Kofan bosnalek®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KOFAN BOSNALJEK®

Composition:

Active substances: 1 tablet contains 200 mg of paracetamol, 200 mg of propyphenazone, 50 mg of caffeine.

Excipients: microcrystalline cellulose, corn starch, talc, povidone, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white, round tablets.

Pharmacotherapeutic group.

Analgesics. Paracetamol combinations without psychotropic agents.

ATC code N02BE51.

Pharmacological properties.

Pharmacodynamics.

Kofan Bosnalek® is a combination drug whose active ingredients act synergistically. Paracetamol and propyphenazone have analgesic, anti-inflammatory, and antipyretic effects. The mechanism of analgesic and anti-inflammatory action is associated with inhibition of prostaglandin synthesis, while the antipyretic effect is mediated via the thermoregulatory center of the hypothalamus. Caffeine exerts a stimulating effect on the central nervous system, particularly on the respiratory and circulatory centers, within this combination.

Pharmacokinetics.

All components of Kofan Bosnalek® tablets are rapidly absorbed from the gastrointestinal tract. The pharmaceutical formulation is designed to accelerate dissolution and absorption of the active ingredients. Paracetamol reaches effective plasma concentrations within 60 minutes, while propyphenazone and caffeine achieve effective concentrations within 30 minutes.

Paracetamol is widely distributed throughout body systems. Propyphenazone penetrates well into synovial and joint structures. Caffeine is distributed across all body tissues and crosses the blood-brain barrier. All active ingredients cross the placental barrier and are excreted into breast milk.

Biotransformation of paracetamol occurs in the liver; metabolites in the form of glucuronic and sulfuric acid conjugates are excreted in urine. Children have a lower capacity for glucuronidation of paracetamol compared to adults.

Propyphenazone and caffeine are also metabolized in the liver, and their metabolites are excreted in urine.

Clinical characteristics.

Indications.

Pain relief: headache and toothache, menstrual pain, postoperative and rheumatic pain. Pain relief and reduction of elevated body temperature in influenza and colds.

Contraindications.

• Hypersensitivity to pyrazolone and related substances (phenazone, aminophenazone, metamizole), as well as to phenylbutazone, acetylsalicylic acid, or any other component of the medicinal product;
• Glucose-6-phosphate dehydrogenase deficiency;
• Severe hepatic insufficiency (>9 points on the Child–Pugh scale);
• Severe liver function disorders (chronic alcoholism, hepatitis);
• Severe renal insufficiency;
• Congenital hyperbilirubinemia, acute hepatic porphyria, pancreatitis;
• Blood disorders, bone marrow suppression (leukopenia, anemia, including hemolytic);
• Conditions associated with respiratory depression, closed-angle glaucoma, intracranial hypertension, acute myocardial infarction, ischemic heart disease, organic cardiovascular diseases, decompensated heart failure, severe atherosclerosis, tendency to vascular spasm, conduction disorders, history of arrhythmia, thrombosis, thrombophlebitis, severe arterial hypertension;
• Bronchial asthma, chronic rhinitis, urticaria;
• States of increased excitation, sleep disturbances. Epilepsy. Alcoholism;
• Prostate hyperplasia with urinary retention, diabetes mellitus, marked hyperthyroidism;
• Should not be used concomitantly with tricyclic antidepressants, beta-blockers, monoamine oxidase inhibitors (MAOIs), or within 2 weeks after discontinuation of MAOIs;
• Advanced age.

Interaction with other medicinal products and other types of interactions.

When using CoFan BosnaLek® tablets, as with other analgesics, alcohol should not be consumed due to unpredictable individual reactions.

Prolonged concurrent use of the medicinal product with acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs may lead to kidney damage. Paracetamol increases plasma levels of acetylsalicylic acid and chloramphenicol.

Probenecid affects the plasma concentration of paracetamol and its excretion.

Inducers of hepatic microsomal enzymes (rifampicin and phenobarbital) increase paracetamol toxicity, as a large amount of toxic epoxide is formed during its biotransformation. Paracetamol may reduce lamotrigine bioavailability, thereby reducing its effect, possibly due to induction of its hepatic metabolism.

Concomitant administration of paracetamol and zidovudine increases the risk of neutropenia. CoFan BosnaLek® may be taken simultaneously with zidovudine only on a physician's prescription.

Anticonvulsant drugs (including phenytoin, barbiturates, carbamazepine), which stimulate the activity of hepatic microsomal enzymes, rifampicin, and excessive alcohol consumption may enhance the hepatotoxic effect of paracetamol due to increased conversion of the drug into hepatotoxic metabolites, even when safe doses are used. Concurrent use of paracetamol with hepatotoxic agents increases the hepatotoxic effects of the drugs. Concurrent use of high doses of paracetamol with isoniazid increases the risk of hepatotoxic syndrome.

Paracetamol reduces the effectiveness of diuretics.

Delayed gastric emptying, as occurs with propantheline, may slow the absorption of paracetamol and delay the onset of its action. Accelerated gastric emptying, as with metoclopramide, increases the rate of absorption. The rate of paracetamol absorption may be increased when used with domperidone and decreased with cholestyramine.

Interaction between paracetamol and warfarin or coumarin derivatives increases the risk of bleeding. Therefore, patients taking oral anticoagulants should not take paracetamol for prolonged periods without medical supervision.

Barbiturates reduce the antipyretic effect of paracetamol.

Caution should be exercised when using paracetamol concomitantly with flucloxacillin, as co-administration is associated with high anion gap metabolic acidosis, particularly in patients with risk factors (see section "Special precautions").

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) (including barbiturates, antihistamines), as well as adenosine and adenosine triphosphate (ATP) preparations; it reduces blood lithium concentration.

Caffeine enhances tachycardia caused by sympathomimetics (including ephedrine) and thyroxine. Interaction with broad-spectrum agents (benzodiazepines) may manifest in various forms and cannot be predicted.

Oral contraceptives, cimetidine, and disulfiram reduce caffeine metabolism, whereas barbiturates and smoking enhance it. Isoniazid enhances the effect of caffeine.

Caffeine delays the elimination of theophylline. Caffeine increases the risk of dependence on ephedrine-like substances. Concurrent administration of certain inhibitors of xanthine oxidase may prolong the elimination of caffeine and its metabolite paraxanthine.

Concomitant use of caffeine with monoamine oxidase inhibitors (MAOIs) may cause dangerous elevation of blood pressure. Caffeine enhances the effect (improves bioavailability) of analgesic-antipyretic drugs, improves gastrointestinal absorption of ergotamine, potentiates the effects of xanthine derivatives, alpha- and beta-adrenergic agonists, psychostimulants, enhances the thyroid effect of thyroid-stimulating agents. There is a hypothesis that caffeine may increase the risk of dependence on analgesics such as paracetamol, but clinical data confirming this are insufficient.

The effect of propyphenazone is enhanced when used concomitantly with hypnotic agents.

The drug enhances the action of oral antidiabetic agents (tolbutamide, chlorpropamide, acetazolamide) and oral anticoagulants such as coumarin.

Concomitant use of the medicinal product with drugs and other agents that stimulate the CNS is not recommended.

Although there are no clinical data on interaction with propyphenazone, interactions of these drug classes with other nonsteroidal anti-inflammatory drugs have been reported:

• Angiotensin-converting enzyme (ACE) inhibitors, beta-blockers: reduced antihypertensive effect;
• Antithrombotic agents, excluding salicylates: increased risk of bleeding;
• Methotrexate: increased concentration and, consequently, toxicity of methotrexate;
• Lithium: increased serum lithium levels.

Special precautions for use

Patients should be informed that the medicinal product is not recommended for use for more than 7 days without consulting a physician. Do not exceed the recommended doses. Avoid using other medications containing paracetamol.

Concurrent use with other paracetamol-containing preparations may lead to overdose. Paracetamol overdose can cause liver failure, which may necessitate liver transplantation or result in fatal outcomes. Prolonged use beyond the recommended duration may lead to severe hepatotoxic effects and liver complications such as cirrhosis. 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 of the liver, or other hepatotoxic medicinal products. Individuals prone to alcohol consumption have an increased risk of hepatotoxicity. The risk of overdose is highest in patients with non-cirrhotic alcoholic liver disease.

Prolonged use of analgesics containing high cumulative doses of paracetamol may, in individual cases, lead to analgesic nephropathy or irreversible renal failure. Patients suffering from kidney disease should consult a physician before initiating paracetamol therapy, as dose adjustment may be required. Monitoring of renal function is necessary.

Patients with liver disorders or infections causing liver involvement, such as viral hepatitis, should consult a physician before starting treatment with this medicinal product. These patients may require monitoring of liver function during treatment with high doses or during prolonged therapy. The product should be used with caution in patients with mild to moderate hepatic insufficiency (Child–Pugh score < 9 points). During paracetamol use, alanine aminotransferase (ALT) levels in blood plasma may increase.

When treating with oral anticoagulants, monitoring of prothrombin time is required if high doses of paracetamol are used concurrently.

The risk of hepatotoxic effects of paracetamol at therapeutic doses increases in conditions associated with increased renal oxidative stress and reduced glutathione stores in the liver, such as concomitant use of multiple medicinal products, alcoholism, sepsis, or diabetes mellitus. In patients with 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. Immediate medical attention is required if these symptoms occur.

The risk of neutropenia and agranulocytosis is primarily due to the presence of propyphenazone. If such a reaction occurs after taking the product (e.g., fever, sore throat, oral ulcers and abscesses, perianal abscesses, decreased granulocyte count in blood), the product should be discontinued immediately. These adverse effects are usually reversible and resolve within 1–2 weeks.

During treatment with this product, it is not recommended to consume excessive amounts of beverages containing caffeine (coffee, tea), as this may cause sleep disturbances, tremor, and palpitations. If tachycardia occurs, the product should be discontinued immediately. Individuals sensitive to caffeine or those who have not previously consumed it are more susceptible to caffeine-related adverse effects.

Prolonged use of analgesics for headache treatment may lead to medication-overuse headache (chronic headache). If headaches become persistent, medical advice should be sought.

The medicinal product should be used with particular caution in patients with heart disease combined with fluid retention and edema, immediate-type hypersensitivity, or history of bone marrow suppression, gastrointestinal disorders, or a history of peptic ulcer formation. Patients with polyposis have an increased risk of allergic reactions. Cases of bronchial asthma attacks and anaphylactic shock in sensitive individuals have been reported following administration of medicinal products containing propyphenazone and paracetamol. If symptoms persist, medical advice should be sought.

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

Caution is recommended when using paracetamol concurrently with flucloxacillin due to an increased risk of high anion gap metabolic acidosis, particularly in patients with severe renal impairment, sepsis, malnutrition, and other sources of glutathione deficiency (e.g., chronic alcoholism), as well as those taking the maximum daily dose of paracetamol. Close monitoring, including measurement of urinary 5-oxoproline, is recommended.

Use during pregnancy or breastfeeding

The use of this product during pregnancy is not recommended, as caffeine intake increases the risk of spontaneous abortion.

Components of the medicinal product pass into breast milk; therefore, if use of the product is necessary, breastfeeding should be discontinued.

Ability to affect reaction speed when driving or operating machinery

The use of this product may reduce reaction speed and cause dizziness; therefore, caution is required when driving vehicles or operating other precision machinery.

Dosage and Administration.

Take tablets orally, with water or another liquid.

For adults: prescribe 1–2 tablets.

For children aged 12–16 years: prescribe 1 tablet.

If necessary, this dose may be repeated up to 3 times daily.

The duration of treatment is determined individually by a physician, but should not exceed 7 days.

Children.

Do not use in children under 12 years of age.

Overdose.

Paracetamol overdose: may lead to hepatic failure, which could necessitate liver transplantation or result in death. Acute pancreatitis has been observed, usually concomitant with liver function abnormalities and hepatotoxicity. Liver damage may occur in adults who have ingested 6–8 g or more of paracetamol, and in children who have ingested more than 0.15 g/kg body weight. In patients with risk factors [long-term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John’s wort, or other drugs inducing liver enzymes; chronic excessive alcohol consumption; glutathione depletion (due to malnutrition, cystic fibrosis, HIV infection, fasting, cachexia)], ingestion of 5 g or more of paracetamol may cause liver damage.

Symptoms within the first 24 hours: pallor, nausea, vomiting, loss of appetite, and abdominal pain. Clinical signs of liver damage typically become apparent 24–48 hours after overdose and usually peak within 4–6 days. Glucose metabolism disturbances and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, hemorrhage, hypoglycemia, coma, and may be fatal. 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 damage. Cardiac arrhythmias have been reported.

With prolonged use of the drug in high doses, hematological disorders may include aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia. High-dose intake may cause central nervous system effects such as dizziness, psychomotor agitation, and disorientation; urinary system effects may include nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis).

Symptoms of overdose may be limited to nausea and vomiting, or may not reflect the severity of overdose or risk of organ damage. Immediate medical attention is required in case of overdose. Treatment must be initiated immediately. Immediate medical care is necessary even if no symptoms of overdose are observed. If overdose is confirmed or suspected, the patient must be taken to the nearest medical facility capable of providing appropriate medical care, due to the risk of delayed liver damage. Administration of activated charcoal should be considered if excessive paracetamol was ingested within the past 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 administered within 8 hours. The efficacy of the antidote declines sharply after this time. If required, 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.

Propyphenazone overdose: may cause central nervous system effects (seizures, coma).

Caffeine overdose: may cause epigastric pain, vomiting, diuresis, hyperventilation, tachycardia, extrasystoles, cardiac arrhythmia, and effects on the central nervous system (insomnia, restlessness, nervous excitation, anxiety, dizziness, irritability, emotional lability, tremor, seizures). Clinically significant symptoms of caffeine overdose may also be associated with severe paracetamol-induced liver injury, which may occur when the amount of drug ingested causes caffeine overdose. There is no specific antidote, but beta-adrenergic receptor antagonists may help alleviate cardiotoxic effects. Supportive measures and symptomatic therapy are required, including gastric lavage, recommended oxygen therapy, and diazepam in case of seizures.

Adverse reactions.

Kofan Bosnaliek® is generally well tolerated, but in individual cases the following adverse effects may occur:

Gastrointestinal tract: heartburn, epigastric pain, nausea, vomiting, loss of appetite, gastrointestinal spasms, abdominal pain, diarrhea;

Hepatobiliary system: impaired liver function, increased activity of liver enzymes, usually without development of jaundice, hepatonecrosis (dose-dependent effect), hepatic failure, jaundice; with prolonged use without medical supervision, hepatic fibrosis and cirrhosis (up to fatal outcome) may develop;

Nervous system (usually occurs when taking high doses): insomnia, restlessness, dizziness, anxiety and irritability, nervousness;

Hematopoietic system: granulocytopenia, anemia, agranulocytosis; sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), hemolytic anemia, thrombocytopenia, bruising or bleeding, neutropenia, leukopenia, pancytopenia;

Allergic reactions: skin itching, skin and mucous membrane rashes (usually generalized rash, erythematous, urticaria), angioneurotic edema, hypersensitivity reactions. In individual cases, some patients may develop erythema multiforme (including Stevens–Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome), anaphylaxis, acute generalized exanthematous pustulosis;

Skin and subcutaneous tissues: itching, rashes, sweating, purpura, oral mucosal ulcers;

Endocrine system: hypoglycemia, up to hypoglycemic coma;

Cardiovascular system: tachycardia, arrhythmia, increased blood pressure, palpitations, edema;

Urinary system: when taking high doses, signs of nephrotoxicity are possible (renal colic, interstitial nephritis, papillary necrosis);

Respiratory system: bronchospasm may occur in patients sensitive to acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs.

Concomitant use 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.

However, periodic short-term use of Kofan Bosnaliek® tablets at recommended doses generally does not cause adverse effects.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after medicinal product registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua and by email to Bosnaliek d.d. representative office: [email protected]

Shelf life. 5 years.

Storage conditions.

Store out of reach of children at a temperature not exceeding 30°C.

Packaging.

10 tablets per blister, 1 blister per cardboard box.

Availability category.

Over-the-counter.

Manufacturer/Marketing Authorization Holder.

Bosnaliek d.d.

Manufacturer's address and location of business activity.

71000, Yukicheva 53, Sarajevo, Bosnia and Herzegovina.