Efferalgan

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT EFERALGAN

Composition:

Active ingredient: paracetamol;

1 rectal suppository contains 80 mg, 150 mg, or 300 mg of paracetamol;

Excipient: hard fat.

Pharmaceutical form. Rectal suppositories.

Main physicochemical properties: white, smooth and glossy suppositories.

Pharmacotherapeutic group.

Analgesics and antipyretics. ATC code N02B E01.

Pharmacological properties.

Pharmacodynamics.

Exerts analgesic, antipyretic, and weak anti-inflammatory effects. The mechanism of action is associated with 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 more complete. Peak plasma concentration is achieved within 2–3 hours after administration.

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

Paracetamol is mainly metabolized in the liver to form inactive compounds conjugated with glucuronic acid and sulfates.

A minor metabolic pathway, catalyzed by cytochrome P450, leads to the formation of a reactive intermediate metabolite (N-acetylbenzoquinoneimine), which under normal conditions 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 via urine. About 90 % of the administered dose of paracetamol is eliminated 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 ranges from 4 to 5 hours.

In severe renal impairment (creatinine clearance below 10 ml/min), elimination of paracetamol and its metabolites is slowed.

Clinical characteristics.

Indications.

Symptomatic treatment of diseases accompanied by mild to moderate pain and/or elevated body temperature.

Contraindications.

Hypersensitivity to paracetamol or to other components of the drug.

Age under 1 month (body weight under 4 kg).

Severe impairment of kidney and/or liver function, hepatocellular insufficiency, congenital hyperbilirubinemia, glucose-6-phosphate dehydrogenase deficiency, alcoholism, blood disorders, severe anemia, leukopenia.

Inflammation of the rectal mucosa and dysfunction of the anus, rectal bleeding.

Do not use the drug during diarrhea.

Special precautions.

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. Do not exceed the recommended doses.

Do not use the drug during diarrhea.

If hyperthermia persists beyond 3 days of treatment with the drug or if the patient's condition worsens, medical advice should be sought.

Interaction with other medicinal products and other types of interactions.

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

The absorption rate of paracetamol may be increased by metoclopramide and domperidone and decreased by cholestyramine. Barbiturates reduce the antipyretic effect of paracetamol. Anticonvulsant drugs (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. Concurrent use of paracetamol with hepatotoxic agents increases the hepatotoxic effect of the drug on the liver. Concurrent use of high doses of paracetamol with isoniazid, rifampicin increases the risk of developing hepatotoxic syndrome. Paracetamol reduces the effectiveness of diuretics. Do not use concurrently with alcohol.

High concentrations of paracetamol may affect laboratory test results for blood glucose by the oxidase-peroxidase method and for uric acid when using the phosphotungstic acid method.

Paracetamol should be used with caution concomitantly with flucloxacillin, as this concurrent use is associated with metabolic acidosis with a high anion gap due to pyroglutamic acidosis, especially in patients with risk factors ("Special instructions for use").

Special precautions for use.

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 kg 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.

When using suppositories, there is a risk of local toxicity; the frequency and severity of toxic manifestations increase with prolonged use, shorter intervals between administrations, and increased dosage.

Cases of high anion gap metabolic acidosis due to pyroglutamic acidosis have been reported in patients with severe conditions such as severe renal insufficiency and sepsis, or 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 with a combination of paracetamol and 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's condition. 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 product in this pharmaceutical form is intended for use in children only.

A substantial amount of data in pregnant women does not indicate developmental malformations or fetal/neonatal toxicity. Epidemiological studies on neurodevelopmental outcomes in children exposed to paracetamol in utero have shown inconclusive results. If clinically necessary, paracetamol may be used during pregnancy at the lowest effective dose, for the shortest possible duration, and with the least possible frequency.

Traditional reproductive and developmental toxicity studies using currently accepted standards are lacking.

Ability to affect reaction speed when driving or operating machinery.

This medicinal product in this pharmaceutical form is intended for use in children only.

Method of Administration and Dosage

The medication 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 dosage. If, based on body weight calculations, a single dose less than the content of one suppository is required, 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 an appropriate pharmaceutical form should be selected accordingly.

Approximate age ranges based on body weight are provided only as a guideline.

Efferalgan 80 mg rectal suppositories are intended for children with a body weight of 4 to 6 kg (approximately 1 to 4 months of age). The recommended dosage is 3 to 4 suppositories per day, administered at 6-hour intervals, calculated according to body weight as 60 mg/kg/day.

Example calculation for a child weighing 4 kg:

where:

60 mg – daily dose of paracetamol per 1 kg of child's body weight per day,

80 mg – amount of paracetamol in one suppository.

Efferalgan, 150 mg rectal suppositories, intended for children with body weight from 8 to 12 kg (approximately from 6 months to 2 years of age). From 3 to 4 suppositories per day, administered at intervals of 6 hours, depending on the child's body weight, calculated at 60 mg/kg/day.

Example calculation for a child weighing 10 kg:

where:

60 mg – daily dose of paracetamol per 1 kg of child's body weight per day,

150 mg – amount of paracetamol in one suppository.

Efferalgan, 300 mg rectal suppositories, is intended for children with body weight from 15 to 24 kg (approximately 4 to 9 years of age).

Example calculation for a child with body weight of 20 kg:

where:

60 mg – daily dose of paracetamol per 1 kg of child's body weight per day,

300 mg – amount of paracetamol in one suppository.

The recommended daily dose of paracetamol is approximately 60 mg/kg body weight/day, which should be divided into 4 doses, i.e. 15 mg/kg body weight every 6 hours. In severe renal impairment (creatinine clearance less than 10 ml/min), the dosing interval should be at least 8 hours.

Administration involves the rectal insertion of one suppository of 80 mg, 150 mg, or 300 mg, repeated as necessary at intervals of not less than 6 hours, but without exceeding the maximum daily dose or 4 suppositories per day.

Due to the risk of local toxicity, administration of suppositories more than 4 times a day is not recommended, and the duration of rectal administration should be kept as short as possible.

Children.

When treating children, the dosing regimen should be followed according to the child's body weight, and the appropriate dosage form should be selected accordingly.

Efferalgan, 80 mg rectal suppositories, is indicated for children with body weight from 4 to 6 kg (approximately 1 to 4 months of age).

Efferalgan, 150 mg rectal suppositories, is indicated for children with body weight from 8 to 12 kg (approximately 6 months to 2 years of age).

Efferalgan, 300 mg rectal suppositories, is indicated for children with body weight from 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 young children (medication overdose and accidental poisoning are common). This may lead to fatal outcome.

A single dose of 150 mg/kg body weight may cause hepatocellular insufficiency, disturbances in glucose metabolism, metabolic acidosis, hemorrhages, hypoglycemia, encephalopathy, coma, and may lead to fatal outcome. In such cases, levels of liver transaminases, lactate dehydrogenase, and bilirubin increase; 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 the drug in high doses, hematological disorders such as aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia may develop. In the central nervous system, high doses may cause dizziness, psychomotor agitation, and disorientation; in the urinary system – nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis); in the digestive system – hepatonecrosis. 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), administration of 5 g or more of paracetamol may lead to liver damage. Liver injury may become evident 12–48 hours after overdose. In case of overdose, the patient should be immediately taken to hospital, 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 – and may not reflect the severity of overdose or risk of injury. 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 (Quincke's edema), erythema, urticaria, pruritus, skin and mucous membrane rashes, multiform exudative erythema, toxic epidermal necrolysis;

Hematologic system: anemia, sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), hemolytic anemia, thrombocytopenia, leukopenia, and neutropenia;

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

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

Endocrine system: hypoglycemia, up to hypoglycemic coma.

Related to the dosage form: irritation of the rectum and anal opening.

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

If any adverse reactions occur, discontinue the drug immediately and consult a physician without delay.

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C, in a place inaccessible to children.

Packaging.

5 suppositories per blister, 2 blisters per cardboard box.

Prescription status.

Over-the-counter (without prescription).

Manufacturer.

UPSA SAS, France.

Manufacturer's name and address of place of business.

304, avenue du Docteur Jean Bru, 47000 Agen, France.

979, avenue des Pyrenees, 47520 Le Passage, France.