Paracetamol

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

Composition:

Active ingredient: paracetamol;

1 capsule contains 325 mg of paracetamol;

Excipients: potato starch, povidone, magnesium stearate; the capsule shell contains patented blue (E 131), titanium dioxide (E 171), gelatin.

Pharmaceutical form. Capsules.

Main physicochemical properties: hard gelatin capsules ranging in color from light blue to blue. The capsule contents – a mixture containing granules and powder from white to almost white. The presence of particle agglomerates is permissible.

Pharmacotherapeutic group. Analgesics and antipyretics. 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.

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 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, severe 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 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 by prolonged concurrent 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 hepatic microsomal enzyme activity, 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 hepatotoxic effects of the drugs.

Concurrent 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 concurrently with flucloxacillin, as this combination has been associated with metabolic acidosis with a high anion gap due to 5-oxoproline (pyroglutamic) acidosis, particularly in patients with risk factors (see section «Special precautions»).

Do not use concurrently with alcohol.

Special precautions for use.

The medicinal 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 may cause liver failure, which may necessitate liver transplantation or result in fatal outcome.

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

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

Cases of liver function impairment/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.

Cases of high anion gap metabolic acidosis (HAGMA) due to 5-oxoprolinuria (pyroglutamic acidosis) have been reported in patients with severe conditions such as severe renal insufficiency and sepsis, or in those with malnutrition and 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 HAGMA due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol is recommended, along with close monitoring of the patient. 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. 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 hazardous.

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.

As with any other medicinal product, consult a physician before using paracetamol during pregnancy.

Extensive data from pregnant women do not indicate any malformative or fetal/neonatal toxicity. Epidemiological studies on neurodevelopmental outcomes in children exposed to paracetamol in utero have yielded inconclusive results. Paracetamol may be used during pregnancy if clinically necessary, but it should be administered at the lowest effective dose, for the shortest duration, and with the least possible frequency.

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

Ability to affect reaction speed when driving or operating machinery.

No effect.

Method of Administration and Dosage

The medicine 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: 1–3 capsules 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 12 capsules (3900 mg) within 24 hours.

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

Maximum duration of use 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 could lead to the need for liver transplantation or result in death. Clinical experience shows that signs of liver damage after paracetamol overdose usually 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 include pallor, nausea, vomiting, loss of appetite, and abdominal pain. Asymptomatic presentation of overdose is also possible.

Overdose of paracetamol following 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 fatal outcomes. Concurrently, elevated levels of liver transaminases (AST, ALT), lactate dehydrogenase, bilirubin, and prothrombin time may occur within 12–48 hours after ingestion.

Liver damage is possible in adults who have taken more than the recommended amount of paracetamol. It is believed that an increased amount of the paracetamol metabolite (normally neutralized by glutathione during standard-dose administration) binds irreversibly to liver tissues.

Acute renal failure with acute tubular necrosis may present as severe flank pain, hematuria, and proteinuria, and may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have also been reported, typically accompanied by impaired liver function 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 use of carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John's wort, or other drugs that induce liver enzymes;
• Chronic alcohol abuse;
• Reduced glutathione levels, for example: malnutrition, fasting, cachexia, cystic fibrosis, HIV infection.

In case of overdose, prompt medical assistance is required. Treatment for overdose, or even suspected overdose, must be initiated immediately by transporting the patient to a hospital, even if early symptoms are absent, as liver damage may not develop immediately. Paracetamol plasma concentration should be measured at least 4 hours or later after ingestion (earlier concentrations are unreliable).

Treatment with activated charcoal should be considered if an excessive dose of more than 150 mg/kg paracetamol was ingested within 1 hour. Treatment with N-acetylcysteine or methionine should also be considered. Symptomatic treatment is also necessary.

Adverse Reactions

Immune system disorders: (rare: < 1/10,000) — anaphylaxis, hypersensitivity reactions including skin rash, angioneurotic edema, Stevens-Johnson syndrome, and Lyell's syndrome.

Blood and lymphatic system disorders: (rare: < 1/10,000) — thrombocytopenia.

Respiratory, thoracic and mediastinal disorders: (rare: < 1/10,000) — bronchospasm in patients sensitive to acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs.

Hepatobiliary disorders: (rare: < 1/10,000) — liver function abnormalities.

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

Cases of metabolic acidosis with high anion gap, resulting from pyroglutamic acidosis, have been observed in patients with risk factors during paracetamol use (see section "Special precautions"). Pyroglutamic acidosis may occur as a consequence of low glutathione levels in these patients.

Additionally, following administration of paracetamol-containing medicinal products, the following adverse reactions may occur: 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.

Shelf life. 4 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging. Capsules: 10, 10×2 in blisters in a box.

Supply category. Over-the-counter (without prescription).

Manufacturer.

LIMITED LIABILITY COMPANY "CORPORATION "ZDOROV'YA".

LIMITED LIABILITY COMPANY "FARMEKS GROUP".

Manufacturer's address and location of business activity.

Ukraine, 61013, Kharkiv region, city of Kharkiv, Shevchenka Street, 22.

(LIMITED LIABILITY COMPANY "CORPORATION "ZDOROV'YA")

Ukraine, 08301, Kyiv region, city of Boryspil, Shevchenka Street, 100.

(LIMITED LIABILITY COMPANY "FARMEKS GROUP")