Efferalgan^® (Tablets, Solution, Suppositories) Instructions for Use

ATC Code

N02BE01 (Paracetamol)

Active Substance

Paracetamol (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Analgesic-antipyretic

Pharmacotherapeutic Group

Analgesics; other analgesics and antipyretics; anilides

Pharmacological Action

Paracetamol has analgesic, antipyretic, and very weak anti-inflammatory effects, which is associated with its influence on the thermoregulation center in the hypothalamus and its weak ability to inhibit the synthesis of prostaglandins in peripheral tissues.

The absence of a blocking effect on the synthesis of prostaglandins in peripheral tissues determines the absence of a negative effect on water-salt metabolism (retention of sodium and water) and the gastrointestinal mucosa.

Pharmacokinetics

Absorption

When taken orally, Paracetamol is absorbed quickly and completely. C_max (maximum plasma concentration of paracetamol) is reached within 10-60 minutes after administration.

Distribution

Paracetamol is rapidly distributed in all tissues. Concentrations in blood, saliva, and plasma are the same. It crosses the BBB. Less than 1% of the paracetamol dose taken by a nursing mother passes into breast milk. The therapeutic effective plasma concentration of paracetamol is achieved when administered at a dose of 10-15 mg/kg. Binding to plasma proteins is insignificant.

Metabolism

Paracetamol is mainly metabolized in the liver. There are two main metabolic pathways resulting in glucuronides and sulfates. The latter is mainly used if the taken dose of paracetamol exceeds the therapeutic dose.

A small amount of paracetamol is metabolized by the cytochrome P450 isoenzyme to form an intermediate compound, N-acetyl-p-benzoquinone imine, which under normal conditions undergoes rapid detoxification with glutathione and is excreted in the urine after conjugation with cysteine and mercapturic acid. However, in massive intoxication, the content of this toxic metabolite increases.

Excretion

It is carried out mainly with urine. 90% of the taken paracetamol dose is excreted by the kidneys within 24 hours, mainly in the form of glucuronide (from 60% to 80%) and sulfate (from 20% to 30%). Less than 5% is excreted unchanged. T_1/2 is about 2 hours.

Pharmacokinetics in special patient groups

In severe renal impairment (creatinine clearance less than 30 ml/min), the excretion of paracetamol and its metabolites is delayed.

Indications

• As an antipyretic for acute respiratory diseases and other infectious and inflammatory diseases accompanied by fever;
• As an analgesic for mild to moderate pain syndromes: arthralgia, myalgia, neuralgia, migraine, toothache and headache, primary dysmenorrhea, pain from injuries and burns.

ICD codes

Dosage Regimen

Suppositories

The drug is used rectally. After freeing the suppository from its packaging, insert it into the child’s anus (preferably after a cleansing enema or spontaneous bowel movement).

The average single dose of Efferalgan^® depends on the child’s body weight and is 15 mg/kg 4 times/day (every 4-6 hours). The maximum daily dose should not exceed 60 mg/kg.

Children weighing from 6 to 8 kg (age from 3 to 5 months) are administered 1 suppository (80 mg) 4 times/day every 4-6 hours.

Children weighing from 10 to 14 kg (age from 6 months to 3 years) are administered 1 suppository (150 mg) 4 times/day every 4-6 hours.

Children weighing from 20 to 30 kg (age from 5 to 10 years) are administered 1 suppository (300 mg) 4 times/day every 4-6 hours.

Regular intervals between suppository applications should be observed – from 4 to 6 hours.

No more than 4 suppositories should be used per day.

Duration of treatment

Due to possible local toxic effects, the use of suppositories more than 4 times a day is not recommended, and the duration of use should be as short as possible: 3 days as an antipyretic and up to 5 days as an analgesic.

If there is no therapeutic effect, treatment should be discontinued and a doctor should be consulted.

In patients with chronic or compensated active liver diseases, especially those accompanied by hepatic insufficiency, in patients with chronic alcoholism, chronic malnutrition (insufficient glutathione reserves in the liver), Gilbert’s syndrome, dehydration, or body weight less than 50 kg, the drug dose should be reduced or the interval between doses increased. The daily dose should not exceed 2 g.

Solution

The average single dose of the drug depends on the child’s body weight and is 10-15 mg/kg of body weight. The maximum daily dose should not exceed 60 mg/kg of body weight. The minimum interval between doses of the drug should be 4 hours. Regular time intervals between doses of the drug should be maintained.

For convenience and accurate dosing, a measuring spoon should be used. The measuring spoon has markings indicating the child’s body weight: 4, 6, 8, 10, 12, 14, or 16 kg. Unmarked divisions correspond to intermediate body weights: 5, 7, 9, 11, 13, or 15 kg.

Children weighing from 4 to 16 kg

Fill the measuring spoon to the mark corresponding to the child’s body weight, or to the mark closest in value to the child’s body weight. For example, if the child’s body weight is from 4 to 5 kg, fill the measuring spoon to the mark corresponding to 4 kg. If necessary, the drug should be taken every 4-6 hours.

Children weighing from 16 to 32 kg

Fill the measuring spoon to the mark corresponding to 10 kg, then refill the measuring spoon to the mark to obtain the child’s total body weight. For example, if the child’s body weight is from 18 to 19 kg, fill the measuring spoon to the mark corresponding to 10 kg, then refill the measuring spoon to the 8 kg mark. If necessary, the drug should be taken every 4-6 hours.

The drug can be given to the child either undiluted or after dilution (with water, milk, or juice).

Duration of treatment – 3 days as an antipyretic and up to 5 days as an analgesic. If it is necessary to continue taking the drug, a doctor’s consultation is required.

Children aged from 1 to 3 months can be given the drug only as prescribed by a doctor.

In severe renal impairment, the time interval between doses of the drug should be at least 8 hours with creatinine clearance less than 10 ml/min, and at least 6 hours with creatinine clearance of 10-50 ml/min.

In patients with chronic or compensated active liver diseases, especially those accompanied by hepatic insufficiency, in patients with chronic alcoholism, chronic malnutrition (insufficient glutathione reserves in the liver), Gilbert’s syndrome, dehydration, or body weight less than 50 kg, the drug dose should be reduced or the interval between doses increased. The daily dose should not exceed 2 g.

Tablets

The drug is taken orally. The tablet should be dissolved in a glass of water (200 ml). Do not chew or swallow the tablets.

Usually, 1-2 tablets are taken 2-3 times/day with intervals of at least 4 hours.

The maximum single dose is 2 tablets (1 g), the maximum daily dose is 8 tablets (4 g), which corresponds to a single dose of 10-15 mg/kg of body weight.

As a rule, there is no need to exceed the recommended daily dose of paracetamol equal to 3 g. The daily dose can be increased to the maximum (4 g) only in case of severe pain.

In renal impairment, the time interval between doses of the drug should be at least 8 hours with creatinine clearance less than 10 ml/min, and at least 6 hours with creatinine clearance of 10-50 ml/min.

In patients with chronic or compensated active liver diseases, especially those accompanied by hepatic insufficiency, in patients with chronic alcoholism, chronic malnutrition (insufficient glutathione reserves in the liver), Gilbert’s syndrome (hereditary hyperbilirubinemia), dehydration or body weight less than 50 kg, the drug dose should be reduced or the interval between doses increased. The daily dose should not exceed 2 g, i.e., 4 tablets.

The drug should be used with caution in children and patients with body weight less than 50 kg to avoid the risk of exceeding the recommended dose.

The dosing regimen for children over 12 years of age and weighing more than 43 kg is the same as for adults, with the interval preferably being 6 hours (strictly not less than 4 hours).

The duration of use without consulting a doctor is no more than 5 days when prescribed as an analgesic and 3 days as an antipyretic.

Adverse Reactions

The following side effects were noted with the use of the drug (frequency not established).

Allergic reactions hypersensitivity reactions, skin itching, rash on the skin and mucous membranes (erythema or urticaria), angioedema, exudative erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome), anaphylactic shock, acute generalized exanthematous pustulosis.

From the respiratory system bronchospasm.

From the central and peripheral nervous system (when taking high doses): dizziness, psychomotor agitation, and disorientation.

From the digestive system nausea, vomiting, diarrhea, epigastric pain, increased activity of liver enzymes, usually without the development of jaundice, hepatonecrosis (dose-dependent effect), hepatitis, tenesmus, liver failure.

From the kidneys and urinary tract: increased creatinine.

From the endocrine system hypoglycemia, up to hypoglycemic coma.

From the hematopoietic system anemia (cyanosis), sulfhemoglobinemia, methemoglobinemia (shortness of breath, heart pain), hemolytic anemia (especially in patients with glucose-6-phosphate dehydrogenase deficiency), thrombocytopenia, neutropenia, leukopenia.

Other decreased blood pressure (as a symptom of anaphylaxis), changes in prothrombin time and INR.

Contraindications

• Hypersensitivity to paracetamol, propacetamol hydrochloride (a prodrug of paracetamol) or any other component of the drug;
• Severe hepatic insufficiency or decompensated liver diseases in the acute stage;
• Sucrase/isomaltase deficiency, fructose intolerance, glucose-galactose malabsorption;
• Children under 12 years of age.

With caution severe renal failure (creatinine clearance <30 ml/min), hepatic insufficiency, chronic alcoholism, anorexia, bulimia, cachexia, hypovolemia, dehydration, glucose-6-phosphate dehydrogenase deficiency, congenital hyperbilirubinemias (Gilbert, Dubin-Johnson, and Rotor syndromes), viral hepatitis, elderly age.

Use in Pregnancy and Lactation

Studies in animals and humans have not revealed any risk of using the drug in pregnant women or any harmful effects of the drug on the development of the embryo and fetus. Paracetamol can be used during pregnancy; however, it is advisable to use the minimum effective doses for the shortest possible course.

It passes into breast milk in small quantities. Studies have not established any harmful effects of paracetamol on the infant’s body during breastfeeding.

Use in Hepatic Impairment

The use of the drug is contraindicated in severe hepatic insufficiency or decompensated liver diseases in the acute stage.

The drug should be used with caution in hepatic insufficiency.

Use in Renal Impairment

The drug should be used with caution in severe renal failure (creatinine clearance <30 ml/min).

Pediatric Use

The use of the drug is contraindicated in children under 12 years of age.

Geriatric Use

The drug should be used with caution in elderly patients.

Special Precautions

To avoid overdose, the paracetamol content in other drugs that the patient is taking simultaneously with Efferalgan^® should be taken into account. Taking paracetamol in doses exceeding the recommended ones can cause severe liver damage.

If the febrile syndrome continues for more than 3 days during the use of paracetamol, and the pain syndrome for more than 5 days, a doctor’s consultation is required.

Taking Efferalgan^® may distort laboratory test indicators during the quantitative determination of glucose and uric acid in plasma.

To avoid toxic liver damage, Paracetamol should not be combined with the intake of alcoholic beverages, and should not be taken by persons prone to chronic alcohol consumption.

The risk of liver damage increases in patients with alcoholic hepatosis. In patients with malnutrition (low liver glutathione reserves), Paracetamol should be used with caution, reducing the daily dose and/or increasing the interval between doses.

With prolonged use of the drug, monitoring of the peripheral blood picture and the functional state of the liver is necessary.

Paracetamol can cause serious skin reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, which can be fatal. At the first appearance of a rash or other hypersensitivity reactions, the use of the drug should be discontinued.

The use of paracetamol should be discontinued if the patient is found to have acute viral hepatitis.

The drug Efferalgan^® contains 412.4 mg of sodium per 1 tablet, which should be taken into account by patients on a strict low-salt diet.

Since the drug contains sorbitol, it should not be used in cases of sucrase/isomaltase deficiency, fructose intolerance, glucose-galactose malabsorption.

Effect on ability to drive vehicles and machinery

When using paracetamol in the recommended dose range, no effect on concentration and speed of psychomotor reactions has been established. If the patient experiences dizziness, psychomotor agitation, and disorientation, they are not recommended to drive a car or operate machinery during treatment with the drug.

Overdose

In case of overdose, intoxication is possible, especially in children, patients with liver diseases (caused by chronic alcoholism), in patients with nutritional disorders, as well as in patients taking enzyme inducers, in which fulminant hepatitis, liver failure, cholestatic hepatitis, cytolytic hepatitis may develop, in the cases mentioned above – sometimes with a fatal outcome. The clinical picture of acute overdose develops within 24 hours after taking paracetamol.

Symptoms gastrointestinal disorders (nausea, vomiting, loss of appetite, abdominal discomfort and/or abdominal pain), pale skin, sweating, malaise. With a single administration of 7.5 g or more to adults or more than 140 mg/kg to children, cytolysis of hepatocytes occurs with complete and irreversible liver necrosis, development of liver failure, metabolic acidosis, and encephalopathy, which can lead to coma and death. 12-48 hours after paracetamol administration, an increase in the activity of liver transaminases, LDH, bilirubin concentration, and a decrease in prothrombin concentration are noted. Clinical symptoms of liver damage appear 1-2 days after drug overdose and reach a maximum on the 3rd-4th day.

Treatment immediate hospitalization; determination of the quantitative content of paracetamol in blood plasma before starting treatment as soon as possible after overdose; gastric lavage; administration of SH-group donors and precursors of glutathione synthesis – methionine and acetylcysteine – within 8 hours after overdose. The need for additional therapeutic measures (further administration of methionine, intravenous administration of acetylcysteine) is determined depending on the concentration of paracetamol in the blood, as well as the time elapsed after its administration; symptomatic treatment; liver tests should be performed at the beginning of treatment and then every 24 hours. In most cases, the activity of liver transaminases normalizes within 1-2 weeks. In very severe cases, a liver transplant may be required.

Drug Interactions

Inducers of liver microsomal enzymes or potentially hepatotoxic substances (for example, ethanol, rifampicin, isoniazid, hypnotics and antiepileptic drugs, including phenobarbital, phenytoin, and carbamazepine) increase the toxicity of paracetamol and may lead to liver damage even at non-toxic doses of paracetamol; therefore, liver function should be monitored.

Phenytoin reduces the effectiveness of paracetamol and increases the risk of hepatotoxicity; consequently, patients taking phenytoin should avoid frequent use of paracetamol, especially in high doses.

Paracetamol reduces the effectiveness of uricosuric drugs.

Paracetamol may increase the risk of elevated chloramphenicol concentration and, as a result, may increase the risk of neutropenia; therefore, hematological parameters should be monitored. Simultaneous use of these two drugs is possible only after consultation with a doctor.

Probenecid reduces the clearance of paracetamol by almost 2 times, which requires a reduction in the dose of paracetamol.

Repeated use of paracetamol for more than 4 days increases the anticoagulant effect. INR monitoring should be performed during and after the end of simultaneous use of paracetamol (especially in high doses and/or for a prolonged time) and coumarin derivatives. If necessary, the dose of anticoagulants should be adjusted. Irregular use of paracetamol does not significantly affect the action of anticoagulants.

Propantheline and other drugs that slow gastric evacuation reduce the rate of absorption of paracetamol, which may delay or reduce the onset of effect.

Metoclopramide and domperidone increase the rate of absorption of paracetamol and, accordingly, the onset of analgesic and antipyretic action.

Long-term use of barbiturates reduces the effectiveness of paracetamol.

Ethanol contributes to the development of acute pancreatitis.

Long-term combined use of paracetamol and other NSAIDs increases the risk of analgesic nephropathy and renal failure.

Simultaneous long-term administration of paracetamol in high doses and salicylates increases the risk of kidney or bladder cancer.

Diflunisal increases the plasma concentration of paracetamol by 50% – risk of hepatotoxicity.

Myelotoxic drugs enhance the manifestations of the hematotoxicity of the drug.

Salicylamide may increase the T_1/2 of paracetamol.

Caution should be exercised with the simultaneous use of paracetamol and flucloxacillin, which is associated with an increased risk of developing metabolic acidosis with a high anion gap, especially in patients with risk factors for glutathione deficiency (including patients with severe renal failure, sepsis, malnutrition, and chronic alcoholism). Careful monitoring is recommended to identify signs of acid-base imbalance, namely metabolic acidosis with a high anion gap, including the determination of urinary 5-oxoproline.

Storage Conditions

The drug should be stored out of the reach of children at a temperature of 15-30°C (-22°F).

Shelf Life

Shelf life – 3 years. Do not use after the expiration date.

Dispensing Status

The drug is available without a prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.