative results in occult blood testing of feces are possible. Overall, chemical testing methods based on color reactions may yield false results.

Chlorpheniramine maleate may reduce the intensity of reactions during skin allergy testing.

With prolonged high-dose use, the following are possible: damage to renal glomerular apparatus, formation of urate and/or oxalate calculi in kidneys and urinary tract, renal failure; damage to pancreatic islet apparatus (hyperglycemia, glucosuria) and impaired glycogen synthesis up to onset of diabetes mellitus; myocardial dystrophy; thrombocytosis, thrombus formation, hyperthrombinemia, erythrocytopenia, neutrophilic leukocytosis, decreased capillary permeability (possible worsening of tissue trophism, increased arterial pressure); in patients with glucose-6-phosphate dehydrogenase deficiency — erythrocyte hemolysis; oral dysbiosis; disturbances in zinc and copper metabolism.

Concomitant intake of the medicinal product at recommended doses with products containing caffeine may enhance caffeine-related adverse 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 of great importance. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Shelf life.

3 years.

Storage conditions.

No special storage conditions required. Store in the original packaging, in a place inaccessible to children.

Packaging.

2.02 g of granules in stick-packets; 12 stick-packets in a cardboard box.

Prescription status.

Available without prescription.

Manufacturer.

STADA Arzneimittel AG.

Manufacturer's address and place of business.

Stadastrasse 2-18, 61118 Bad Vilbel, Germany.