Paracetamol-darnitsa
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PARACETAMOL-DARNITSA (PARACETAMOLO-DARNITSA)
Composition:
Active substance: paracetamol;
One tablet contains 200 mg of paracetamol;
Excipients: pregelatinized starch, povidone, microcrystalline cellulose, sodium croscarmellose, calcium stearate.
Pharmaceutical form. Tablets.
Main physicochemical properties: tablets are white or almost white, flat cylindrical in shape, with beveled edges and a score line. A greyish tint is permissible.
Pharmacotherapeutic group.
Analgesics and antipyretics. Anilides. Paracetamol. ATC code N02BE01.
Pharmacological Properties.
Pharmacodynamics.
A non-narcotic analgesic. Non-selectively inhibits cyclooxygenase (COX), affecting pain and thermoregulation centers. In inflamed tissues, cellular peroxidases neutralize the effect of paracetamol on COX, which explains its minimal anti-inflammatory effect. The absence of influence on prostaglandin synthesis in peripheral tissues accounts for the lack of negative impact of paracetamol on water-electrolyte balance (sodium and water retention) and gastrointestinal mucosa. The possibility of methemoglobin and sulfhemoglobin formation is unlikely.
Pharmacokinetics.
Absorption – high, nearly 100%. In systemic circulation, 15% of the absorbed drug is bound to plasma proteins. Time to reach maximum plasma concentration (TCmax) is 20–30 minutes. Therapeutically effective plasma concentrations of paracetamol are achieved at doses of 10–15 mg/kg. Paracetamol crosses the blood-brain barrier and is excreted into breast milk. The amount of drug in breast milk is less than 1% of the dose administered to the nursing mother. It is metabolized in the liver: 80% undergoes conjugation with glucuronic acid and sulfates, forming inactive metabolites. 17% of the drug undergoes hydroxylation, forming active metabolites that conjugate with glutathione to form inactive metabolites. In glutathione deficiency, these metabolites may block hepatic enzyme systems and lead to hepatocyte necrosis. The elimination half-life (T1/2) of paracetamol is 2–3 hours. In elderly patients, drug clearance is reduced and T1/2 is prolonged. Excretion occurs via the kidneys – 3% unchanged.
Clinical characteristics.
Indications.
Mild to moderate pain of various origins (headache, including migraine and tension headache, back pain, rheumatic pain, muscle pain, menstrual pain in women, neuralgia, toothache). Relief of symptoms associated with colds and influenza, such as fever and malaise.
Contraindications.
Hypersensitivity to the components of the drug, severe impairment of liver and/or kidney function, congenital hyperbilirubinemia, glucose-6-phosphate dehydrogenase deficiency, alcoholism, blood disorders, Gilbert's syndrome, severe anemia, leukopenia.
Interaction with other medicinal products and other forms of interaction.
The absorption rate of paracetamol may be increased when used concomitantly with metoclopramide and domperidone, and decreased when used with cholestyramine.
Paracetamol should be administered 1 hour before or 4–6 hours after cholestyramine.
The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular use of paracetamol, increasing the risk of bleeding. Occasional use does not have a significant effect.
Barbiturates reduce the antipyretic effect of paracetamol.
Anticonvulsant agents (including phenytoin, barbiturates, carbamazepine), which stimulate hepatic microsomal enzyme activity, 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 their hepatotoxic potential. Concurrent use of high doses of paracetamol with isoniazid increases the risk of developing hepatotoxic syndrome.
Probenecid reduces paracetamol clearance by half by blocking its conjugation with glucuronic acid; therefore, when used in combination with probenecid, the dose of paracetamol should be reduced.
Paracetamol should be used with caution together with chloramphenicol due to prolonged elimination half-life and increased toxicity of the latter.
Caution is advised when using paracetamol concomitantly with flucloxacillin, as co-administration has been associated with metabolic acidosis with a high anion gap, particularly in patients with risk factors.
Paracetamol reduces the effectiveness of diuretics.
Do not use concurrently with alcohol.
Special precautions for use.
Do not exceed the recommended doses. Do not take this medicinal product with other products containing paracetamol, as this may lead to overdose. Paracetamol overdose may cause liver failure, which may necessitate liver transplantation or result in fatal outcome.
It should be noted that patients with liver disease have an increased risk of hepatotoxic effects of paracetamol.
Cases of impaired liver function/liver failure have been reported in patients with reduced glutathione levels, such as those with severe malnutrition, anorexia, low body mass index, chronic alcoholism, or sepsis.
Consult a physician regarding the possibility of using the medicinal product:
- in patients with impaired kidney or liver function;
- in patients taking warfarin or similar anticoagulant agents;
- in patients using analgesics for mild forms of arthritis;
− if headache becomes persistent.
In patients with severe infections such as sepsis, which are associated with reduced glutathione levels, the use of paracetamol increases the risk of metabolic acidosis. Symptoms of metabolic acidosis include deep, rapid, or labored breathing, nausea, vomiting, and loss of appetite. If these symptoms occur, seek immediate medical attention.
Caution is advised when using paracetamol concomitantly with flucloxacillin due to an increased risk of high anion gap metabolic acidosis, particularly in patients with severe renal insufficiency, sepsis, malnutrition, and other sources of glutathione deficiency (e.g., chronic alcoholism), as well as in those taking maximum daily doses of paracetamol. Careful monitoring is recommended, including measurement of urinary 5-oxoproline.
The medicinal product may affect laboratory test results for blood glucose and uric acid levels.
With prolonged use of paracetamol, monitoring of peripheral blood picture and liver function is required.
In patients with alcoholic liver disease, the risk of hepatotoxic effects of paracetamol is increased. Alcohol consumption must be avoided during treatment with paracetamol.
If symptoms do not resolve, consult a physician.
Use during pregnancy or breastfeeding.
Pregnancy. The use of this medicinal product during pregnancy is possible only if the expected benefit to the mother outweighs the potential risk to the fetus or infant.
As with other medicinal products, consult a physician before using paracetamol during pregnancy. A substantial amount of data in pregnant women does not indicate teratogenic or fetal/neonatal toxic effects. Epidemiological studies on the neurodevelopmental outcomes in children exposed to paracetamol in utero have not provided conclusive results. Paracetamol may be used during pregnancy if clinically necessary, but should be administered at the lowest effective dose, for the shortest duration, and with the lowest possible frequency.
Breastfeeding period. Paracetamol passes into breast milk, but in clinically insignificant amounts. Available published data do not contain contraindications to breastfeeding.
Ability to affect reaction speed when driving or operating machinery.
Does not affect.
Dosage and Administration
Take orally with a large amount of fluid, 1–2 hours after a meal (taking immediately after a meal may prolong absorption time).
For adults and children aged 12 years and older (body weight over 40 kg): the single dose is 400–1000 mg; frequency of administration – up to 4 times daily as needed. Do not exceed 4000 mg within 24 hours. For patients with hepatic or renal impairment and for elderly patients, the daily dose should be reduced and the interval between doses increased.
For children aged 3 years and older: administer at a dose of 10–15 mg/kg (single dose). The dose may be repeated every 6 hours (up to 4 times daily) as needed.
Maximum daily dose for children: aged 3 to 6 years (up to 22 kg) – 1000 mg; aged 6 to 9 years (up to 30 kg) – 1500 mg; aged 9 to 12 years (up to 40 kg) – 2000 mg. Maximum duration of use in children without medical consultation – 3 days.
Do not exceed the recommended dose.
Do not take with other medicinal products containing paracetamol.
Children
This medicinal form is not recommended for children under 3 years of age.
Overdose
Paracetamol overdose can cause liver failure, which may necessitate liver transplantation or result in death. Clinical signs of liver damage after paracetamol overdose typically appear within 24–48 hours after ingestion and peak at 4–6 days.
There is an increased risk of paracetamol poisoning, particularly in elderly patients, children, patients with liver disease, chronic alcoholism, and chronic malnutrition.
Liver damage is possible in adults who ingest 10 g or more of paracetamol and in children who ingest more than 150 mg/kg body weight. In patients with risk factors (long-term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John's wort, or other drugs inducing liver enzymes; regular consumption of excessive amounts of ethanol; glutathione depletion due to malnutrition, cystic fibrosis, HIV infection, starvation, or cachexia), ingestion of 5 g or more of paracetamol may lead to liver damage.
Symptoms within the first 24 hours: pallor, nausea, vomiting, loss of appetite, and abdominal pain; however, overdose may also be asymptomatic.
Overdose following a single ingestion of paracetamol in adults and children may cause reversible or irreversible hepatocellular necrosis, leading to disturbances in glucose metabolism, metabolic acidosis, hepatocellular failure, encephalopathy, hemorrhage, hypoglycemia, coma, and potentially death. Within 12–48 hours after ingestion, elevated levels of liver transaminases (aspartate aminotransferase, alanine aminotransferase), lactate dehydrogenase, bilirubin, and prothrombin time may occur.
Acute renal failure with acute tubular necrosis may present with severe flank 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 side effects may include aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia. High-dose use may also affect the central nervous system, causing dizziness, psychomotor agitation, and disorientation. Effects on the urinary system may include nephrotoxicity (renal colic, interstitial nephritis, cortical necrosis).
Treatment: immediate medical intervention is required in case of overdose. The patient should be taken to hospital immediately, even if early symptoms are absent, as liver damage may not develop immediately. Symptoms such as nausea and vomiting may be mild and not reflect the severity of overdose or risk of organ damage. Consider treatment with activated charcoal if excessive paracetamol was ingested within the past hour. Plasma paracetamol concentration should be measured 4 hours or more after ingestion (earlier measurements are unreliable). Treatment with N-acetylcysteine may be administered within 24 hours after paracetamol ingestion, but maximum protective effect is achieved when administered within 8 hours after ingestion. The efficacy of the antidote decreases significantly after this time. If required, intravenous N-acetylcysteine should be administered according to current guidelines. In the absence of vomiting, oral methionine may be used as an alternative in remote areas outside hospital settings.
Symptomatic treatment should also be provided.
Adverse reactions.
If adverse reactions occur, discontinue use of the medicinal product and seek immediate medical advice.
Adverse reactions to paracetamol are rare (< 1/10,000):
Respiratory system: bronchospasm in patients sensitive to acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs.
Gastrointestinal tract: nausea, epigastric pain.
Hepatobiliary system: liver function abnormalities, increased liver enzyme activity, usually without development of jaundice.
Endocrine system: hypoglycemia, up to hypoglycemic coma.
Blood and lymphatic system: thrombocytopenia, agranulocytosis, anemia, sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), hemolytic anemia, bruising or bleeding.
Immune system: anaphylaxis, hypersensitivity reactions, including skin itching, rash on skin and mucous membranes (usually generalized rash, erythematous rash, urticaria), angioneurotic edema, multiform exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome).
Reporting of suspected adverse reactions.
Reporting of suspected adverse reactions after medicinal product authorization is an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.
Shelf life. 4 years.
Storage conditions.
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach and sight of children.
Packaging.
10 tablets in a blister pack; 1 or 10 blisters per carton; 10 tablets in blister packs.
Dispensing category.
Without prescription – tablets pack of 10. By prescription only – tablets (pack of 10×10).
Manufacturer: JSC "Pharmaceutical company "Darnitsya".
Manufacturer's address and place of business:
13, Boryspylska Street, Kyiv, 02093, Ukraine.