Paracetamol

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

Composition:

Active substance: paracetamol;

1 tablet contains 200 mg of paracetamol, calculated as 100 % substance;

Excipients: sodium starch glycolate (type A), povidone, calcium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: tablets are white or almost white, with a flat surface, a score line and beveled edges.

Pharmacotherapeutic group. Other analgesics and antipyretics. Anilides. Paracetamol.

ATC code N02B E01.

Pharmacological Properties

Pharmacodynamics

The drug contains paracetamol, an analgesic and antipyretic (pain-relieving and fever-reducing agent).

Pharmacokinetics

Paracetamol is rapidly and almost completely absorbed in the gastrointestinal tract. Maximum plasma concentration is reached within 30–60 minutes. The elimination half-life is 1–4 hours. It is uniformly distributed in all body fluids. Plasma protein binding is variable. It is primarily excreted by the kidneys in the form of conjugated metabolites.

Clinical characteristics

Indications

Mild to moderate pain of various origins: headache, including migraine and tension headache, back pain, rheumatic pain, muscle pain, menstrual pain in women, neuralgia, toothache; relief of symptoms of cold and flu, such as fever and body aches.

Contraindications

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

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 during long-term concomitant use of paracetamol. Occasional use has no significant effect. Barbiturates reduce the antipyretic effect of paracetamol.

Paracetamol should be used with caution when administered concomitantly with flucloxacillin, as such concomitant use 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").

Anticonvulsant drugs, including phenytoin, barbiturates, and 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. Concomitant use of high doses of paracetamamol with isoniazid increases the risk of developing hepatotoxic syndrome.

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

Special precautions for use

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

In patients with liver or kidney disease, consult a physician before using this medicinal product.

Consult a physician before using this product if the patient is taking warfarin or similar agents with anticoagulant effect.

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

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. Immediate medical attention should be sought if these symptoms occur.

Cases of high anion gap metabolic acidosis (HAGMA) due to 5-oxoproline (pyroglutamic) acidosis have been reported in patients with severe underlying conditions such as severe renal failure and sepsis, as well as in patients with inadequate nutrition or other causes 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 high anion gap metabolic acidosis due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol is recommended, along with careful monitoring of the patient. Measurement of 5-oxoproline levels in urine may be useful in identifying pyroglutamic acidosis as the underlying cause of high anion gap metabolic acidosis in patients with multiple risk factors.

Prolonged use without medical supervision may be dangerous.

If symptoms persist, consult a physician.

The medicinal product should be used only when clearly necessary.

Keep the medicine out of sight and reach of children.

Use during pregnancy or breastfeeding

Extensive data on the use of paracetamol in pregnant women do not indicate any malformative or fetal/neonatal toxicity.

Available epidemiological studies on neurodevelopmental outcomes in children exposed to paracetamol during fetal development do not allow definitive conclusions to be drawn.

Paracetamol may be used during pregnancy when clinically necessary and when the expected benefit to the mother outweighs the potential risk to the fetus or infant. However, it should be administered at the lowest effective dose, for the shortest duration, and with the least frequent dosing possible.

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

Effect on ability to drive and use machines

No effect.

Method of Administration and Dosage

The medication is intended for oral administration.

Take with a large amount of liquid, 1–2 hours after eating (taking immediately after food may prolong absorption time).

Adults and children aged 12 years and older: 2–5 tablets, 4 times daily as needed.

Children aged 6 to 12 years: 1–2 tablets, 3–4 times daily as needed.

Children aged 3 to 6 years: dose calculated as 10–15 mg/kg body weight – single dose. Dosing may be repeated every 6 hours (up to 4 times daily) as needed.

The interval between doses should be at least 4 hours.

Do not exceed 20 tablets (4,000 mg) within 24 hours.

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

Do not exceed the recommended dose.

Do not take together with other medicinal products containing paracetamol.

Children

This medicinal form is not recommended for children under 3 years of age.

Overdose

Paracetamol overdose may cause liver failure, which could lead to the need for liver transplantation or result in death.

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

Risk factors for paracetamol overdose include:

• Long-term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John’s wort, and other drugs that induce liver enzyme synthesis;
• Regular alcohol abuse;
• Reduced glutathione levels, for example, in nutritional disorders, fasting, body exhaustion, cystic fibrosis, HIV.

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

Clinical experience shows that signs of liver damage after paracetamol overdose usually appear 24–48 hours after ingestion and peak at 4–6 days.

Paracetamol overdose after a single dose in adults or children may cause reversible or irreversible hepatocellular necrosis, leading to disturbances in glucose metabolism, metabolic acidosis, hepatocellular failure, encephalopathy, hemorrhage, hypoglycemia, coma, and potentially death. Concurrently, elevated levels of liver transaminases (aspartate aminotransferase, alanine aminotransferase), lactate dehydrogenase, bilirubin, and prolonged prothrombin time occur within 12–48 hours after ingestion. Liver damage is likely in adults who have taken 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 tissue.

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 damage. Cardiac arrhythmias and acute pancreatitis have also been reported, usually accompanied by liver function disturbances and hepatotoxicity.

With prolonged use of the drug in high doses, hematological side effects may include aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia. High-dose intake may affect the central nervous system, causing dizziness, psychomotor agitation, and disorientation. The urinary system may be affected by nephrotoxicity (renal colic, interstitial nephritis, capillary necrosis).

When paracetamol is taken at more than 1 tablet per day, with a cumulative intake of 1,000 or more tablets over a lifetime, the risk of developing severe analgesic nephropathy leading to end-stage renal failure doubles.

In case of overdose, excessive sweating, psychomotor agitation or central nervous system depression, drowsiness, impaired consciousness, cardiac arrhythmias, tachycardia, extrasystoles, tremor, hyperreflexia, and seizures may occur.

In case of overdose, immediate medical assistance is required. Treatment for overdose, or even suspected overdose, must be initiated immediately by hospitalizing the patient, even if early symptoms are absent, as liver damage may not develop immediately.

Symptoms may be limited to nausea and vomiting and may not reflect the severity of the overdose or the risk of organ damage.

Consider treatment with activated charcoal if a paracetamol dose exceeding 150 mg/kg was ingested within 1 hour. Plasma paracetamol concentration should be measured 4 hours or later after ingestion (earlier measurements are unreliable).

Consider treatment with N-acetylcysteine or methionine. Symptomatic treatment should also be provided.

Adverse Reactions

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

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

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 not known (cannot be estimated from available data) – metabolic acidosis with high anion gap.

Description of selected adverse reactions

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 taking paracetamol (see section "Special precautions for use"). Pyroglutamic acidosis may occur due to low glutathione levels in these patients.

Other adverse reactions observed after administration of paracetamol-containing medicinal products include: pruritus, 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives are encouraged to report any suspected adverse reactions 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 °C. Keep out of reach of children.

Packaging. 200 mg tablets, 10 tablets in a blister; 10 tablets in a blister, 2 blisters per carton.

Availability. Over-the-counter.

Manufacturer

1. JSC "Kyivmedpreparat".
2. JSC "Halychpharm".

Manufacturer's address and place of business

1. 139 Saksaganskoho Street, Kyiv, 01032, Ukraine.
2. 6/8 Opryshkovska Street, Lviv, 79024, Ukraine.