Paracetamol for children

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Paracetamol for CHILDREN (Paracetamol for CHILDREN)

Composition:

Active substance: paracetamol;

5 ml of syrup contain 120 mg of paracetamol (calculated as 100 % dry substance);

Excipients: methyl 4-hydroxybenzoate (E 218), propyl 4-hydroxybenzoate (E 216), propylene glycol, glycerin, ethanol 96 %, sorbitol (E 420), raspberry flavor, Ponceau 4R (E 124), purified water.

Pharmaceutical form. Syrup.

Main physicochemical characteristics: clear viscous liquid, pink in color, with a sweet taste and characteristic raspberry odor.

Pharmacotherapeutic group. Analgesics and antipyretics. ATC code N02B E01.

Pharmacological properties.

Pharmacodynamics.

Exerts analgesic and antipyretic effects. The mechanism of action is associated with inhibition of prostaglandin synthesis and effects on the thermoregulatory center in the hypothalamus.

Pharmacokinetics.

After oral administration, paracetamol is rapidly absorbed from the gastrointestinal tract, mainly in the small intestine, primarily via passive transport. Following a single 500 mg dose, maximum plasma concentration is reached within 30–60 minutes. It is well distributed in tissues and predominantly in body fluids, except for adipose tissue and cerebrospinal fluid. Plasma protein binding is less than 10% and increases only slightly with higher doses. Sulfate and glucuronide metabolites do not bind to plasma proteins even at relatively high concentrations. Paracetamol is metabolized mainly in the liver via conjugation with glucuronides, conjugation with sulfates, and oxidation involving hepatic mixed-function oxidases and cytochrome P450. A reactive hydroxylated metabolite, N-acetyl-p-benzoquinone imine, formed in very small amounts in the liver and kidneys by mixed-function oxidases, is normally detoxified by conjugation with glutathione; however, it may accumulate in cases of paracetamol overdose and cause tissue damage. In adults, the majority of paracetamol is conjugated with glucuronic acid, and to a lesser extent with sulfuric acid. These conjugated metabolites are biologically inactive. In premature infants, neonates, and infants during the first year of life, sulfate conjugation predominates. The elimination half-life ranges from 1 to 4 hours. In patients with liver cirrhosis, the elimination half-life is slightly prolonged. Renal clearance of paracetamol is approximately 5%. The drug is excreted in the urine mainly as glucuronide and sulfate conjugates. Less than 5% is excreted unchanged as paracetamol.

Clinical characteristics.

Indications.

Pain during teething, toothache, sore throat, fever associated with colds, influenza, and childhood infections such as chickenpox, pertussis, measles, mumps.

Contraindications.

• Hypersensitivity to paracetamol and to other components of the drug, particularly parabens (methyl- and propylparahydroxybenzoate);
• severe impairment of liver and kidney function (including hepatic and renal failure);
• glucose-6-phosphate dehydrogenase deficiency;
• blood disorders (e.g. severe anemia, leukopenia);
• congenital hyperbilirubinemias (Gilbert’s syndrome, Dubin-Johnson syndrome, Rotor syndrome);
• alcoholism.

Interaction with other medicinal products and other forms of interaction.

The drug should not be used simultaneously with other medicinal products containing paracetamol to avoid exceeding the maximum daily dose of paracetamol.

When paracetamol is used concomitantly with hepatotoxic agents, the toxic effects of the drugs on the liver are increased.

Agents inducing hepatic microsomal enzymes (e.g. barbiturates, phenytoin, carbamazepine, primidone, other anticonvulsants, tricyclic antidepressants, oral contraceptives, St. John’s wort preparations), ethanol: increased risk of hepatotoxic effects of paracetamol due to enhanced formation of hepatotoxic metabolites, especially when high doses of paracetamol are used.

Barbiturates: reduced antipyretic effect of paracetamol.

Do not use simultaneously with ethanol or with other medicinal products containing ethanol.

Probenecid, propranolol: possible enhancement of paracetamol's effect.

Pramlintide: possible reduction in paracetamol absorption when administered 1–4 hours after pramlintide.

Chloramphenicol: increased toxicity due to prolonged elimination half-life and elevated plasma concentration of chloramphenicol.

Metoclopramide, domperidone: possible increased rate of paracetamol absorption.

Cholestyramine: possible decreased rate of paracetamol absorption.

Warfarin, other coumarins: possible potentiation of anticoagulant effect, increasing the risk of bleeding when high doses of paracetamol are used over several days; regular monitoring of the International Normalized Ratio (INR) is recommended. Single doses of paracetamol do not have a significant effect. If necessary, the dose of oral anticoagulant should be adjusted during paracetamol treatment.

Diclofenac and other NSAIDs: increased serum paracetamol levels, raising the risk of hepatotoxicity and nephrotoxicity.

Isoniazid, rifampicin, other hepatotoxic agents: increased risk of developing hepatotoxic syndrome.

Flucloxacillin: paracetamol should be used with caution when administered concomitantly with flucloxacillin, as co-administration 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").

Diuretics: paracetamol reduces their effectiveness.

Antiviral agents: regular use of paracetamol may reduce zidovudine metabolism (increased risk of neutropenia).

Interaction with diagnostic tests: paracetamol may interfere with blood uric acid determination when using the phosphotungstic acid method, and with blood glucose determination by the oxidase-peroxidase method.

Special precautions for use.

Do not use simultaneously with other medicinal products containing paracetamol, which are used, for example, to reduce fever, treat pain, symptoms of flu and colds, 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.

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 patients with malnutrition or other sources of glutathione deficiency (e.g., chronic alcoholism), who received paracetamol at therapeutic doses for prolonged periods or in combination with flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol and careful monitoring are recommended. Measurement of urinary 5-oxoproline may be helpful in identifying pyroglutamic acidosis as the underlying cause of HAGMA in patients with risk factors.

Consult a physician before using the medicine.

Do not exceed the recommended dose or duration of treatment.

Maximum duration of use without medical consultation is 3 days.

If symptoms persist or worsen, consult a physician immediately.

Patients taking analgesics daily for mild forms of arthritis should consult a physician before using this medicine. When treating with paracetamol at a dose of 60 mg/kg/day, concomitant use of another antipyretic is justified only if paracetamol is insufficiently effective.

Consult a physician before using paracetamol if the patient is taking warfarin or similar anticoagulant agents.

Use with caution in patients with hepatic or renal disease (consult a physician before use in such cases). Note that patients with liver disorders, including non-cirrhotic alcoholic liver disease, have an increased risk of hepatotoxic effects of paracetamol.

Hepatic function impairment/liver failure has been reported in patients with reduced glutathione levels, such as in severe malnutrition, anorexia, low body mass index, or chronic alcoholism. In patients with reduced glutathione levels, e.g., in severe infections such as sepsis, paracetamol use increases the risk of metabolic acidosis. Symptoms of metabolic acidosis include deep, rapid, or labored breathing, nausea, vomiting, and loss of appetite. Seek immediate medical attention if these symptoms occur.

With prolonged use of the medicine, monitoring of peripheral blood count and liver and kidney function is required (the role of paracetamol has not been fully excluded in the development of analgesic-associated nephropathy).

The medicine contains sorbitol (E 420); therefore, patients with rare hereditary fructose intolerance should not use this medicine. It may also cause a mild laxative effect.

The medicine contains Ponceau 4R (E 124), methylparahydroxybenzoate, and propylparahydroxybenzoate, which may cause allergic reactions (possibly delayed-type).

The medicine contains ethanol (alcohol) (125 mg of 96% ethanol in 5 ml of syrup). It is harmful for patients suffering from alcoholism. Exercise caution when administering to pregnant women, breastfeeding women, children, patients with liver disease, and patients with epilepsy.

The medicine may affect laboratory test results for blood glucose and uric acid levels.

Use during pregnancy or breastfeeding.

There are no standard studies conducted according to currently accepted standards for evaluating reproductive and ontogenetic toxicity.

Extensive data on the use of paracetamol in pregnant women do not indicate any malformative or fetal/neonatal toxicity. Epidemiological studies on the development of the nervous system in children exposed to paracetamol in utero show inconclusive results. If paracetamol use is clinically necessary, it may be used during pregnancy, but at the lowest effective dose, for the shortest possible duration, and with the lowest possible frequency.

This medicinal product is intended for use in children.

Ability to affect reaction speed when driving or operating machinery.

This medicinal product is intended for use in children.

Method of administration and dosage.

The medication is intended for oral use only. The dose of paracetamol for all children is calculated based on age and body weight. The lowest effective dose required to achieve the therapeutic effect should be used.

The single dose of paracetamol is 10–15 mg/kg body weight. The maximum daily dose of paracetamol is 60 mg/kg body weight.

The medication may be repeated every 4–6 hours if necessary. Do not administer more than 4 doses within 24 hours. The interval between doses should be at least 4 hours. The maximum duration of treatment without consulting a physician is 3 days.

Children aged 6 months to 12 years.

Find the appropriate dose corresponding to the child's age in the table below. Measure the dose using the dosing spoon provided, which has markings for 2.5 mL and 5 mL.

Single doses of paracetamol syrup 120 mg/5 mL for children

Children.

The drug is contraindicated for use in children under 6 months of age. This medicinal form should be used in children aged from 6 months to 12 years.

Overdose.

Hepatic injury is possible in adults who have taken 10 g or more of paracetamol; in children who have taken more than 150 mg/kg body weight.

In patients with risk factors, ingestion of 5 g or more of paracetamol may lead to liver damage. Paracetamol overdose can cause hepatic failure, which may necessitate liver transplantation or result in fatal outcome.

Risk factors:

• prolonged treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John's wort preparations, or other drugs inducing liver enzymes;
• chronic excessive ethanol consumption;
• glutathione depletion (digestive disorders, cystic fibrosis, HIV infection, fasting, cachexia).

Symptoms of overdose within the first 24 hours: pallor, nausea, vomiting, anorexia, and abdominal pain, increased activity of "liver" transaminases and prolonged prothrombin time. Liver damage may become evident 12–48 hours after overdose. Glucose metabolism disturbances and metabolic acidosis, hepatocellular insufficiency, and hepatonecrosis may occur. In severe poisoning, hepatic failure may progress to hypoglycemia, encephalopathy, hemorrhages, cerebral edema, coma, and death.

Acute renal failure with acute tubular necrosis, accompanied by severe back pain, hematuria, and proteinuria, may develop even in the absence of severe liver injury.

With high-dose use, the following may occur:

• nervous system – dizziness, psychomotor agitation or central nervous system depression, disorientation and attention disturbances, insomnia/somnolence, tremor, nervousness, restlessness, impaired consciousness, hyperreflexia, seizures;
• urinary system – nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis).

Overdose may also lead to cardiac arrhythmias (including tachycardia, extrasystoles) and pancreatitis, usually accompanied by liver function abnormalities and hepatotoxicity, as well as increased sweating.

With prolonged use of high doses, aplastic anemia, thrombocytopenia, pancytopenia, agranulocytosis, neutropenia, and leukopenia may develop.

Treatment. In case of overdose (even if asymptomatic), prompt medical assistance and immediate hospitalization are required. Symptoms may be limited to nausea or vomiting and may not reflect the severity of overdose or risk of organ damage.

Plasma paracetamol concentration should be measured at least 4 hours or later after ingestion (earlier measurements are unreliable).

Within the first hour after ingestion of a large paracetamol dose, gastric lavage, induction of emesis, or administration of activated charcoal should be performed.

Acetylcysteine treatment should be initiated within 24 hours after paracetamol ingestion, but maximum protective effect is achieved when administered within 8 hours after overdose. The efficacy of the antidote decreases sharply after this time. Intravenous acetylcysteine should be administered according to the established dosing regimen. In the absence of vomiting, oral methionine may be used as an alternative in areas remote from hospitals.

Symptomatic measures should also be implemented.

Adverse Reactions.

Immune system: hypersensitivity reactions and anaphylactic reactions, including skin and mucous membrane rashes (usually generalized, erythematous rash; urticaria may occur due to the presence of methyl- and propylparahydroxybenzoates in the formulation), pruritus, angioneurotic edema, exudative multiform erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome). If rash occurs, the drug must be discontinued immediately.

Respiratory system: bronchospasm in patients sensitive to acetylsalicylic acid and other NSAIDs.

Nervous system (usually occurs with high-dose administration): dizziness, psychomotor agitation, disorientation.

Gastrointestinal system: nausea, epigastric pain, liver function disturbances, increased activity of "liver" enzymes in blood serum, usually without jaundice development; hepatonecrosis (dose-dependent effect); cases of acute pancreatitis have been reported (usually in cases of overdose). The product contains sorbitol, which may cause a mild laxative effect.

Endocrine system: hypoglycemia; hypoglycemic coma may develop.

Blood and lymphatic system: anemia, sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), hemolytic anemia. With prolonged use at doses exceeding therapeutic levels — aplastic anemia, pancytopenia, thrombocytopenia, which may lead to bruising, hemorrhages, including nosebleeds and/or gingival bleeding; leukopenia, neutropenia, agranulocytosis.

Urinary system: with high-dose administration — nephrotoxic effects (renal colic, interstitial nephritis, papillary necrosis), aseptic pyuria.

Metabolic and nutritional disorders: 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 receiving paracetamol (see section "Special precautions"). Pyroglutamic acidosis may occur as a result of low glutathione levels in these patients.

Adverse effects associated with paracetamol use are rare and depend on the dose and duration of treatment.

If any adverse effects occur, administration of the drug must be discontinued immediately.

Reporting of suspected adverse reactions

Reporting of adverse reactions following drug registration is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

3 years.

After opening the bottle, the shelf life of the product is 30 days at a temperature of 20–25 °C.

Storage conditions.

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

Keep out of reach of children.

Packaging.

50 mL in a bottle, 1 bottle per carton with a dosing spoon; 100 mL in a bottle or jar, 1 bottle or jar per carton with a dosing spoon.

Availability.

Over-the-counter.

Manufacturer.

Public Joint-Stock Company "Scientific-Production Center "Borshchahivskiy Chemical-Pharmaceutical Plant".

Manufacturer's address and location of operations.

17, Miru Street, Kyiv, 03134, Ukraine.