Daleron (Tablets, Suspension) Instructions for Use

ATC Code

N02BE01 (Paracetamol)

Active Substance

Paracetamol (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Analgesic-antipyretic

Pharmacotherapeutic Group

Non-narcotic analgesic agent

Pharmacological Action

Analgesic-antipyretic. It has antipyretic and analgesic effects. It blocks COX-1 and COX-2 predominantly in the central nervous system, affecting the centers of pain and thermoregulation.

In inflamed tissues, cellular peroxidases neutralize the effect of paracetamol on COX, which explains the almost complete absence of an anti-inflammatory effect.

Since Paracetamol has an extremely minor influence on the synthesis of prostaglandins in peripheral tissues, it does not alter water-electrolyte balance and does not cause damage to the gastrointestinal mucosa.

Pharmacokinetics

After oral administration, Paracetamol is rapidly absorbed from the gastrointestinal tract, mainly in the small intestine, primarily via passive transport. After a single dose of 500 mg, C_max in plasma is reached within 0.5-2 hours and is 5-20 µg/ml.

It is widely distributed in tissues and mainly in body fluids, with the exception of adipose tissue and cerebrospinal fluid.

Protein binding is about 15% and increases slightly in overdose. Sulfate and glucuronide metabolites do not bind to plasma proteins even at relatively high concentrations.

Paracetamol is metabolized primarily in the liver by conjugation with glucuronide, conjugation with sulfate, and oxidation involving mixed-function oxidases of the liver and cytochrome P450.

A hydroxylated metabolite with a negative effect – N-acetyl-p-benzoquinone imine, which is formed in very small amounts in the liver and kidneys under the influence of mixed oxidases and is usually detoxified by binding with glutathione, can accumulate in paracetamol overdose and cause tissue damage.

In adults, most of the paracetamol is bound to glucuronic acid and to a lesser extent to sulfuric acid. These conjugated metabolites have no biological activity. In premature infants, newborns, and in the first year of life, the sulfate metabolite predominates.

T_1/2 is 1-4 hours. The renal clearance of paracetamol is 5%.

It is excreted in the urine mainly as glucuronide and sulfate conjugates. Less than 5% is excreted as unchanged paracetamol.

Indications

Mild to moderate pain syndrome of various origins (including headache, migraine, toothache, neuralgia, myalgia, dysmenorrhea; pain from injuries, burns). Fever in infectious and inflammatory diseases.

ICD codes

Dosage Regimen

Tablets, Suspension

Orally or rectally in adults and adolescents weighing more than 60 kg, a single dose of 500 mg is used, frequency of administration – up to 4 times/day. The maximum duration of treatment is 5-7 days.

Maximum doses single – 1 g, daily – 4 g.

Single oral doses for children aged 6-12 years – 250-500 mg, 1-5 years – 120-250 mg, from 3 months to 1 year – 60-120 mg, up to 3 months – 10 mg/kg. Single doses for rectal use in children aged 6-12 years – 250-500 mg, 1-5 years – 125-250 mg.

Frequency of application – 4 times/day with an interval of at least 4 hours. The maximum duration of treatment is 3 days.

Maximum dose 4 single doses per day.

Adverse Reactions

In therapeutic doses, Paracetamol is usually well tolerated.

The adverse effects listed below were identified spontaneously during post-registration use.

From the blood and lymphatic system often – postoperative bleeding; very rarely – anemia, thrombocytopenia, leukopenia, neutropenia, agranulocytosis, hemolytic anemia; frequency unknown – pancytopenia, sulfhemoglobinemia, methemoglobinemia.

From the immune system rarely – allergic reactions (including skin rash, itching, urticaria, angioedema); very rarely – acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), anaphylaxis.

From the psyche often – insomnia, anxiety.

From the nervous system often – headache; frequency unknown – dystonia, dizziness, psychomotor agitation, disorientation (when taken in high doses).

From the organ of vision often – periorbital edema.

From the cardiovascular system often – tachycardia, chest pain, peripheral edema, arterial hypertension; rarely – decreased blood pressure.

From the respiratory system often – dyspnea, pathological breathing, pulmonary edema, hypoxia, pleural effusion, wheezing, shortness of breath, cough; very rarely – bronchospasm (in patients with hypersensitivity to acetylsalicylic acid and other NSAIDs).

From the digestive system often – diarrhea, constipation, dyspepsia, abdominal bloating; rarely – abdominal pain, nausea, vomiting; frequency unknown – dry mouth.

From the liver and biliary tract rarely – increased activity of liver enzymes; frequency unknown – liver failure, hepatitis, liver necrosis.

From the skin and subcutaneous tissues frequency unknown – exanthema.

From the musculoskeletal system often – muscle spasms, trismus.

From the urinary system often – oliguria; frequency unknown – renal colic, nonspecific bacteriuria, interstitial nephritis, papillary necrosis.

General reactions often – pyrexia, feeling of tiredness; rarely – general malaise/weakness.

Influence on the results of laboratory and instrumental studies often – hypokalemia, hyperglycemia; rarely – decrease or increase in prothrombin index; frequency unknown – increase in creatinine (mainly secondary, in relation to hepatorenal syndrome).

Contraindications

Hypersensitivity to paracetamol, severe liver dysfunction, severe kidney dysfunction.

With caution

Mild to moderate renal failure, mild to moderate hepatic failure, benign hyperbilirubinemia (including Gilbert’s syndrome), dehydration, hypovolemia, anorexia, bulimia, cachexia (insufficient glutathione reserve in the liver), viral hepatitis, glucose-6-phosphate dehydrogenase deficiency, alcoholic liver disease, alcoholism, elderly age, pregnancy, breastfeeding period.

Use in Pregnancy and Lactation

Paracetamol crosses the placental barrier. To date, no negative effects of paracetamol on the human fetus have been observed.

Paracetamol is excreted in breast milk: the content in milk is 0.04-0.23% of the dose taken by the mother.

If it is necessary to use paracetamol during pregnancy and lactation (breastfeeding), the expected benefit of therapy for the mother and the potential risk to the fetus or child should be carefully weighed.

In experimental studies, no embryotoxic, teratogenic or mutagenic effects of paracetamol were established.

Use in Hepatic Impairment

Use with caution in patients with impaired liver function.

Use in Renal Impairment

Use with caution in patients with impaired renal function.

Pediatric Use

Use is possible according to the dosage regimen.

Geriatric Use

Use with caution in elderly patients.

Special Precautions

If improvement is not observed when taking paracetamol or the headache becomes constant, it is necessary to consult a doctor. If the febrile syndrome continues for more than 3 days and the pain syndrome for more than 5 days while using paracetamol, a doctor’s consultation is required.

Patients with glutathione deficiency are susceptible to overdose, precautions must be taken. Glutathione deficiency due to eating disorders, cystic fibrosis, HIV infection, starvation, exhaustion determines the possibility of severe liver damage with small overdoses of paracetamol (5 g or more). Cases of liver failure and impaired liver function have been reported in patients with low glutathione levels, in particular in extremely emaciated patients suffering from anorexia, chronic alcoholism or in patients with low BMI. The risk of liver damage increases in patients with alcoholic liver disease.

Taking paracetamol affects the indicators of laboratory tests in the quantitative determination of glucose and uric acid in plasma.

During long-term treatment, monitoring of the peripheral blood picture and the functional state of the liver is necessary.

At the first appearance of a rash or other hypersensitivity reactions, the use of paracetamol should be discontinued and a doctor should be consulted immediately.

If a patient is found to have acute viral hepatitis, paracetamol should be discontinued.

Do not take simultaneously with other drugs containing Paracetamol.

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.

Influence on the ability to drive vehicles and mechanisms

There are no data on the effect of paracetamol on the ability to drive a car or other mechanisms. However, given the possible adverse reactions, it is recommended to exercise caution when taking paracetamol while driving a car or other mechanisms.

Drug Interactions

With simultaneous use with inducers of microsomal liver enzymes, agents with hepatotoxic effects, there is a risk of increased hepatotoxic effect of paracetamol.

With simultaneous use with anticoagulants, a slight or moderate increase in prothrombin time is possible.

With simultaneous use with anticholinergic agents, a decrease in the absorption of paracetamol is possible.

With simultaneous use with oral contraceptives, the excretion of paracetamol from the body is accelerated and a decrease in its analgesic effect is possible.

With simultaneous use with uricosuric agents, their effectiveness is reduced.

With simultaneous use of activated charcoal, the bioavailability of paracetamol is reduced.

With simultaneous use with diazepam, a decrease in the excretion of diazepam is possible.

There are reports of the possibility of enhancing the myelodepressive effect of zidovudine when used simultaneously with paracetamol. A case of severe toxic liver damage has been described.

Cases of manifestations of the toxic effect of paracetamol when used simultaneously with isoniazid have been described.

With simultaneous use with carbamazepine, phenytoin, phenobarbital, primidone, the effectiveness of paracetamol decreases, which is due to an increase in its metabolism (glucuronidation and oxidation processes) and excretion from the body. Cases of hepatotoxicity have been described with simultaneous use of paracetamol and phenobarbital.

When using cholestyramine for a period of less than 1 hour after taking paracetamol, a decrease in the absorption of the latter is possible.

With simultaneous use with lamotrigine, the excretion of lamotrigine from the body is moderately increased.

With simultaneous use with metoclopramide, an increase in the absorption of paracetamol and an increase in its concentration in blood plasma is possible.

With simultaneous use with probenecid, a decrease in the clearance of paracetamol is possible; with rifampicin, sulfinpyrazone – an increase in the clearance of paracetamol due to an increase in its metabolism in the liver is possible.

With simultaneous use with ethinylestradiol, the absorption of paracetamol from the intestine increases.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Over-the-Counter

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.