Caffetin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KAFFETIN®

Composition:

Active substances: paracetamol, propyphenazone, caffeine, codeine;

1 tablet contains paracetamol 250 mg, propyphenazone 210 mg, caffeine 50 mg, codeine 7.1 mg (in the form of codeine phosphate sesquihydrate 10 mg);

Excipients: povidone, sodium starch glycolate (type A), sodium lauryl sulfate, magnesium stearate, colloidal anhydrous silicon dioxide, microcrystalline cellulose, sodium croscarmellose, calcium hydrogen phosphate dihydrate, glycerol dibehenate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white, round, flat tablets with a bevel, marked with the manufacturer's logo «» on one side and «CAFFETIN» on the other.

Pharmacotherapeutic group.

Other analgesics and antipyretics. Anilides. Paracetamol, combinations without psychotropic agents.

ATC code N02B E51.

Pharmacological properties.

Pharmacodynamics.

A combined agent with analgesic and antipyretic effects.

Three of the four active components of the Kauffetin® preparation – paracetamol, propyphenazone, and codeine – exert analgesic effects, while caffeine, in turn, is a substance that enhances the analgesic effect of the other components.

Paracetamol and propyphenazone exert analgesic, antipyretic, and weak anti-inflammatory effects. Their mechanism of action is associated with the ability to inhibit prostaglandin synthesis.

Codeine is a weak-acting opioid analgesic and is a component of multi-ingredient analgesic preparations to achieve a cumulative effect resulting from different mechanisms of action. The combination of components in the Kauffetin® medicinal product ensures an analgesic effect, and since the components are present in small amounts, this reduces the risk of their adverse effects.

Pharmacokinetics.
All active components of the preparation are absorbed very rapidly, and their maximum plasma concentrations are reached within 30–60 minutes after administration. They are metabolized in the liver and excreted in the urine.

Clinical characteristics.

Indications.

Symptomatic pain relief: headache, dental pain, menstrual pain, postoperative and traumatic pain; relief of symptoms associated with colds and influenza.

Contraindications.

Hypersensitivity to the components of the drug, as well as to pyrazolone or related compounds (containing phenazone, propyphenazone, aminophenazone, metamizole), to phenylbutazone, acetylsalicylic acid, or opioid analgesics. Severe impairment of kidney or liver function; acute hepatitis, acute pancreatitis; benign prostatic hyperplasia; peptic ulcer of the stomach or duodenum in the acute phase; conditions where inhibition of peristalsis should be avoided or which are associated with abdominal distension; risk of paralytic intestinal obstruction; congenital hyperbilirubinemia (including Gilbert’s syndrome); acute porphyria; glucose-6-phosphate dehydrogenase deficiency; blood disorders (including agranulocytosis), severe anemia (including hemolytic anemia), leukopenia (including cytostatic and infectious neutropenias); thrombocytopenia; thrombosis, thrombophlebitis, arterial hypertension, severe arterial hypotension; organic cardiovascular diseases (including atherosclerosis); decompensated heart failure, conduction disorders of the heart, severe atherosclerosis, tendency to vascular spasm, ischemic heart disease, acute myocardial infarction, cardiac arrhythmias; head injuries or conditions associated with increased intracranial pressure (in addition to the risk of respiratory depression and elevated intracranial pressure, codeine may affect pupillary response and other vital signs during neurological assessment); sleep disorders and increased excitability; alcohol, drug, or medication dependence (including history), alcohol intoxication; myasthenia gravis, glaucoma; epilepsy; hyperthyroidism; diabetes mellitus; closed-angle glaucoma; elderly age. Do not use together with monoamine oxidase inhibitors (MAOIs) or within 2 weeks after discontinuation of MAOIs; contraindicated in patients taking tricyclic antidepressants or beta-blockers. Bronchial asthma (opioids should not be used during an asthma attack); conditions associated with respiratory depression; acute respiratory depression, respiratory diseases with dyspnea or obstructive syndrome; postoperative period after biliary tract surgery. Pregnancy or breastfeeding. Children under 12 years of age. Children aged 12 to 18 years undergoing tonsillectomy and/or adenoidectomy to prevent obstructive sleep apnea. Children aged 12 to 18 years with compromised respiratory function.

Patients of any age who are ultra-rapid metabolizers via CYP2D6.

The use of the medicinal product is contraindicated if there is suspicion of acute surgical pathology in a patient prior to diagnosis.

Interaction with other medicinal products and other forms of interaction.

Caused by paracetamol content.

When used with drugs that induce hepatic enzyme activity, such as certain sedatives, antiepileptic agents (e.g., phenobarbital, phenytoin, carbamazepine), and rifampicin, hepatotoxicity due to paracetamol may be increased, even at normal non-toxic doses.

Paracetamol increases plasma levels of acetylsalicylic acid and chloramphenicol.

Paracetamol should be used with caution when administered concomitantly with floxocillin, as co-administration has been associated with metabolic acidosis with a high anion gap due to pyroglutamic acidosis, especially in patients with risk factors (see section "Special precautions for use").

The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular use of paracetamol, increasing the risk of bleeding. Occasional use does not have a significant effect.

If gastric emptying is delayed, e.g., by propantheline, the absorption rate of paracetamol may be reduced and onset of action delayed.

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

Long-term regular use of paracetamol in patients previously taking oral anticoagulants should be conducted only under medical supervision.

Barbiturates reduce the antipyretic effect of paracetamol.

Paracetamol reduces the efficacy of diuretics.

Probenecid affects the elimination and plasma concentration of paracetamol. Paracetamol may reduce the bioavailability of lamotrigine, potentially decreasing its effect due to possible induction of its hepatic metabolism. Concurrent use of paracetamol and zidovudine increases the risk of neutropenia.

Caused by propyphenazone content.

The effect of propyphenazone is enhanced when used concomitantly with sedatives.

Caused by caffeine content.

Caffeine is an antagonist of many sedative substances such as barbiturates and antihistamines; therefore, the drug enhances tachycardia caused by sympathomimetics and thyroxine.

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

Caffeine reduces the effect of opioid analgesics, anxiolytics, hypnotics, and sedatives; it is an antagonist of anesthetic agents and other drugs that depress the central nervous system (CNS), and a competitive antagonist of adenosine and ATP preparations. Concurrent use of caffeine with ergotamine improves absorption of ergotamine from the gastrointestinal tract (GI tract); with thyrotropic agents, it increases thyroid effect. Concurrent use of caffeine with monoamine oxidase inhibitors (MAOIs) may cause a dangerous increase in blood pressure.

Caffeine reduces blood lithium concentration. Cimetidine, hormonal contraceptives, and isoniazid enhance the effect of caffeine.

Other medicinal products whose action may be altered by interaction with caffeine: hydroxyzine, mexiletine, ciprofloxacin, enoxacin, pipemidic acid, fluvoxamine, phenylpropanolamine, phenytoin, clozapine, lithium, theophylline, pentobarbital, diazepam, methoxsalen.

Caused by codeine content.

Codeine may inhibit the effects of metoclopramide and domperidone on gastrointestinal motility. Codeine enhances the effects of agents that depress the central nervous system (CNS), including alcohol, anesthetics, hypnotics, sedatives, tricyclic antidepressants, and phenothiazine tranquilizers.

Codeine should not be used in combination with MAO inhibitors or within 2 weeks after discontinuation of MAO inhibitors. The use of MAO inhibitors in combination with pethidine has been associated with severe CNS excitation or depression (including arterial hypertension/hypotension). Although such effects have not been documented with codeine, such an interaction cannot be ruled out. Tricyclic antidepressants may enhance the depressant effects of opioid analgesics.

Sedative medicinal products, such as benzodiazepines or similar-acting substances.

Concomitant use of opioids with sedatives such as benzodiazepines or similar-acting substances increases the risk of sedation, respiratory depression, coma, and fatal outcome due to additive CNS depressant effects. The dose and duration of concomitant use should be limited (see section "Special precautions for use").

Concurrent use of codeine with alcohol may enhance the hypotensive and sedative effects of alcohol and increase alcohol’s respiratory depressant effects; with anesthetics, sodium oxybate, and antihistamines with sedative properties – possible enhancement of CNS depression and/or respiratory depression and/or arterial hypotension; with neuroleptics – enhanced sedative and hypotensive effects; with anxiolytics, sedatives, and hypnotics – enhanced sedative effect and increased risk of respiratory depression; with antihypertensive agents – enhanced hypotensive effect; with antiarrhythmics – codeine slows the absorption of mexiletine; when codeine is used concomitantly with quinidine, the analgesic effect of codeine is likely to be significantly reduced due to quinidine’s negative effect on its metabolism; with chloramphenicol – increased plasma concentration of codeine due to inhibition of its metabolism; with non-opioid analgesics – enhanced analgesic effect; with antiulcer agents – cimetidine may inhibit codeine metabolism, leading to increased plasma concentration; with antidiarrheal agents and anticholinergic agents (e.g., atropine) – risk of severe constipation, which may lead to paralytic intestinal obstruction and/or urinary retention. Codeine antagonizes the effects of cisapride, metoclopramide, and domperidone on gastrointestinal activity. Use of codeine in combination with opioid antagonists (e.g., buprenorphine, naloxone, naltrexone) may accelerate the onset of withdrawal syndrome. Opioid premedication should be avoided, as it reduces plasma concentrations of ciprofloxacin. Use with ritonavir may increase plasma levels of opioid analgesics (including codeine). When used in high doses, codeine may enhance the effect of cardiac glycosides (digoxin and others). Opioid use may interfere with assessment of gastric emptying, as opioids delay gastric evacuation, and may also impair hepatobiliary imaging with Technetium Tc99m Disofenin, as opioid therapy may cause sphincter of Oddi constriction and increased pressure in the biliary tract.

Other interactions.

Do not use simultaneously with alcohol. Alcohol and isoniazid enhance the hepatotoxicity of paracetamol.

For substances with a broad range of action (e.g., benzodiazepines), interactions are possible in various forms and are unpredictable. Oral contraceptives, cimetidine, and disulfiram reduce caffeine metabolism, while smoking enhances it. The drug slows the elimination of theophylline. Due to the presence of caffeine in the formulation, the effect of ephedrine-like substances is enhanced. Concurrent use of certain CYP1A2 inhibitors may prolong the elimination of caffeine and its metabolite paraxanthine.

Concomitant use of the drug with CNS stimulants and with medicinal products or beverages containing caffeine is not recommended.

Concomitant use with nonsteroidal anti-inflammatory drugs may lead to gastrointestinal adverse reactions.

The frequency of neutropenia (decreased white blood cell count) increases when paracetamol and AZT (zidovudine) are used concurrently.

Combination with chloramphenicol may prolong elimination of this drug, increasing the risk of toxicity.

The drug enhances the effect of oral antidiabetic agents (tolbutamide, chlorpropamide, acetohexamide) and oral anticoagulants such as coumarins.

Opioid analgesics may interact with MAO inhibitors, potentially causing serotonin syndrome.

Special precautions for use

Before using the medicine, consult a physician.

Do not take the medicine for more than 3 days unless otherwise recommended by a physician.

If symptoms persist or worsen, consult a physician.

Do not exceed the recommended dose. In case of overdose, seek immediate medical attention.

Do not use the medicine to relieve acute abdominal pain (until the cause is determined).

Do not use in patients with increased excitability or sleep disorders.

The medicine contains paracetamol. Concurrent use with other paracetamol-containing medicines may lead to overdose. Paracetamol may be hepatotoxic at doses exceeding 6–8 g per day. Liver damage may occur even at significantly lower doses when combined with alcohol, enzyme inducers in the liver, or other hepatotoxic medicines. Paracetamol overdose may lead to liver failure, which may necessitate liver transplantation or result in death.

Liver diseases increase the risk of liver damage from paracetamol.

Cases of liver dysfunction/liver failure have been reported in patients with reduced glutathione levels, particularly in patients who are debilitated, those with anorexia, those with low body mass index, or those who abuse alcohol.

In patients with conditions associated with reduced glutathione levels, such as sepsis, the use of paracetamol may increase the risk of metabolic acidosis. Symptoms of metabolic acidosis include deep, rapid, or labored breathing, nausea, vomiting, and loss of appetite. Seek immediate medical attention if these symptoms occur.

Cases of high anion gap metabolic acidosis (HAGMA) due to 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 for prolonged periods 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 useful in identifying pyroglutamic acidosis as the underlying cause of HAGMA in patients with multiple risk factors.

Patients with a history of cholecystectomy should consult a physician before using the medicine, as there is a risk of developing acute pancreatitis.

Codeine is metabolized to morphine in the liver by the CYP2D6 enzyme. In patients with deficiency or complete absence of this enzyme, adequate analgesic effect will not be achieved. However, if a patient is an "extensive" or "ultra-rapid" metabolizer of codeine, there is an increased risk of opioid toxicity, even when the medicine is used at standard doses (see section "Contraindications").

Use of the medicine during acute asthma attacks is contraindicated (see section "Contraindications"). Patients with atopic bronchial asthma and pollen allergies have an increased risk of hypersensitivity reactions. The medicine should be used with caution in patients with hypersensitivity to analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs), and in patients with allergic reactions (due to increased risk of anaphylactic shock in this patient group).

Use the medicine with caution in patients with peptic ulcer disease of the stomach and duodenum in remission, hepatic or renal dysfunction (see section "Contraindications"), thyroid disorders (including hypothyroidism; see section "Contraindications"), urinary tract disorders, hyperkinesia, chronic respiratory infections, pneumonia, respiratory function disorders, acute drug intoxication, or during cytostatic therapy (only under physician supervision). Reduce the codeine dose in debilitated patients, patients with arterial hypotension (see section "Contraindications"), adrenal insufficiency (e.g., Addison's disease), inflammatory bowel diseases including ulcerative colitis and Crohn's disease (codeine reduces intestinal peristalsis, increases intestinal tone and segmentation, and may increase pressure in the colon) (see section "Contraindications"), urethral stricture, seizure disorders, or in shock. Reduce the codeine dose in patients with renal insufficiency. Exercise caution when using the medicine in patients with a history of kidney disease (pyelonephritis, glomerulonephritis). Codeine should be used with caution in patients who have recently undergone gastrointestinal surgery (due to possible reduced gastrointestinal motility) or urinary tract surgery (such patients are more prone to urinary retention caused directly by urethral sphincter spasm and constipation due to codeine use). Codeine should be used with caution in patients with pheochromocytoma (opioids may stimulate catecholamine release by inducing endogenous histamine release). Patients with biliary tract disorders (particularly cholelithiasis) should avoid opioid analgesics or use them in combination with spasmolytics.

The use of pethidine and possibly other opioid analgesics in patients taking monoamine oxidase inhibitors (MAOIs) may lead to severe, sometimes fatal, reactions. If the use of codeine in patients taking MAOIs is essential, discontinue MAOI treatment 14 days prior to starting codeine therapy (see sections "Contraindications", "Interaction with other medicinal products and other forms of interaction").

Risk of concomitant use with sedative medicines such as benzodiazepines or similar active substances

Concomitant use of KAFFETIN® with sedative medicines such as benzodiazepines or similar active substances may result in sedation, respiratory depression, coma, and death. Due to these risks, concomitant prescription of these sedative medicines should only be considered for patients for whom alternative treatment options are not possible. If the decision to prescribe KAFFETIN® together with sedative medicines is made, the lowest effective dose should be used, and the duration of treatment should be as short as possible. Patients should be closely monitored for signs and symptoms of respiratory depression and sedation. In this regard, patients and their caregivers should be strongly advised and informed about these symptoms (see section "Interaction with other medicinal products and other forms of interaction").

Metabolism involving CYP2D6

Codeine is converted to its active metabolite, morphine, in the liver via the CYP2D6 enzyme. If a patient has a deficiency of this enzyme or if CYP2D6 is completely absent, adequate analgesic effect will not be achieved. Up to 7% of the Caucasian population may have this CYP2D6 metabolism characteristic. However, if a patient is an ultra-rapid metabolizer via CYP2D6, there is an increased risk of adverse effects—symptoms of opioid toxicity—even when standard doses are used. In such patients, the conversion of codeine to morphine rapidly leads to higher serum morphine levels than expected.

General symptoms of opioid toxicity: confusion, drowsiness, shallow breathing, pinpoint pupils, nausea, vomiting, constipation, loss of appetite. In severe cases, symptoms of circulatory and respiratory depression may occur, which can be life-threatening and very rarely fatal.

Data on the prevalence of ultra-rapid metabolizers via CYP2D6 in various populations are provided below:

Postoperative use in children

There have been reports that the use of codeine in children after tonsillectomy and/or adenoidectomy for prevention of obstructive sleep apnea rarely led to life-threatening adverse reactions, including fatal outcomes (see section "Contraindications"). All children received codeine doses within the recommended dosage range. However, evidence suggests that these children were either ultra-rapid or extensive metabolizers of codeine.

Children with compromised respiratory function

Codeine is contraindicated in children whose respiratory function may be compromised by neuromuscular disorders, severe cardiac or respiratory diseases, upper respiratory tract infections or lung infections, multiple trauma, or extensive surgical interventions. These factors may exacerbate symptoms of morphine toxicity.

Opioid analgesics reduce salivation, which may contribute to the development of dental caries and candidiasis of the oral mucosa.

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

Caution should be exercised when prescribing the drug to patients with chronic respiratory diseases and chronic urticaria.

Consult a physician regarding the possibility of using the drug in patients with renal or hepatic impairment.

Precautions should be taken in cases of reduced tolerance to analgesics, hypersensitivity to other analgesics (risk of provoking asthma attacks), to other anti-inflammatory agents, as well as in the presence of gastrointestinal ulcers or bleeding.

Patients with obstructive gastrointestinal disorders or acute abdominal conditions should consult a physician before using the drug.

There are isolated reports of asthma attacks and cases of anaphylactic shock due to individual hypersensitivity to propyphenazone and drugs containing paracetamol.

Special caution (reduced dosage and splitting the daily dose into more frequent administrations) is necessary in hepatitis and renal function impairment.

Particular caution is required for patients with blood dyscrasias or bone marrow suppression, and careful monitoring of hematological parameters is recommended. The risk of neutropenia and agranulocytosis is mainly associated with the presence of propyphenazone. If such a reaction occurs after taking Kauffetin® (fever, sore throat, oral ulcers and abscesses, perianal abscesses, and decreased granulocytes in blood), the drug should be discontinued immediately. These adverse effects are usually reversible and disappear within 1–2 weeks.

Special attention is also required for patients experiencing anxiety, nervousness, restlessness, tremor, as well as patients with arterial hypertension or insomnia. If tachycardia or rapid heartbeat occurs, the drug should be discontinued immediately.

During treatment with the drug, it is not recommended to consume excessive amounts of beverages containing caffeine (e.g., coffee, tea), as this may intensify caffeine-related side effects such as dizziness, increased excitability, insomnia, restlessness, anxiety, irritability, headache, gastrointestinal disturbances, tachycardia, and rapid heartbeat. This may also cause sleep problems, tremor, tension, irritability, and discomfort in the chest due to palpitations.

Inform the physician about the use of drugs containing codeine, as well as metoclopramide or domperidone, and medications used to treat nausea and vomiting.

Before using the drug, inform the physician about the use of sedatives, hypnotics, neuroleptics, or alcohol.

Concomitant use of Kauffetin® with alcohol should be avoided, as individual reactions cannot be predicted.

It should be noted that patients with alcohol-induced liver damage have an increased risk of paracetamol-induced hepatotoxicity.

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

Patients should be informed that analgesics should not be used for prolonged periods.

Long-term use of analgesics containing high cumulative doses of paracetamol may, in individual cases, lead to analgesic nephropathy or irreversible renal failure.

Long-term use of analgesics for headache treatment may lead to chronic headache.

Prolonged and excessive use of codeine may lead to dependence.

The drug should be prescribed with caution to patients whose condition may worsen due to opioid use, particularly those being treated for depression or with respiratory diseases.

Do not exceed the recommended doses.

Do not use the medicinal product for longer than the recommended duration without consulting a physician.

Do not take the medicinal product with other drugs containing paracetamol, caffeine, or codeine.

If symptoms do not resolve, consult a physician.

Symptoms of codeine-induced toxic effects: disturbances of consciousness of varying degrees, loss of appetite, drowsiness, constipation, respiratory depression, marked constriction of pupils ("pinpoint pupils"), nausea, vomiting.

Alcohol consumption is prohibited during treatment with this medicinal product.

If symptoms do not resolve (particularly if headache becomes persistent) or, conversely, if the patient's condition worsens, or if adverse reactions occur, discontinue use of the medicinal product and consult a physician for further guidance.

In case of overdose, seek immediate medical attention due to the risk of liver damage, even if the patient feels well.

Use during pregnancy or breastfeeding

Kauffetin® should not be used during pregnancy or breastfeeding.

If use of the drug is necessary, breastfeeding should be discontinued.

Ability to affect reaction speed when driving or operating machinery

During treatment with the drug, drowsiness, dizziness, excitement, confusion, hallucinations, visual disturbances, or seizures may occur. The effects of alcohol are potentiated by opioid analgesics. This should be taken into account by patients who drive vehicles or operate complex machinery requiring concentration.

Method of Administration and Dosage.

Kaffetin® is administered orally. Tablets should be taken with sufficient amount of liquid.

Adults and children aged 16 years and older: take 1–2 tablets as a single dose. Do not use more than 3 single doses per day.

Children aged 12–16 years: take ½ tablet or 1 tablet as a single dose. Do not use more than 3 single doses per day.

Do not take for more than 3 days without consulting a physician. Do not exceed the recommended dose. The lowest effective dose should be used to achieve the desired therapeutic effect.

Children.

The medicinal product is indicated for use in children aged 12 to 18 years for the treatment of acute moderate pain not relieved by other analgesics such as paracetamol or ibuprofen (as monotherapies) (see section "Indications").

The use of the medicinal product is contraindicated in children under 12 years of age due to the risk of developing serious and life-threatening adverse reactions resulting from the variable and unpredictable metabolism of codeine into morphine in this age group (see section "Contraindications").

Codeine must not be used in children aged 12 to 18 years undergoing tonsillectomy and/or adenoidectomy due to the risk of developing life-threatening respiratory depression, including obstructive sleep apnea (see sections "Contraindications", "Special Warnings and Precautions for Use").

Codeine must not be used in children aged 12 to 18 years with compromised respiratory function due to the risk of serious and life-threatening adverse reactions (see sections "Contraindications", "Special Warnings and Precautions for Use").

Codeine must not be used in children aged 12 to 18 years who are ultra-rapid metabolizers via CYP2D6 (see sections "Contraindications", "Special Warnings and Precautions for Use").

Overdose.

With prolonged use of the drug in high doses, hematological disorders may develop, including aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia. Central nervous system (CNS) effects may include dizziness, psychomotor agitation, disorientation, insomnia, tremor, nervousness, restlessness, and anxiety. Renal effects may include nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis).

In case of overdose, symptoms may include increased sweating, psychomotor agitation or CNS depression, somnolence, impaired consciousness, cardiac arrhythmia, tachycardia, extrasystoles, tremor, hyperreflexia, and seizures.

Paracetamol overdose symptoms. Paracetamol overdose can lead to liver failure, which may require liver transplantation or result in death. Liver damage may occur in adults who have ingested 6–8 g of paracetamol depending on body weight, and in children who have ingested more than 150 mg/kg body weight. In patients with risk factors (long-term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John's wort, or other drugs inducing liver enzymes; chronic excessive alcohol consumption; glutathione deficiency (malnutrition, cystic fibrosis, HIV infection, fasting, cachexia)), ingestion of 5 g or more of paracetamol may lead to liver damage.

Symptoms within the first 24 hours: pallor, nausea, vomiting, anorexia, 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, coma, and death. Acute renal failure with acute tubular necrosis may present as severe flank pain, hematuria, proteinuria, and may develop even in the absence of severe liver injury. Cardiac arrhythmias and pancreatitis have also been reported.

Treatment. In case of overdose, prompt medical attention is required, even if early symptoms are absent. The patient should be taken to hospital immediately, even if no early symptoms are present. Symptoms may be limited to nausea and vomiting and may not reflect the severity of the overdose or the risk of organ damage.

The use of activated charcoal to reduce paracetamol absorption in the gastrointestinal tract is controversial. The specific antidote, N-acetylcysteine, should be administered within 8–15 hours after paracetamol overdose, although a beneficial effect has been observed even with later administration. However, the efficacy of the antidote decreases significantly after this time. Plasma paracetamol concentration should be measured at least 4 hours or later after ingestion (earlier concentrations are unreliable). If necessary, intravenous N-acetylcysteine should be administered according to the established dosing regimen. In the absence of vomiting, oral methionine may be used as an alternative in remote areas outside hospital settings.

Propyphenazone overdose symptoms. Central nervous system (CNS) toxicity may occur (seizures, coma).

Caffeine overdose symptoms. Caffeine overdose may cause tachypnea, extrasystoles, epigastric pain, vomiting, diuresis, flushing, tachycardia, or cardiac arrhythmia, gastrointestinal disturbances, and CNS stimulation (insomnia, restlessness, excitement, anxiety, increased nervous-reflex excitability, headache, tremor, seizures, dizziness, nervousness, irritability, affective disturbances, disorganized thoughts and speech, psychomotor agitation, or periods of hyperactivity). Clinically significant symptoms of caffeine overdose may also be associated with liver damage caused by paracetamol.

Treatment. Treatment of caffeine overdose: gastric lavage and oxygen therapy are required. In case of seizures, diazepam should be administered. Symptomatic therapy.

There is no specific antidote. However, supportive measures such as the use of beta-adrenergic antagonists may help alleviate cardiotoxic effects.

Codeine overdose symptoms. Codeine overdose in the initial phase is characterized by nausea and vomiting. Symptoms of codeine overdose include CNS depression, including acute respiratory center depression, which may lead to cyanosis, slowed breathing, dyspnea, somnolence, ataxia, and less frequently, pulmonary edema; respiratory arrest, miosis, seizures, collapse, urinary retention, hypotension, and tachycardia. Signs of histamine release have also been observed.

Treatment: symptomatic therapy. Supportive measures include ensuring access to fresh air and monitoring vital signs. If more than 350 mg of codeine has been ingested in adults or more than 5 mg/kg body weight in children, administration of activated charcoal is recommended within 1 hour. Gastric lavage and bowel cleansing are indicated.

In cases of coma or respiratory depression, the specific antidote naloxone should be administered, and the patient should be observed for at least 4 hours, or at least 8 hours if a sustained-release formulation of naloxone is used. Apnea and severe CNS depression require oxygen administration and mechanical ventilation.

Overdose of codeine may result in complications that could be part of the toxic effect of excessive paracetamol doses on the liver. In case of overdose, immediate medical help should be sought, even if symptoms are not present.

Side effects

Therapeutic doses of the drug are generally well tolerated. Adverse effects are mainly due to the presence of paracetamol in the formulation.

Immune system disorders: hypersensitivity reactions, including anaphylaxis, anaphylactic shock, erythema multiforme, toxic epidermal necrolysis (Lyell’s syndrome), skin hypersensitivity reactions including skin rash; angioedema, Stevens–Johnson syndrome, acute generalized exanthematous pustulosis.

Skin and subcutaneous tissue disorders: skin and mucous membrane rashes, erythematous rash, urticaria, pruritus, hemorrhages, sweating, oral mucosal ulcers, purpura, allergic dermatitis.

Central nervous system disorders (with high-dose administration): dizziness, psychomotor agitation and disorientation, insomnia, irritability, increased excitability, nervousness, headache, tremor, convulsions, paresthesia, restlessness.

Cardiac disorders: tachycardia, arrhythmia (tachycardia, bradycardia), increased blood pressure, arterial hypotension, chest pain, palpitations.

Gastrointestinal disorders: nausea, vomiting, dry mouth, dyspepsia, abdominal discomfort, constipation, digestive disturbances, acute pancreatitis in patients with a history of cholecystectomy, heartburn, epigastric pain.

Endocrine system disorders: hypoglycemia (up to hypoglycemic coma).

Blood and lymphatic system disorders: anemia, sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), hemolytic anemia. With prolonged use at high doses – aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, thrombocytopenia. Discontinue the drug and immediately inform a physician if unexplained bruising or bleeding occurs.

Renal and urinary disorders (with high-dose administration): nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis), urinary retention.

Respiratory, thoracic and mediastinal disorders: bronchospasm in patients sensitive to aspirin and other NSAIDs.

Hepatobiliary disorders: liver function abnormalities, increased activity of liver enzymes, usually without jaundice, hepatonecrosis (dose-dependent effect), hepatic failure, jaundice.

Psychiatric disorders: anxiety, fear, irritability, sleep disturbances, confusion, euphoria, dysphoria, depression, hallucinations, anxiety, sedation, drowsiness (depending on dose and individual sensitivity); prolonged use of high doses may lead to dependence.

Metabolism and nutrition disorders: frequency unknown – metabolic acidosis with high anion gap*.

Other: general weakness, miosis, visual disturbances.

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

*Description of individual adverse reactions

Metabolic acidosis with high anion gap

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

Reporting of suspected adverse reactions after drug registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the drug. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy via the Automated Pharmacovigilance Information System at the following link: http://aisf.dec.gov.ua/.

Shelf life.

3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

Tablets No. 6: 6 tablets in a perforated strip; 1 strip in a cardboard box.

Tablets No. 10: 10 tablets in a perforated strip; 1 strip in a cardboard box.

Tablets No. 12: 6 tablets in a perforated strip; 2 strips (12 tablets) in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

ALKALOID AD Skopje.

ALKALOID AD Skopje.

Manufacturer's address and place of business.

Boulevard Aleksandar Makedonski 12, Skopje, 1000, Republic of North Macedonia.