Paracetamol-darnitsa
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PARACETAMOL-DARNITSA (PARACETAMOL-DARNITSA)
Composition:
Active substance: paracetamol;
One tablet contains 500 mg of paracetamol;
Excipients: pregelatinized starch, povidone, microcrystalline cellulose, sodium croscarmellose, calcium stearate.
Pharmaceutical form. Tablets.
Main physico-chemical properties: white or almost white tablets, flat cylindrical 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 is high, nearly 100%. In systemic circulation, 15% of the absorbed drug binds to plasma proteins. Time to reach maximum plasma concentration (Tmax) is 20–30 minutes. A therapeutically effective plasma concentration of paracetamol is achieved at doses of 10–15 mg/kg. Paracetamol penetrates the blood-brain barrier and is excreted into breast milk. The amount of the drug in breast milk is less than 1% of the dose taken by the nursing mother. It is metabolized in the liver: 80% undergoes conjugation with glucuronic acid and sulfates, forming inactive metabolites. About 17% of the drug undergoes hydroxylation, forming reactive metabolites that conjugate with glutathione to form inactive compounds. In glutathione deficiency, these metabolites may block hepatic enzyme systems and cause 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, with 3% excreted unchanged.
Clinical characteristics.
Indications.
Headache, including migraine and tension headache, dental pain, back pain, rheumatic pain, muscle pain, menstrual pain in women, moderate pain associated with arthritis; relief of fever and pain symptoms associated with cold and flu.
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 intake.
The anticoagulant effect of warfarin and other coumarins, increasing the risk of bleeding, may be enhanced during prolonged concomitant use of paracetamol. Occasional use does not have a significant effect.
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 formation of hepatotoxic metabolites. Concomitant use of paracetamol with hepatotoxic agents increases the risk of liver toxicity. Concurrent use of high doses of paracetamol with isoniazid increases the risk of hepatotoxic syndrome.
Probenecid reduces paracetamol clearance by half by inhibiting its conjugation with glucuronic acid; therefore, when used in combination with probenecid, the dose of paracetamol should be reduced.
Paracetamol should be used cautiously 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 high anion gap metabolic acidosis, particularly in patients with risk factors.
Paracetamol reduces the effectiveness of diuretics.
Do not use concomitantly with alcohol.
Special precautions for use.
Do not exceed the recommended doses. Do not take the medication with other products containing paracetamol, as this may lead to overdose. Paracetamol overdose can cause liver failure, which may require liver transplantation or result in death.
It should be noted that in patients with alcoholic non-cirrhotic liver disease, the risk of hepatotoxic effects of paracetamol is increased.
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.
Medical advice should be sought 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 accompanied by 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, immediate medical attention is required.
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 impairment, sepsis, malnutrition, and other sources of glutathione deficiency (e.g., chronic alcoholism), as well as those taking the maximum daily doses of paracetamol. Close monitoring is recommended, including measurement of urinary 5-oxoproline.
The drug may affect laboratory test results for blood glucose and uric acid levels.
Alcoholic beverages must not be consumed during treatment with paracetamol.
If symptoms persist, medical advice should be sought.
Use during pregnancy or breastfeeding.
Pregnancy. The use of this medication 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, consultation with a physician is recommended before using paracetamol during pregnancy. A large amount of data on pregnant women does not indicate any malformative or fetal/neonatal toxicity. Epidemiological studies on the neurodevelopmental outcomes in children exposed to paracetamol in utero have not provided conclusive results. If clinically necessary, paracetamol may be used during pregnancy, but it 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 any contraindications to breastfeeding.
Ability to influence reaction speed when driving or operating machinery.
No effect.
Dosage and Administration.
The medicinal product is intended for oral administration.
Adults and children aged 12 years and older: 1−2 tablets 4 times daily as needed. Do not take more than 8 tablets (4000 mg) within 24 hours.
Children (6−12 years of age): ½−1 tablet 3−4 times daily as needed.
The single dose of paracetamol is 10−15 mg/kg body weight; the maximum daily dose is 60 mg/kg body weight. Do not take more than 4 doses within 24 hours.
The maximum duration of use in children without prior medical consultation is 3 days.
The interval between doses should be at least 4 hours.
Do not exceed the recommended dose.
Do not take together with other medicinal products containing paracetamol.
Children.
Do not use in children under 6 years of age.
Overdose.
Paracetamol overdose may cause liver failure, which may necessitate liver transplantation or result in death. Clinical signs of liver damage following paracetamol overdose usually 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 have ingested 10 g or more of paracetamol, and in children who have ingested more than 150 mg/kg body weight. 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., digestive disorders, cystic fibrosis, HIV infection, fasting, 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.
Acute paracetamol overdose in adults and children, following a single ingestion, 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 manifest as severe flank pain, hematuria, proteinuria, and may develop even in the absence of severe liver injury. 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. High-dose intake may also cause central nervous system effects such as dizziness, psychomotor agitation, and disorientation. Urinary system effects may include nephrotoxicity (renal colic, interstitial nephritis, capillary necrosis).
Treatment: in case of overdose, prompt medical attention is required. The patient should be taken to hospital immediately, even if no early symptoms of overdose are present, as liver damage may not develop immediately. Symptoms may be limited to nausea and vomiting and may not reflect the severity of overdose or risk of organ damage. Activated charcoal should be considered if the excessive dose of paracetamol was ingested within the past hour. Plasma paracetamol concentration should be measured at least 4 hours after ingestion (earlier concentrations 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, N-acetylcysteine should be administered intravenously according to current guidelines. In the absence of vomiting, oral methionine may be used as an appropriate alternative in remote areas outside hospital settings.
Symptomatic treatment should also be provided.
Side effects.
If side effects occur, the use of the medicinal product must be discontinued and immediate medical advice should be sought.
Side effects of paracetamol are rare (< 1/10,000):
Respiratory system: bronchospasm in patients sensitive to acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs.
Gastrointestinal system: 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, rashes on the 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 suspected adverse reactions.
Reporting suspected adverse reactions after the medicinal product is authorized is an important procedure. It allows continued 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 the reach of children.
Packaging.
10 tablets in a blister pack; 1 blister pack in a carton; 10 tablets in blister packs.
Availability.
Over-the-counter – tablets № 10.
Manufacturer. JSC "Pharmaceutical company "Darnytsia".
Manufacturer's address and location of its business activity.
13, Boryspylska Street, Kyiv, 02093, Ukraine.