Paracetamol

I N S T R U C T I O N for medical use of the medicinal product PARACETAMOL (PARACETAMOL)

Composition:

Active ingredient: paracetamol;

1 suppository contains paracetamol 80 mg or 170 mg or 330 mg;

Excipient: hard fat.

Pharmaceutical form. Rectal suppositories.

Main physicochemical properties: white or off-white colored suppositories.

Pharmacotherapeutic group. Analgesics and antipyretics. Paracetamol.

ATC code N02BE01.

Pharmacological properties.

Pharmacodynamics.

Exerts analgesic, antipyretic, and weak anti-inflammatory effects. The mechanism of action is due to inhibition of prostaglandin synthesis and predominant influence on the thermoregulatory center in the hypothalamus.

Pharmacokinetics.

Absorption of paracetamol after rectal administration is slower than after oral administration, but it is more complete. Peak plasma concentration is reached within 2–3 hours after administration.

Paracetamol rapidly distributes into all tissues. Concentrations in blood, saliva, and plasma are comparable. Plasma protein binding is weak.

Paracetamol is mainly metabolized in the liver, forming inactive compounds with glucuronic acid and sulfates.

As a result of metabolism catalyzed by cytochrome P450, an intermediate reactive metabolite (N-acetyl-benzoquinone imine) is formed, which, when paracetamol is used at therapeutic doses, is rapidly detoxified by reduced glutathione and excreted in urine after conjugation with cysteine and mercapturic acid. However, in cases of massive overdose, the amount of this toxic metabolite increases.

Excretion is primarily renal. Approximately 90% of the administered paracetamol dose is excreted by the kidneys within 24 hours, mainly as glucuronide conjugates (60–80%) and sulfate conjugates (20–30%).

Less than 5% of the drug is excreted unchanged.

The elimination half-life is 4 to 5 hours.

In severe renal insufficiency (creatinine clearance below 10 ml/min), excretion of paracetamol and its metabolites is delayed.

Clinical characteristics.

Indications.

Symptomatic treatment of diseases accompanied by mild to moderate pain and/or fever.

Contraindications.

Hypersensitivity to paracetamol or to any of the excipients.

Hepatic failure. Severe impairment of renal and/or hepatic function, congenital hyperbilirubinemia.

Recent proctitis, anitis, or rectal bleeding.

Alcoholism.

Glucose-6-phosphate dehydrogenase deficiency, blood disorders, severe anemia, leukopenia.

Inflammation of the rectal mucosa and impaired anal function.

Diarrhea.

Interaction with other medicinal products and other forms of interactions.

Interactions requiring caution during concomitant use

Oral anticoagulants

When taking the maximum daily dose of paracetamol (4 g/day) for at least 4 days, the effect of oral anticoagulants may be enhanced, increasing the risk of bleeding. The INR (International Normalized Ratio) should be monitored at regular intervals. If necessary, the dose of the oral anticoagulant should be adjusted during paracetamol treatment.

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

Barbiturates reduce the antipyretic effect of paracetamol.

Anticonvulsants (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 hepatotoxic effect of the drug on the liver. Concurrent use of high-dose paracetamol with isoniazid or rifampicin increases the risk of developing hepatotoxic syndrome.

Paracetamol reduces the efficacy of diuretics.

Do not use concomitantly with alcohol.

Effect on laboratory tests

Administration of paracetamol may interfere with blood glucose measurement by the glucose oxidase-peroxidase method in cases of abnormally high concentrations.

Administration of paracetamol may interfere with blood uric acid measurement by the phosphotungstic acid method.

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").

Special precautions for use.

For suppositories, there is a risk of local toxicity, the frequency and intensity of which increase with prolonged use and depend on the frequency of administration and dosage level.

Do not administer the drug to children together with other medicinal products containing paracetamol.

When treating with paracetamol at a dose of 60 mg/kg/day, concomitant use of another antipyretic is justified only if paracetamol is ineffective. Recommended doses should not be exceeded.

The drug is contraindicated in diarrhea.

If hyperthermia persists for more than 3 days of treatment or if the patient's condition worsens, medical advice must be sought.

Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported in patients with severe underlying conditions, such as severe renal insufficiency and sepsis, or in patients who were undernourished or had other causes of glutathione deficiency (e.g., chronic alcoholism) and who had been treated with paracetamol at therapeutic doses over a prolonged period or with a combination of paracetamol and flucloxacillin. If high anion gap metabolic acidosis due to pyroglutamic acidosis is suspected, paracetamol should be discontinued immediately and the patient's condition should be closely monitored. Measurement of urinary 5-oxoproline levels may be helpful in identifying pyroglutamic acidosis as the underlying cause of high anion gap metabolic acidosis in patients with multiple risk factors.

Use during pregnancy or breastfeeding.

This medicinal form in these dosage strengths is intended for use in children.

Ability to influence reaction rate when driving vehicles or operating machinery.

The drug is intended for use in children.

Method of Administration and Dosage

The drug should be used under strict medical supervision, with particular caution in children under 1 year of age.

Administer rectally. Suppositories must not be divided to achieve the required dose. If, after calculating the daily dose based on the child's body weight, the required single dose is less than the amount contained in one suppository, after consulting a physician, it is recommended to use other dosage forms of paracetamol (e.g., oral solution).

When treating children, the dosing regimen should be based on the child's body weight, and the appropriate dosage form of the drug should be selected accordingly.

Approximate age ranges based on body weight are provided for guidance only.

The single dose is 15 mg/kg of body weight. The drug should be administered in 4 doses at 6-hour intervals.

The recommended daily dose of paracetamol is approximately 60 mg/kg body weight/day in 4 divided doses, i.e., 15 mg/kg body weight every 6 hours.

80 mg rectal suppositories are intended for children approximately 3 to 4 months of age, with a body weight of 4 to 6 kg. Administer 3 to 4 suppositories per day, with 6-hour intervals between doses, depending on the child's body weight, based on a total daily dose of 60 mg/kg/day.

Example calculation for a child weighing 4 kg:

4 kg × 60 mg
= 3,
80 mg

where
4 kg – child's body weight;
60 mg – daily dose of paracetamol per 1 kg of body weight;
80 mg – amount of paracetamol in 1 suppository.

170 mg rectal suppositories are intended for children approximately 6 months to 2 years of age, with an average body weight of 8 to 12 kg. Administer 3 to 4 suppositories per day, with 6-hour intervals between doses, depending on the child's body weight, based on a total daily dose of 60 mg/kg/day.

Example calculation for a child weighing 12 kg:

12 kg × 60 mg
= 4,
170 mg

where
12 kg – child's body weight;
60 mg – daily dose of paracetamol per 1 kg of body weight;
170 mg – amount of paracetamol in 1 suppository.

330 mg rectal suppositories are intended for children approximately 4 to 9 years of age, with an average body weight of 15 to 24 kg. Administer 3 to 4 suppositories per day, with 6-hour intervals between doses, depending on the child's body weight, based on a total daily dose of 60 mg/kg/day.

The daily dose of paracetamol is 60 mg/kg body weight.

Example calculation for a child weighing 22 kg:

22 kg × 60 mg
= 4,
330 mg

where
22 kg – child's body weight;
60 mg – daily dose of paracetamol per 1 kg of body weight;
330 mg – amount of paracetamol in 1 suppository.

If pain or fever persists for more than 3 days, or new symptoms appear, a physician should be consulted regarding the appropriateness of continuing treatment.

The recommended daily dose of paracetamol is approximately 60 mg/kg body weight/day in 4 divided doses, i.e., 15 mg/kg body weight every 6 hours.

In cases of severe renal impairment (creatinine clearance less than 10 ml/min), the dosing interval should be at least 8 hours.

Administration involves rectal insertion of one 80 mg, 170 mg, or 330 mg suppository, repeated as necessary at intervals of not less than 6 hours, without exceeding the maximum daily dose (no more than 4 suppositories per day).

Due to the risk of local toxicity, suppositories should not be used more than 4 times daily, and the duration of rectal treatment should be kept as short as possible.

Children

When treating children, the dosing regimen should be based on the child's body weight, and the appropriate dosage form of the drug should be selected accordingly.

Paracetamol 80 mg rectal suppositories are intended for children with a body weight of 4 to 6 kg (approximately 3 to 4 months of age).

Paracetamol 170 mg rectal suppositories are intended for children with a body weight of 8 to 12 kg (approximately 6 months to 2 years of age).

Paracetamol 330 mg rectal suppositories are intended for children with a body weight of 15 to 24 kg (approximately 4 to 9 years of age).

Overdose

To avoid overdose, do not use other medicinal products containing paracetamol.

There is a risk of overdose in children (common cases of medication overdose and accidental poisoning), which may lead to fatal outcomes. For children with body weight less than 37 kg, the maximum daily dose of paracetamol should not exceed 80 mg/kg body weight/day.

For children with body weight from 38 to 50 kg, the maximum daily dose of paracetamol should not exceed 3 g/day.

For children with body weight over 50 kg, the maximum daily dose of paracetamol should not exceed 4 g/day.

A single dose of paracetamol at 150 mg/kg body weight may cause hepatocellular insufficiency, glucose metabolism disturbances, metabolic acidosis, hemorrhages, hypoglycemia, encephalopathy, coma, and may lead to fatal outcomes. In such cases, levels of liver transaminases, lactate dehydrogenase, and bilirubin increase, and prothrombin levels decrease within 12–48 hours. Acute renal failure with acute tubular necrosis may manifest as severe lumbar pain, hematuria, proteinuria, and may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have also been reported. With prolonged use of 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, papillary necrosis). Gastrointestinal effects may include hepatic necrosis.

In patients with risk factors (long-term use of carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John's wort, or other drugs inducing liver enzymes; alcohol abuse; glutathione system deficiency, e.g., due to malnutrition, AIDS, fasting, cystic fibrosis, cachexia), ingestion of 5 g or more of paracetamol may lead to liver damage. Liver injury may become apparent 12–48 hours after overdose. In cases of overdose, the patient should be immediately hospitalized, even if early symptoms of overdose are absent.

Symptoms of overdose appear within the first 24 hours: nausea, vomiting, loss of appetite, pallor, abdominal pain – or may not reflect the severity of overdose or risk of organ damage.

Emergency measures:

• Immediate hospitalization;
• Determination of plasma paracetamol levels;
• Gastric lavage;
• Administration of the antidote N-acetylcysteine intravenously or oral methionine within the first 10 hours;
• Symptomatic therapy.

Side effects.

Very rare:

Allergic reactions: anaphylaxis, anaphylactic shock, angioedema, erythema, urticaria, pruritus, skin and mucous membrane rashes, Stevens-Johnson syndrome, toxic epidermal necrolysis;

Blood and lymphatic system disorders: anaemia, sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), hemolytic anemia, thrombocytopenia, leukopenia, and neutropenia;

Respiratory system disorders: bronchospasm in patients sensitive to aspirin and other NSAIDs;

Gastrointestinal disorders: nausea, epigastric pain, liver function disturbances, increased liver enzyme activity (usually without jaundice), hepatonecrosis (dose-dependent effect);

Endocrine system disorders: hypoglycemia, up to hypoglycemic coma.

Metabolism and nutrition disorders: metabolic acidosis with high anion gap (frequency unknown).

Product-related reactions: irritation of the rectum and anal opening.

If any adverse reactions occur, discontinue use of the medication and consult a physician immediately.

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

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after a medicinal product has been authorized is important. It allows ongoing 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 through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

5 suppositories per strip. 2 strips per carton.

Availability.

Over-the-counter.

Manufacturer. JSC "Monfarm".

Manufacturer's address and location of operations.

8, Zavodska St., Avramivka village, Uman district, Cherkasy region, 19161, Ukraine.