Paracetamol

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT PARACETAMOL

Composition:

Active ingredient: paracetamol;

One tablet contains 200 mg of paracetamol;

Excipients: potato starch, calcium stearate, colloidal anhydrous silicon dioxide, hydroxypropylmethylcellulose.

Pharmaceutical form. Tablets.

Main physico-chemical properties: intact, regular, round cylindrical tablets with flat upper and lower surfaces, beveled edges, a score line for division, white or white with a creamy shade.

Pharmacotherapeutic group.

Analgesics and antipyretics. Paracetamol. ATC code N02BE01.

Pharmacological Properties.

Pharmacodynamics.

Paracetamol is 4-hydroxyacetanilide – a non-narcotic, non-salicylate analgesic and antipyretic; its analgesic activity is associated with central and peripheral actions. It increases the pain sensitivity threshold and has weak anti-inflammatory effects due to inhibition of prostaglandin synthesis and blocking impulses at bradykinin-sensitive receptors.

Pharmacokinetics.

The drug is rapidly and completely absorbed after oral administration. Maximum plasma concentrations are reached within 15–60 minutes after intake. Therapeutically effective plasma concentrations of paracetamol are achieved when administered at a dose of 10–15 mg/kg. Paracetamol is metabolized in the liver primarily via conjugation reactions with sulfuric and glucuronic acids, forming paracetamol glucuronide and sulfate. Paracetamol is excreted by the kidneys, with less than 5% excreted unchanged. The elimination half-life after oral administration is approximately 1–4 hours. In severe renal impairment (creatinine clearance below 10 mL/min), elimination of paracetamol and its metabolites is slower.

Clinical characteristics.

Indications.

Headache, including migraine and tension headache; neuralgias; toothache; relief of cold and flu symptoms such as fever, aches, and pain.

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, severe anemia, leukopenia.

Interaction with other medicinal products and other types of interactions.

When administered simultaneously with barbiturates, anticonvulsants (antiepileptics), rifampicin, or with alcohol consumption, the risk of hepatotoxic effects significantly increases.

Paracetamol enhances the effect of indirect anticoagulants (coumarin derivatives). Metoclopramide and domperidone increase, while cholestyramine decreases, the rate of absorption. Paracetamol should be administered 1 hour before or 4–6 hours after cholestyramine. Barbiturates reduce antipyretic activity.

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

Anticonvulsant drugs (including phenytoin, barbiturates, carbamazepine), which stimulate the activity of hepatic microsomal enzymes, may enhance the toxic effect of paracetamol on the liver due to increased conversion of the drug into hepatotoxic metabolites. Concurrent use of paracetamol with hepatotoxic agents increases the hepatotoxic effects of the drugs.

Concomitant use of high doses of paracetamol with isoniazid increases the risk of developing hepatotoxic syndrome. Paracetamol reduces the effectiveness of diuretics.

Caution is advised when using paracetamol concomitantly with flucloxacillin, as this combination is associated with metabolic acidosis with a high anion gap due to pyroglutamic acidosis, especially in patients at risk (see "Special precautions for use").

Probenecid reduces paracetamol clearance by half by blocking its conjugation with glucuronic acid; therefore, when used in combination with probenecid, the dose of paracetamol should be reduced.

Paracetamol should be used with caution in combination with chloramphenicol due to prolonged half-life and increased toxicity of the latter.

Special precautions for use.

Consult a physician regarding the possibility of using the medicine:

• in patients with impaired kidney or liver function;
• in patients taking warfarin or similar agents with anticoagulant effects;
• in patients taking analgesics for mild forms of arthritis;
• in patients with severe infections such as sepsis, which are associated with reduced glutathione levels, the use of paracetamol increases the risk of developing 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;
  • if headache becomes persistent.

Note that in patients with alcoholic liver disease, the risk of hepatotoxic effects of paracetamol is increased; the drug may affect laboratory test results for blood glucose and uric acid levels.

If symptoms persist, consult a physician.

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

Use during pregnancy or breastfeeding.

The drug may be prescribed during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus or infant.

Paracetamol passes into breast milk, but in clinically insignificant amounts. Available published data do not contain contraindications to breastfeeding.

Ability to influence reaction rate when driving or operating machinery.

No effect.

Method of Administration and Dosage

The medication is intended for oral administration.

Adults and children aged 12 years and older: 2 tablets (400 mg) 3–4 times daily, with intervals between doses of at least 4 hours. Do not exceed 4000 mg within 24 hours.

Children (6–12 years of age): 1–2 tablets (200–400 mg) every 4–6 hours.

Do not take more than 20 tablets (4000 mg) within 24 hours.

Children aged 3–6 years: ½–1 tablet (100–200 mg) up to 4 times daily.

The interval between doses should be at least 4 hours.

The duration of treatment should be determined by a physician.

Maximum duration of use without medical consultation – 3 days.

Do not exceed the recommended dose.

Do not take together with other medicinal products containing paracetamol.

Children.

Use is not recommended for children under 3 years of age.

Overdose.

Hepatic damage is possible in adults who have ingested 10 g or more of paracetamol, and in children who have ingested 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 depletion (digestive disorders, cystic fibrosis, HIV infection, fasting, cachexia)), ingestion of 5 g or more of paracetamol may lead to hepatic damage.

Symptoms within the first 24 hours include pallor, nausea, vomiting, anorexia, and abdominal pain. Hepatic damage may become evident 12–48 hours after overdose. Glucose metabolism disturbances and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, hemorrhage, hypoglycemia, coma, and death. Acute renal failure with acute tubular necrosis may present with severe flank pain, hematuria, proteinuria, and may develop even in the absence of severe hepatic injury. Cardiac arrhythmias and pancreatitis have also been reported.

With prolonged use of the drug in high doses, hematological disorders such as aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia may develop. Central nervous system effects from high doses include dizziness, psychomotor agitation, and disorientation. Urinary system effects include nephrotoxicity (renal colic, interstitial nephritis, cortical necrosis).

In case of overdose, prompt medical assistance is required. The patient should be immediately transported to a hospital, even if early symptoms of overdose are absent. Symptoms may be limited to nausea and vomiting, or may not reflect the severity of the overdose or risk of organ damage. Administration of activated charcoal should be considered if the excessive dose of paracetamol was ingested within 1 hour. Plasma paracetamol concentrations should be measured 4 hours or more after ingestion (earlier concentrations 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 ingestion. The efficacy of the antidote decreases sharply after this time. If necessary, intravenous N-acetylcysteine should be administered according to the established dosage regimen. In the absence of vomiting, oral methionine may be used as an appropriate alternative in remote areas outside the hospital setting.

Side effects.

Discontinue use of the medicine and seek immediate medical attention if side effects occur.

Side effects of paracetamol are very rare (< 1/10,000):

• Allergic reactions: anaphylaxis, skin itching, rashes on the skin and mucous membranes (usually generalized rash, erythematous urticaria), angioneurotic edema, multiform exudative erythema (including Stevens–Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome);
• Gastrointestinal effects: nausea, epigastric pain, increased activity of liver enzymes, usually without development of jaundice;
• Endocrine system effects: hypoglycemia, up to hypoglycemic coma;
• Blood and lymphatic system disorders: thrombocytopenia, agranulocytosis, anemia, sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), hemolytic anemia, bruising or bleeding;
• Respiratory system disorders: bronchospasm in patients sensitive to acetylsalicylic acid (aspirin) and other nonsteroidal anti-inflammatory drugs.

Frequency unknown (cannot be estimated from available data):

• Metabolism and nutrition disorders: metabolic acidosis with high anion gap.

Description of individual side effects.

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

Reporting of suspected side effects.

Reporting of suspected side effects after drug registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the drug. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected side effects and lack of efficacy via the Automated Pharmacovigilance Information System 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. 10 tablets in blisters;

10 tablets in a blister, 10 blisters in a pack.

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

By prescription: № 100 (10×10).

Manufacturer. JSC "Lubnipharm".

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