Paracetamol

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PARACETAMOL (PARACETAMOL)

Composition:

Active ingredient: paracetamol;

1 tablet contains 500 mg of paracetamol;

Excipients: pregelatinized starch, corn starch, potassium sorbate, povidone, talc, stearic acid, hypromellose, glycerol triacetate (triacetin), carnauba wax.

Medicinal form. Film-coated tablets.

Main physico-chemical properties: film-coated tablets, elongated in shape, white or almost white, with convex edges.

Pharmacotherapeutic group.

Agents acting on the nervous system. Analgesics. Other analgesics and antipyretics. Anilides. Paracetamol. ATC code: N02BE01.

Pharmacological properties.

Pharmacodynamics.

The tablets contain paracetamol – an analgesic and antipyretic (pain-relieving and fever-reducing agent). The effect is based on inhibition of prostaglandin synthesis in the central nervous system.

Pharmacokinetics.

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

Paracetamol is primarily metabolized in the liver and excreted in the urine as metabolites. The mean elimination half-life of paracetamol in plasma after oral administration is approximately 2–3 hours.

Clinical characteristics.

Indications.

Short-term treatment of headache, toothache, muscle pain, menstrual pain, moderate pain associated with osteoarthritis, and symptoms of fever and pain due to colds and influenza.

Contraindications.

Hypersensitivity to the components of the drug, severe impairment of liver and/or kidney function, congenital hyperbilirubinemia, glucose-6-phosphate dehydrogenase deficiency, alcoholism, blood disorders, Gilbert's syndrome, severe anemia, leukopenia. Children under 6 years of age.

Interaction with other medicinal products and other forms of interaction.

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

Paracetamol should be administered 1 hour before or 4–6 hours after cholestyramine.

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

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. Concomitant use of paracetamol with hepatotoxic agents increases the risk of hepatotoxicity. Concurrent use of high doses of paracetamol with isoniazid increases the risk of hepatotoxic syndrome.

Probenecid reduces paracetamol clearance by half by inhibiting its conjugation with glucuronic acid; therefore, in combined therapy with probenecid, the dose of paracetamol should be reduced.

Paracetamol should be used cautiously with chloramphenicol due to prolonged elimination half-life and increased toxicity of the latter.

Paracetamol reduces the effectiveness of diuretics. Do not use concurrently with alcohol.

Caution is advised when paracetamol is used concomitantly with flucloxacillin, as co-administration has been associated with metabolic acidosis with a high anion gap due to pyroglutamic acidosis**, particularly in patients with risk factors (see section "Special precautions").**

Special precautions.

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

Patients with liver or kidney disease should consult a physician before using this product.

It should be noted that patients with liver disease have an increased risk of hepatotoxic effects of paracetamol.

Cases of impaired liver function/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.

Consultation with a physician is required regarding the possibility of using the medicinal product:

• in patients with impaired kidney or liver function;
• in patients taking warfarin or similar agents with anticoagulant effects;
• in patients using analgesics for mild forms of arthritis;

− if headache becomes persistent.

In patients with reduced glutathione levels, the risk of metabolic acidosis increases during paracetamol use. Symptoms of metabolic acidosis include deep, rapid, or labored breathing, nausea, vomiting, and loss of appetite. Immediate medical attention should be sought if these symptoms occur.

If symptoms persist, consult a physician. Prolonged use without medical supervision may be dangerous.

The medicinal product should be used only when clearly necessary.

Alcoholic beverages must not be consumed during treatment with paracetamol.

The product contains potassium compounds (potassium sorbate). Caution is advised when administering to patients on a potassium-controlled diet.

Cases of high anion gap metabolic acidosis (HAGMA) due to 5-oxoprolinemia 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 5-oxoprolinemia is suspected, it is recommended to immediately discontinue paracetamol and to conduct careful monitoring. Measurement of urinary 5-oxoproline levels may be helpful in identifying pyroglutamic acidosis as the underlying cause of HAGMA in patients with multiple risk factors.

Use during pregnancy or breastfeeding.

Pregnancy. As with any other medicinal product, consultation with a physician is recommended before using paracetamol during pregnancy. Extensive data in pregnant women do not indicate any malformative or fetal/neonatal toxicity. Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero have not yielded conclusive results. Paracetamol may be used during pregnancy if clinically necessary, but should be administered at the lowest effective dose, for the shortest possible duration, and with the least possible frequency.

Breastfeeding period. Paracetamol passes into breast milk, but in clinically insignificant amounts when used at recommended doses. Available published data do not contraindicate the use of the product during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

No effect.

Method of Administration and Dosage

The medication is intended for oral use.

Do not exceed the recommended dose. The lowest effective dose required to achieve the treatment goal should be used.

Adults and children aged 12 years and older: 1–2 tablets up to 4 times daily (every 4–6 hours) as needed.

The interval between doses should be at least 4 hours.

Do not take more than 8 tablets (4000 mg) within 24 hours.

Children (6–11 years of age): ½–1 tablet up to 4 times daily (every 4–6 hours) as needed.

The maximum duration of use in children without medical consultation is 3 days.

Do not take more than 4 doses within 24 hours.

The interval between doses should be at least 4 hours.

Children.

The use of this medication is not recommended in children under 6 years of age.

Overdose.

Paracetamol overdose can cause liver failure, which may necessitate liver transplantation or result in death. Clinical experience shows that signs of liver damage following paracetamol overdose typically appear within 24–48 hours after ingestion and peak at 4–6 days.

There is an increased risk of paracetamol poisoning, particularly in elderly patients, children, patients with liver disease, chronic alcoholism, or chronic malnutrition.

Symptoms of overdose within the first 24 hours: pallor, nausea, vomiting, loss of appetite, and abdominal pain; however, overdose may also be asymptomatic.

Paracetamol overdose after a single ingestion by adults or children may cause reversible or irreversible necrosis of liver cells, leading to impaired glucose metabolism, metabolic acidosis, hepatocellular failure, encephalopathy, hemorrhage, hypoglycemia, coma, and potentially death. Concurrently, elevated levels of liver transaminases (AST, ALT), lactate dehydrogenase, bilirubin, and prolonged prothrombin time typically occur 12–48 hours after ingestion. Liver damage is likely in adults who have ingested more than the recommended amount of paracetamol. It is believed that an increased amount of a paracetamol metabolite (normally neutralized by glutathione when standard doses are used) irreversibly binds to liver tissue.

Acute kidney failure with acute tubular necrosis may present as severe flank pain, hematuria, and proteinuria, and can develop even in the absence of severe liver damage. Cardiac arrhythmias and acute pancreatitis have also been reported, usually accompanied by liver function abnormalities and hepatotoxicity.

With prolonged use of the drug in high doses, hematological disorders may include aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia. Central nervous system effects may include dizziness, psychomotor agitation, and disorientation. Effects on the urinary system 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.

Risk factors for paracetamol overdose include:

• Long-term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John’s wort, and other drugs that induce hepatic enzyme synthesis;
• Chronic alcohol abuse;
• Reduced glutathione levels, for example, due to malnutrition, fasting, cachexia, cystic fibrosis, or HIV.

In case of overdose, prompt medical attention is required. Treatment for overdose, or even suspected overdose, must be initiated immediately by transporting the patient to a hospital, even in the absence of early symptoms, as liver damage may not develop immediately. Plasma paracetamol concentration should be measured 4 hours or more after ingestion (earlier concentrations are unreliable).

Activated charcoal should be considered if a paracetamol dose exceeding 150 mg/kg has been ingested within 1 hour. Treatment with N-acetylcysteine or methionine should also be considered. Symptomatic treatment is also necessary.

Adverse reactions.

If adverse reactions occur, it is necessary to discontinue the use of the medicinal product and immediately consult a physician.

Adverse reactions to paracetamol are rare (< 1/10 000):

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

Gastrointestinal tract: nausea, epigastric pain.

Hepatobiliary system: liver function abnormalities, increased liver enzyme activity, usually without development of jaundice.

Endocrine system: hypoglycemia, up to hypoglycemic coma.

Blood and lymphatic system: thrombocytopenia, agranulocytosis, anemia, sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), hemolytic anemia, bruising or bleeding.

Immune system: anaphylaxis, hypersensitivity reactions, including pruritus, skin and mucosal rashes (usually generalized rash, erythematous rash, urticaria), angioneurotic edema, multiform exudative erythema (including Stevens–Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome).

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

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 for use"). Pyroglutamic acidosis may occur as a consequence of low glutathione levels in these patients.

Reporting of 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 and pharmacy professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

2 tablets per blister; 70 blisters per cardboard box;

10 tablets per blister; 1, 2, or 5 blisters per cardboard package.

Prescription status.

Over-the-counter.

Manufacturer.

JSC "Tekhnolog".

Manufacturer's address and location of business activity.

8 Stara Prorina Street, City of Uman, Cherkasy Region, 20300, Ukraine.