Panadol extra advanc

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PANADEXTRA ADVANCE (PANADOL EXTRA ADVANCE)

Composition:

Active substances: paracetamol, caffeine;

One tablet contains 500 mg of paracetamol and 65 mg of caffeine;

Excipients: pregelatinized starch, povidone (K-25), calcium carbonate, crospovidone (type A), mixture of sodium parabens (sodium methylparahydroxybenzoate (E 219), sodium ethylparahydroxybenzoate (E 215), sodium propylparahydroxybenzoate (E 217)), purified water, alginic acid, magnesium stearate, Opadry White YS-1-7003 (titanium dioxide (E 171), hypromellose 3cP, hypromellose 6cP, polyethylene glycol 400, polysorbate 80), carnauba wax.

Dosage form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, oval-shaped, white to almost white, with an imprint xPx, where P is inside the circle.

Pharmacotherapeutic group.

Analgesics and antipyretics. Paracetamol combinations without psychotropic agents.

ATC code N02B E51.

Pharmacological properties.

Pharmacodynamics.

Paracetamol is an analgesic and antipyretic agent. Its effect is based on inhibition of prostaglandin synthesis in the central nervous system (CNS). Due to weak inhibition of peripheral prostaglandins, particularly in the gastrointestinal tract, paracetamol is partially suitable for patients in whom inhibition of peripheral prostaglandins is undesirable, for example, patients with a history of gastrointestinal bleeding, for whom salicylates are contraindicated.

Caffeine acts as a booster, increasing the effectiveness of paracetamol.

Pharmacokinetics.

Paracetamol and caffeine are rapidly absorbed in the gastrointestinal tract and distributed into most body tissues. Plasma protein binding of paracetamol is minimal when administered at therapeutic doses.

Paracetamol and caffeine are primarily metabolized in the liver and excreted in urine as metabolites.

The product contains alginic acid and calcium carbonate, which accelerate the absorption of active substances compared to Panadol Extra, coated tablets.

Clinical characteristics.

Indications.

The drug exerts a moderate analgesic and antipyretic effect. Indications for use include headache, including migraine, toothache, neuralgia, rheumatic pain, menstrual pain in women; for relief of symptoms of colds and flu, sore throat.

Contraindications.

Hypersensitivity to paracetamol, caffeine, or any other component of the drug in medical history; severe liver and/or kidney impairment; congenital hyperbilirubinemia; glucose-6-phosphate dehydrogenase deficiency; alcoholism; blood disorders, pronounced anemia, leukopenia; states of increased excitation, sleep disorders, epilepsy; marked increase in blood pressure, organic cardiovascular diseases, including severe atherosclerosis, severe hypertensive disease; decompensated heart failure, acute myocardial infarction, paroxysmal tachycardia, hyperthyroidism, acute pancreatitis, severe forms of diabetes mellitus, glaucoma; age over 60 years.

Do not use concomitantly with monoamine oxidase inhibitors (MAOIs) and within 2 weeks after discontinuation of MAOIs.

Contraindicated in patients taking tricyclic antidepressants or beta-blockers.

Interaction with other medicinal products and other types of interactions.

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 doses do not show a significant effect. Barbiturates reduce the antipyretic effect of paracetamol. Anticonvulsant drugs (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. 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.

Probenecid causes an almost twofold reduction in paracetamol clearance by inhibiting its conjugation with glucuronic acid. When paracetamol is used concomitantly with probenecid, the need to reduce the dose of paracetamol should be considered.

Salicylamide may prolong the half-life of paracetamol.

Paracetamol may increase the half-life of chloramphenicol.

Oral contraceptives may increase the clearance of paracetamol.

Do not use concomitantly with alcohol.

Paracetamol should be used with caution concomitantly with flucloxacillin, as co-administration has been associated with metabolic acidosis with a high anion gap as a result of pyroglutamic acidosis, especially in patients with risk factors (see section "Special precautions").

Concomitant use of caffeine with MAO inhibitors may cause dangerous elevation of blood pressure. Caffeine enhances the effect (improves bioavailability) of analgesic-antipyretic agents, potentiates the effects of xanthine derivatives, alpha- and beta-adrenomimetics, psychostimulants.

Cimetidine, hormonal contraceptives, isoniazid enhance the effect of caffeine.

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

Caffeine may enhance lithium excretion from the body. Therefore, concomitant use of the medicinal product with lithium preparations is not recommended.

Special precautions for use

The product contains paracetamol; therefore, it should not be used in combination with other medicinal products containing paracetamol, which are used, for example, for fever reduction, pain relief, symptoms of influenza and colds, or insomnia. Concurrent use with other paracetamol-containing products may lead to overdose. Paracetamol overdose can cause liver failure, which may necessitate liver transplantation or result in death.

Patients with liver or kidney disease should consult a physician before using this product. Restrictions on use in such patients are primarily due to the presence of paracetamol. In patients with liver disease, the risk of hepatotoxic effects of paracetamol is increased.

In patients with genetically determined glucose-6-phosphate dehydrogenase deficiency (favism), hemolytic anemia may occur due to reduced glutathione availability following paracetamol administration.

The 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 liver dysfunction/liver failure have been reported in patients with reduced glutathione levels, such as those with severe malnutrition, anorexia, low body mass index, chronic alcoholism, or sepsis.

In patients with reduced glutathione levels, paracetamol use increases the risk of metabolic acidosis. Symptoms of metabolic acidosis include deep, rapid, or labored breathing, nausea, vomiting, and loss of appetite. If these symptoms occur, immediate medical attention is required.

If symptoms persist, consult a physician.

Cases of high anion gap metabolic acidosis (HAGMA) as a result of 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 with a combination of paracetamol and flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol is recommended, along with careful monitoring of the patient's condition. 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.

Prolonged use of the medicinal product without medical supervision may be hazardous. The recommended dose must not be exceeded.

During treatment with this product, excessive consumption of beverages containing caffeine (such as coffee, tea, and certain other drinks) is not recommended. This may lead to sleep disturbances, tremor, and discomfort behind the sternum due to palpitations.

Keep the product out of sight and reach of children.

The product contains sodium methylparahydroxybenzoate (E 219), sodium ethylparahydroxybenzoate (E 215), and sodium propylparahydroxybenzoate (E 217), which may cause allergic reactions (possibly delayed).

Each tablet contains 0.1736 mg of sodium, which is less than 1 mmol/dose (23 mg) of sodium; thus, the medicinal product is practically sodium-free.

Use during pregnancy or breastfeeding

Use of the product during pregnancy is not recommended, as it increases the risk of spontaneous abortion associated with caffeine use.

Use of the product during breastfeeding is not recommended. Paracetamol and caffeine pass into breast milk but in clinically insignificant amounts when taken at recommended doses. Caffeine in breast milk may have a stimulating effect on infants during breastfeeding, but significant toxicity has not been observed.

Ability to affect reaction speed when driving or operating machinery

The likelihood of effect is almost negligible.

Dosage and Administration

The product is intended for oral use.

Adults and children aged 12 years and older: 1–2 tablets every 4–6 hours as needed. Do not exceed 8 tablets (4000 mg paracetamol / 520 mg caffeine) within 24 hours.

Do not exceed the recommended dose.

The lowest effective dose required to achieve therapeutic effect should be used for the shortest possible duration.

The interval between doses should be at least 4 hours.

Children

The product is not recommended for children under 12 years of age.

Overdose

Paracetamol

Paracetamol overdose can cause liver failure, which may require liver transplantation or result in death. Acute pancreatitis has been observed, usually in conjunction with liver dysfunction and hepatotoxicity. A single overdose of paracetamol in adults or children may cause hepatocellular necrosis, leading to liver failure, metabolic acidosis, and encephalopathy, which may progress to coma and death. Concurrently, levels of liver transaminases (AST, ALT), lactate dehydrogenase, and bilirubin increase, along with prolonged prothrombin time, which may appear 12–48 hours after ingestion.

Hepatic injury may occur in adults who ingest 6–8 g or more of paracetamol and in children who ingest more than 150 mg/kg body weight. It is believed that an increased amount of a toxic metabolite, normally detoxified by glutathione at therapeutic doses, becomes irreversibly bound to liver tissue. In patients with risk factors (long-term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John’s wort, or other drugs that induce liver enzymes; chronic excessive alcohol consumption; glutathione deficiency (digestive disorders, cystic fibrosis, HIV infection, fasting, cachexia)), ingestion of 5 g or more of paracetamol may lead to liver injury. There is an increased risk of paracetamol overdose in young or elderly patients, patients with liver disease, chronic alcoholism, or chronic malnutrition.

Immediate medical attention is required in case of overdose. Treatment should be initiated immediately. The patient should be taken to hospital even if early symptoms of overdose are absent.

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

With prolonged use of high doses, hematological side effects may include aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia. High-dose use may also lead to dizziness, psychomotor agitation, and disorientation (central nervous system); and nephrotoxicity (renal colic, interstitial nephritis, capillary necrosis) (urinary system).

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 essential in case of overdose, even if no symptoms are present. If overdose is confirmed or even suspected, the patient must be taken to the nearest medical facility for emergency treatment and professional care. This should be done even in the absence of symptoms due to the risk of delayed liver injury. Administration of activated charcoal should be considered if an excessive dose of paracetamol (>150 mg/kg) 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 of overdose. The efficacy of the antidote decreases sharply after this time. Intravenous N-acetylcysteine should be administered as per recommended dosing if required. In the absence of vomiting, oral methionine may be used as an alternative in remote areas outside hospital settings.

Caffeine

Caffeine overdose may cause epigastric pain, vomiting, diuresis, hyperventilation, tachycardia, or cardiac arrhythmia, and may affect the central nervous system (insomnia, restlessness, nervous excitation, anxiety, dizziness, irritability, affective disturbance, tremor, seizures). Clinically significant symptoms of caffeine overdose may also be associated with severe paracetamol-induced liver injury, which may occur when doses sufficient to cause caffeine overdose are ingested.

There is no specific antidote, but supportive measures such as beta-adrenergic antagonists may help alleviate cardiotoxic effects. Gastric lavage is recommended, oxygen therapy is advised, and diazepam should be administered in case of seizures. Symptomatic therapy is required.

Adverse Reactions

Information on the adverse reactions listed below was obtained from post-marketing surveillance. These reports are voluntary and derived from a population of unknown size; therefore, it is not possible to reliably estimate the frequency of these adverse reactions, although they are likely to be rare (< 1/10,000).

Adverse reactions related to paracetamol

Blood and lymphatic system disorders: thrombocytopenia, neutropenia, leukopenia, pancytopenia.

Immune system disorders: anaphylaxis, hypersensitivity reactions affecting the skin, including but not limited to skin rash, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis.

Respiratory, thoracic and mediastinal disorders: bronchospasm in patients sensitive to acetylsalicylic acid and other non-steroidal anti-inflammatory drugs.

Hepatobiliary disorders: liver function abnormalities, liver failure, hepatic necrosis, jaundice.

Metabolism and nutrition disorders: metabolic acidosis with high anion gap, frequency "unknown" (cannot be estimated from available data).

Description of selected 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 were treated with paracetamol (see section "Special precautions for use"). Pyroglutamic acidosis may occur due to low glutathione levels in these patients.

Adverse reactions related to caffeine

Central nervous system disorders: nervousness, dizziness, insomnia, tremor.

Cardiac disorders: tachycardia, edema.

Gastrointestinal disorders: gastrointestinal discomfort.

Psychiatric disorders: insomnia, restlessness, anxiety, irritability, nervousness.

Additionally, adverse reactions observed after administration of medicinal products containing similar active substances include: headache, pruritus, erythema multiforme, nausea, vomiting, heartburn, epigastric pain, hypoglycemia up to hypoglycemic coma, agranulocytosis, anemia, sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), hemolytic anemia, bruising or bleeding, tachycardia, arrhythmia, increased blood pressure, increased liver enzyme activity (usually without development of jaundice), hepatonecrosis (dose-dependent effect), insomnia, tremor, irritability.

Concomitant use of this medicinal product at recommended doses with caffeine-containing products may lead to increased caffeine intake, thereby potentiating caffeine-related adverse effects.

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C. Keep out of the reach and sight of children.

Packaging.

12 film-coated tablets per blister, 1 blister per cardboard box.

Authorization category. Over-the-counter (without prescription).

Manufacturer.

GlaxoSmithKline Dungarvan Limited, Ireland.

Address of the manufacturer's place of business.

Knockbrack, Dungarvan, Co. Waterford, Ireland.