Paracetamol

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

Composition:

Active ingredient: paracetamol;

One tablet contains 500 mg of paracetamol;

Excipients: corn starch, pregelatinized starch, povidone, potassium sorbate, talc, stearic acid, coating (hypromellose, titanium dioxide (E 171), macrogol, propylene glycol).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: oval-shaped tablets, convex on both upper and lower surfaces, with a score line on one side, coated with a film coating white or almost white in color.

Pharmacotherapeutic group. Analgesics and antipyretics. Anilides. Paracetamol.

ATX code N02B E01.

Pharmacological properties

Pharmacodynamics. The active substance, paracetamol, is an analgesic and antipyretic (pain-relieving and fever-reducing agent). The effect of paracetamol 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 plasma half-life of paracetamol after oral administration is approximately 2.3 hours.

Clinical Characteristics

Indications. For short-term treatment of headache, toothache, muscle pain, menstrual pain, moderate pain associated with osteoarthritis, and symptoms of fever and pain associated with cold and flu.

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, marked anemia, leukopenia.

Age under 6 years.

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. The anticoagulant effect of warfarin and other coumarins, with an increased 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 (particularly phenytoin, barbiturates, carbamazepine), which stimulate the activity of hepatic microsomal enzymes, may enhance the hepatotoxic effect of paracetamol due to increased formation of hepatotoxic metabolites. Concomitant use of paracetamol with hepatotoxic agents increases the hepatotoxic effects of the drugs. Simultaneous use of high doses of paracetamol with isoniazid increases the risk of developing hepatotoxic syndrome.

Caution is advised when using paracetamol concomitantly with flucloxacillin, as this combination 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 for use").

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

Special precautions for use

This medicinal product should not be used in combination with other medicinal products containing paracetamol, which are used, for example, to reduce fever, treat pain, symptoms of flu and colds, or insomnia. Concomitant use with other paracetamol-containing products may lead to overdose. Paracetamol overdose can cause liver failure, which may require liver transplantation or result in death.

In patients with liver or kidney disease, medical advice should be sought before using this medicine.

It should be noted that in patients with liver disease, the risk of hepatotoxic effects of paracetamol is increased.

Cases of impaired liver function / liver failure have been reported in patients with reduced glutathione levels, such as in severe malnutrition, anorexia, low body mass index, chronic alcoholism, or sepsis.

In patients with reduced glutathione levels, 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. Medical attention should be sought immediately if these symptoms occur.

Cases of high anion gap metabolic acidosis due to 5-oxoproline (pyroglutamic acid) accumulation have been reported in patients with severe conditions such as severe renal failure and sepsis, as well as in patients who were undernourished or had other causes of glutathione deficiency (e.g., chronic alcoholism) and who received paracetamol at therapeutic doses for prolonged periods or a combination of paracetamol and flucloxacillin. If high anion gap metabolic acidosis due to pyroglutamic acidosis is suspected, it is recommended to immediately discontinue paracetamol and closely monitor the patient. Measurement of 5-oxoproline levels in urine may be helpful in identifying pyroglutamic acidosis as the underlying cause of high anion gap metabolic acidosis in patients with multiple risk factors.

If this medicinal product does not provide the expected effect, medical advice should be sought. Prolonged use without medical supervision may be dangerous.

This medicine should be used only when clearly necessary.

Keep tablets out of the sight and reach of children.

Use during pregnancy or breastfeeding

As with any other medicinal product, consultation with a physician is recommended before using paracetamol during pregnancy. A large amount of data from pregnant women does not indicate any malformative or fetal/neonatal toxicity. Epidemiological studies on the development of the nervous system in children exposed to paracetamol in utero have not provided conclusive results. If clinically necessary, paracetamol may be used during pregnancy; however, it should be administered at the lowest effective dose, for the shortest possible duration, and with the lowest possible frequency.

Paracetamol is excreted in breast milk, but in clinically insignificant amounts when used at recommended doses. Available published data do not contraindicate the use of the medicine during breastfeeding.

Effect on ability to drive and use machines. No effect.

Method of Administration and Dosage

The medicinal product is intended for oral administration.

Do not exceed the recommended dose. The lowest effective dose required to achieve the treatment objective 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 aged 6–11 years: ½–1 tablet up to 4 times daily (every 4–6 hours) as needed.

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. Not recommended for children under 6 years of age.

Overdose

Paracetamol overdose may cause liver failure, which may require liver transplantation or result in death. Clinical signs of liver damage after paracetamol overdose usually appear within 24–48 hours after overdose 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, and 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 following a single ingestion in adults and children may cause reversible or irreversible hepatocellular necrosis, leading to disturbances in glucose metabolism, metabolic acidosis, hepatocellular insufficiency, encephalopathy, hemorrhages, hypoglycemia, coma, and potentially death. Within 12–48 hours after ingestion, elevated levels of liver transaminases (aspartate aminotransferase, alanine aminotransferase), lactate dehydrogenase, bilirubin, and prolonged prothrombin time may be observed. 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 at therapeutic doses) binds irreversibly to liver tissues.

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 and acute pancreatitis have also been reported, usually accompanied by liver function abnormalities and hepatotoxicity.

With prolonged use of the drug at high doses, hematological side effects may include aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia. Central nervous system effects may include dizziness, psychomotor agitation, and disorientation. Urinary system effects 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, immediate medical attention is required. Treatment for overdose or even suspected overdose must be initiated immediately by hospitalizing the patient, 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).

Administration of activated charcoal should be considered if the paracetamol overdose exceeds 150 mg/kg and ingestion occurred within the last hour. Treatment with N-acetylcysteine or methionine may be required. Symptomatic treatment should also be provided.

Side effects

Blood and lymphatic system disorders: rare (< 1/10000) — thrombocytopenia.

Immune system disorders: rare (< 1/10000) — anaphylaxis, skin hypersensitivity reactions, including skin rash, angioedema, Stevens-Johnson syndrome, and toxic epidermal necrolysis.

Respiratory, thoracic and mediastinal disorders: rare (< 1/10000) — bronchospasm in patients sensitive to acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs.

Hepatobiliary disorders: rare (< 1/10000) — liver function abnormalities.

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

Additionally, the following adverse reactions may occur after administration of paracetamol-containing products: skin itching, erythema multiforme, nausea, epigastric pain, hypoglycemia up to hypoglycemic coma, agranulocytosis, anemia, sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), hemolytic anemia, bruising or bleeding, increased liver enzyme activity, usually without development of jaundice.

Description of selected adverse reactions

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

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

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

Keep out of reach of children.

Packaging. 10 tablets in a blister, 1 blister per cardboard box.

10 tablets in a blister, 10 blisters per cardboard box.

Release category. Over-the-counter: tablets № 10.

By prescription: tablets № 100 (10×10).

Manufacturer. JSC "Lubnipharm".

Manufacturer's address and location of its business activity. 16 Barvinkova Street, Lubny, Poltava region, 37500, Ukraine.