Panadol extra

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

Composition:

Active substances: paracetamol, caffeine;

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

Excipients: sorbitol (E 420), sodium saccharin, sodium hydrogen carbonate, povidone, sodium lauryl sulfate, dimethicone, anhydrous citric acid, anhydrous sodium carbonate.

Pharmaceutical form. Effervescent tablets.

Main physico-chemical characteristics: flat white tablets with bevelled edges, smooth on one side and with a break line on the other.

Pharmacotherapeutic group.

Analgesics and antipyretics. ATC code N02BE51.

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). Inhibition of peripheral prostaglandin synthesis is minimal; therefore, paracetamol is partially suitable for patients for whom inhibition of peripheral prostaglandins is undesirable (e.g., patients with a history of gastrointestinal bleeding).

Caffeine enhances analgesic efficacy due to its stimulatory effect on the CNS, which may counteract the depression often associated with pain.

Pharmacokinetics.

Paracetamol and caffeine are rapidly and almost completely absorbed in the gastrointestinal tract. Paracetamol is uniformly distributed throughout body fluids, and its binding to plasma proteins is minimal when administered at therapeutic doses.

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

Clinical characteristics.

Indications.

Moderate to severe pain (headache, migraine, musculoskeletal pain, muscle pain, toothache, postoperative dental pain and dental procedures, sore throat, menstrual pain), fever and pain after vaccination, elevated body temperature.

Contraindications.

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

Do not use together 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 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 significant effects. Barbiturates reduce the antipyretic effect of paracetamol. Anticonvulsant drugs (including phenytoin, barbiturates, carbamazepine), which stimulate the activity of hepatic microsomal enzymes, 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 toxic effects of drugs on the liver. Concurrent use of high doses of paracetamol with isoniazid increases the risk of developing hepatotoxic syndrome. Paracetamol reduces the efficacy of diuretics.

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

Do not use concurrently with alcohol.

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

Cimetidine, hormonal contraceptives, and isoniazid enhance the action of caffeine.

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

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

Special precautions for use.

The product contains paracetamol; therefore, it should not be used concomitantly with other medicinal products containing paracetamol, which are used, for example, to reduce fever, relieve pain, treat flu and cold symptoms, or for 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 fatal outcome.

Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported in patients with severe conditions such as severe renal insufficiency and sepsis, or in patients with malnutrition or other sources of glutathione deficiency (e.g., chronic alcoholism, severe cachexia, anorexia, low body mass index, or sepsis) who were treated with paracetamol at therapeutic doses for prolonged periods or in combination with flucloxacillin. Symptoms of metabolic acidosis include deep, rapid, or labored breathing, nausea, vomiting, and loss of appetite. If HAGMA due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol is recommended, along with careful monitoring of the patient. 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.

If symptoms persist, medical advice should be sought.

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, palpitations with retrosternal discomfort, nervousness, and irritability.

In patients with liver or kidney disease, consultation with a physician is required before using this product. Restrictions on use in such patients are primarily due to the presence of paracetamol. It should be noted that patients with alcoholic non-cirrhotic liver disease have an increased risk of hepatotoxic effects of paracetamol in cases of overdose. 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 their physician.

One tablet contains 427 mg of sodium. This should be taken into account by patients on a sodium-controlled diet. The product contains sorbitol in the amount of 50 mg per tablet. Patients with rare hereditary forms of fructose intolerance should not take this product.

Keep the product out of the sight and reach of children.

Use during pregnancy or breastfeeding.

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

Use of the product during breastfeeding is not recommended. Paracetamol and caffeine pass into breast milk. Caffeine in breast milk may have a stimulating effect on infants during breastfeeding, although significant toxicity has not been observed.

Effect on ability to drive and use machines.

The likelihood of effect on reaction speed is negligible.

Dosage and Administration.

The product is intended for oral administration.

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.

Adults, elderly patients, and children aged 16 years and older: Dissolve 1–2 tablets in half a glass of water. Take every 4–6 hours as needed. Do not take more than 8 tablets (4000 mg paracetamol / 520 mg caffeine) within 24 hours.

Children aged 12 to 15 years: Dissolve 1 tablet in half a glass of water. Take every 4–6 hours as needed (up to 4 times daily). Do not take more than 4 tablets (2000 mg paracetamol / 260 mg caffeine) within 24 hours. Do not use for more than 3 consecutive days without consulting a physician.

Children: 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 reported, usually in conjunction with liver dysfunction and hepatotoxicity. Liver damage 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. 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 (malnutrition, cystic fibrosis, HIV infection, fasting, cachexia)), ingestion of 5 g or more of paracetamol may lead to liver damage.

Immediate medical attention is required in case of overdose. Treatment must be initiated promptly. The patient should be taken to a hospital even if no early symptoms of overdose are present.

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 at 4–6 days. Metabolic disturbances such as hypoglycemia and metabolic acidosis may occur.

Symptoms of overdose may not reflect the severity of overdose or risk of organ damage. Immediate medical intervention is essential even in the absence of symptoms. If overdose is confirmed or suspected, the patient must be taken immediately to the nearest medical facility capable of providing emergency care and expert treatment, regardless of the absence of symptoms, due to the risk of delayed liver damage. 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 of overdose. The efficacy of the antidote declines 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 settings outside hospital.

In severe poisoning, liver 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 also been reported.

With prolonged use of high doses, hematological disorders such as aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia may develop. High-dose intake may also affect the central nervous system, causing dizziness, psychomotor agitation, and disorientation; and the urinary system, leading to nephrotoxicity (renal colic, interstitial nephritis, cortical necrosis).

Caffeine.

Caffeine overdose may cause epigastric pain, vomiting, diuresis, hyperventilation, tachycardia or cardiac arrhythmia, and affect 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 hepatotoxicity, which may occur when such amounts of the drug are ingested that cause caffeine overdose. There is no specific antidote, but supportive measures such as beta-adrenergic antagonists may help alleviate cardiotoxic effects. Gastric lavage is recommended, oxygen therapy should be administered, and diazepam may be used in case of seizures. Symptomatic treatment is indicated.

Sodium bicarbonate.

High doses of sodium bicarbonate may cause gastrointestinal disturbances such as belching and nausea, and may also lead to hypernatremia; therefore, electrolyte balance should be monitored and appropriate treatment provided.

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, although the frequency of the listed adverse reactions cannot be determined, they are likely to be rare (< 1/10,000).

Adverse reactions associated with paracetamol

Blood and lymphatic system disorders: thrombocytopenia, agranulocytosis.

Immune system disorders: anaphylaxis, skin hypersensitivity reactions, including but not limited to skin rash, angioneurotic edema, Stevens–Johnson syndrome, toxic epidermal necrolysis.

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

Hepatobiliary disorders: liver function abnormalities.

Metabolism and nutrition disorders: metabolic acidosis with high anion gap (frequency unknown).

Description of selected adverse reactions:

Metabolic acidosis with high anion gap.

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

Adverse reactions associated with caffeine

Central nervous system disorders: dizziness, headache.

Cardiovascular disorders: tachycardia.

Gastrointestinal disorders: gastrointestinal discomfort.

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

Concomitant use of the medicinal product at recommended doses with caffeine-containing products may lead to increased caffeine intake, which may intensify caffeine-related adverse effects such as insomnia, restlessness, anxiety, irritability, headache, gastrointestinal disturbances, and tachycardia.

Shelf life. 4 years.

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

Packaging. 2 tablets per multilayer strip, 6 strips per cardboard box; 4 tablets per multilayer strip, 3 strips per cardboard box.

Classification. Over-the-counter (OTC).

Manufacturer.

Famar A.V.E. Anthoussa plant / Famar A.V.E. Anthoussa plant.

GlaxoSmithKline Dungarvan Limited.

Manufacturer's address.

Anthoussa Avenue 7, Anthoussa Attiki, 15349, Greece.

Knockbrack, Dungarvan, Co. Waterford, Ireland.