Paracetamol altan

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PARACETAMOL ALTAN

Composition:

Active substance: paracetamol;

1 ml contains 10 mg of paracetamol;

Excipients: glucose monohydrate, sodium acetate trihydrate, acetic acid, sodium citrate dihydrate, hydrochloric acid, sodium hydroxide, water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear, colorless or slightly amber-yellow solution.

Pharmacotherapeutic group. Analgesics and antipyretics. ATC code N02BE01.

Pharmacological properties.

Pharmacodynamics.

The precise mechanism of the analgesic and antipyretic effects of paracetamol has not yet been fully established; it may involve both central and peripheral actions.

Paracetamol provides pain relief within 5–10 minutes after administration. Peak analgesic effect is reached within 1 hour, and the duration of this effect usually lasts 4–6 hours.

The drug reduces body temperature within 30 minutes after administration; the antipyretic effect persists for at least 6 hours.

Pharmacokinetics.

Adults

Absorption. After single administration of up to 2 g of the drug and after repeated administration within 24 hours, the pharmacokinetics of paracetamol are linear.

The bioavailability after intravenous infusion of 1 g paracetamol is equivalent to that after administration of 2 g propacetamol (which contains 1 g paracetamol). Maximum plasma concentration (C_max) is achieved at the end of a 15-minute infusion of 1 g paracetamol and amounts to 30 µg/mL.

Distribution. The volume of distribution of paracetamol is approximately 1 L/kg. Paracetamol is weakly bound to plasma proteins. A significant concentration level (about 1.5 µg/mL) was detected in cerebrospinal fluid 20 minutes after infusion following administration of 1 g paracetamol.

Metabolism. Paracetamol is extensively metabolized in the liver via two main pathways: conjugation with glucuronic acid and conjugation with sulfuric acid. The latter pathway becomes rapidly saturated at doses exceeding therapeutic levels. A small fraction (less than 4%) is metabolized by cytochrome P450 to form a reactive intermediate metabolite (N-acetylbenzoquinoneimine), which under normal conditions is rapidly detoxified by reduced glutathione and excreted in urine after conjugation with cysteine and mercapturic acid. However, in cases of massive overdose, the amount of this toxic metabolite increases.

Excretion. Paracetamol metabolites are primarily excreted in urine. About 90% of the administered dose is eliminated within 24 hours, predominantly as glucuronide conjugates (60–80%) and sulfate conjugates (20–30%). Less than 5% is excreted unchanged. Elimination half-life is 2.7 hours, and total clearance is 18 L/h.

Special patient groups

Patients with renal impairment. In severe renal impairment (creatinine clearance 10–30 mL/min), elimination of paracetamol is somewhat delayed, and elimination half-life ranges from 2 to 5.3 hours. The rate of excretion of glucuronide and sulfate metabolites in patients with severe renal impairment is three times slower compared to healthy volunteers. Therefore, in patients with severe renal impairment (creatinine clearance ≤ 30 mL/min), the minimum dosing interval should be extended to 6 hours.

Elderly patients. The pharmacokinetics and metabolism of paracetamol in elderly patients are not altered. Dose adjustment is not required.

Clinical characteristics.

Indications.

For short-term treatment of moderate pain, particularly following surgery.

For short-term treatment of fever when intravenous administration is clinically justified by an urgent need to treat pain or hyperthermia, or when other routes of administration are not feasible.

Contraindications.

Hypersensitivity to paracetamol, propacetamol hydrochloride (a paracetamol prodrug), or any other components of the medicinal product. Severe hepatocellular insufficiency.

Interaction with other medicinal products and other forms of interactions.

Probenecid causes an almost twofold reduction in paracetamol clearance by inhibiting its conjugation with glucuronic acid. When paracetamol is used concomitantly with probenecid, consideration should be given to reducing the paracetamol dose.

Salicylamide may prolong the elimination half-life of paracetamol.

Caution is advised when paracetamol is used concomitantly with enzyme-inducing agents (see section "Overdose").

Concomitant use of paracetamol (4 g daily for at least 4 days) with oral anticoagulants may lead to minor changes in INR (International Normalized Ratio) values. In such cases, careful monitoring of INR values should be performed throughout the period of concomitant use and for 1 week after discontinuation of paracetamol treatment.

When used concomitantly with hormonal contraceptives, the elimination of paracetamol from the body may be accelerated, possibly reducing its analgesic effect.

Anticonvulsants (phenytoin, phenobarbital, methylphenobarbital, primidone) reduce paracetamol bioavailability and enhance hepatotoxicity.

Concomitant use with chloramphenicol may enhance chloramphenicol toxicity, likely due to inhibition of its hepatic metabolism.

When used concomitantly with lamotrigine, a moderate increase in lamotrigine elimination from the body may occur.

Concomitant use with metoclopramide or domperidone may increase paracetamol absorption in the small intestine.

Concomitant use with rifampicin may increase paracetamol clearance due to enhanced hepatic metabolism.

Increased toxicity of zidovudine (neutropenia, hepatotoxicity) may occur when used concomitantly with paracetamol.

Caution is required when paracetamol is used concomitantly with flucloxacillin, as such concomitant use 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").

Special precautions for use.

Prolonged or frequent use of the medicinal product is not recommended. Appropriate oral analgesic therapy should be used as soon as this route of administration becomes feasible.

To avoid overdose, it is necessary to check whether other medicinal products being administered contain paracetamol or propacetamol. Dosage may require adjustment (see section "Method of administration and dosage").

Administration of the drug in doses exceeding the recommended ones may result in a risk of severe liver damage. Clinical signs and symptoms of liver injury (including fulminant hepatitis, hepatic failure, cholestatic hepatitis, cytolytic hepatitis) typically become apparent only 2 days after drug administration, with peak severity usually occurring on days 4–6. Antidote treatment should be initiated as soon as possible (see section "Overdose").

Paracetamol may cause serious skin reactions. Patients should be informed about early signs of serious skin reactions, and administration of the drug should be discontinued at the first appearance of skin rash or any other signs of hypersensitivity.

Cases of high anion gap metabolic acidosis due to pyroglutamic acidosis have been reported in patients with severe underlying conditions such as severe renal insufficiency and sepsis, as well as in patients with inadequate nutrition or other causes of glutathione deficiency (e.g., chronic alcoholism) who received paracetamol at therapeutic doses for prolonged periods or a combination of paracetamol and flucloxacillin. If high anion gap metabolic acidosis due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol is recommended, along with careful monitoring of the patient's condition. Measurement of urinary 5-oxoproline levels may be helpful in identifying pyroglutamic acidosis as the underlying cause of high anion gap metabolic acidosis in patients with multiple risk factors.

Paracetamol should be administered with caution in patients with:

• hepatocellular insufficiency;
• severe renal insufficiency (creatinine clearance ≤ 30 mL/min) (see sections "Method of administration and dosage" and "Pharmacokinetics");
• chronic alcoholism;
• chronic malnutrition (low hepatic glutathione stores);
• dehydration;
• Gilbert's syndrome;
• genetically determined glucose-6-phosphate dehydrogenase deficiency — hemolytic anemia may occur due to reduced glutathione availability following paracetamol administration.

Excipients. This medicinal product contains less than 1 mmol of sodium (23 mg) per 100 mL of solution, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

Extensive data on the use of paracetamol in pregnant women confirm the absence of teratogenic effects or fetal/neonatal toxicity.

Epidemiological studies on neurodevelopmental outcomes in children exposed to paracetamol in utero have yielded inconclusive results. Reproductive studies with intravenous paracetamol in animals have not been conducted. Studies with the oral form have not demonstrated developmental abnormalities or fetotoxic effects. Nevertheless, paracetamol should be used during pregnancy only when the expected benefit to the mother outweighs the potential risk to the fetus or child and when there is a clinical need. In such cases, it should be administered at the lowest effective dose, for the shortest duration, and with the least frequency possible.

Breastfeeding

After oral administration, paracetamol is excreted in breast milk in small amounts. No adverse effects in infants have been observed during paracetamol use in breastfeeding women.

Ability to affect reaction speed when driving or operating machinery.

No effect.

Method of administration and dosage.

The medicinal product should be administered intravenously.

PARACETAMOL ALTAN is intended for use in adults, adolescents, and children with body weight exceeding 33 kg.

Dosage depends on the patient's body weight.

Table 1

* The maximum daily dose is intended for patients who are not receiving other medicinal products containing paracetamol and should be appropriately adjusted if such products are taken.

** Patients with lower body weight require smaller volumes.

Paracetamol solution should be administered by intravenous infusion over 15 minutes.

The minimum interval between doses should be 4 hours. The treatment course usually does not exceed 4 infusions within 24 hours.

The minimum dosing interval in patients with severe renal impairment should be at least 6 hours.

Prior to administration, ensure that the solution is clear and free from visible particles. Do not use solutions containing visible foreign matter.

Any unused medicinal product remaining after administration must be discarded.

Special patient groups

Patients with severe renal impairment

When administering paracetamol to patients with severe renal impairment (creatinine clearance ≤ 30 mL/min), it is recommended to extend the minimum dosing interval to 6 hours.

Patients with hepatic insufficiency, chronic alcoholism, chronically undernourished patients (low hepatic glutathione stores), dehydrated patients, Gilbert's syndrome, and patients with body weight below 50 kg

The maximum daily dose should not exceed 3 g.

Elderly patients

Elderly patients generally do not require dose adjustment.

Children

Do not use in children with body weight below 33 kg.

Overdose

There is a risk of liver damage (including fulminant hepatitis, hepatic failure, cholestatic hepatitis, cytolytic hepatitis), especially in elderly individuals, young children, patients with liver disease, chronic alcoholism, chronic malnutrition, and those with reduced enzymatic activity. In these cases, overdose may be fatal.

Symptoms appear within the first 24 hours and manifest as nausea, vomiting, anorexia, pallor, and abdominal pain.

Overdose in adults may occur after a single dose of 7.5 g, and in children after a dose of 140 mg/kg body weight. This leads to hepatic cytolysis, liver failure, metabolic acidosis, and encephalopathy, which may progress to coma and death. Within 12–48 hours, levels of hepatic transaminases (alanine aminotransferase, aspartate aminotransferase), lactate dehydrogenase, bilirubin increase, and prothrombin levels decrease.

Clinical signs of liver damage appear after 2 days and peak at 4–6 days. Doses exceeding 20–25 g are potentially fatal.

Emergency measures:

• Immediate hospitalization;
• Prompt measurement of plasma paracetamol concentration as soon as possible after overdose, prior to initiating treatment;
• Intravenous or oral administration of the antidote N-acetylcysteine (NAC), preferably within 10 hours of overdose. NAC may still be administered later than 10 hours post-overdose, although treatment duration will need to be prolonged;
• Symptomatic treatment.

Liver function tests must be performed prior to initiating treatment and repeated every 24 hours. In most cases, hepatic transaminase levels return to normal within one to two weeks, with complete recovery of liver function. In rare cases, liver transplantation may be required.

Adverse reactions.

As with the use of other products containing paracetamol, adverse reactions occurred rarely (> 1/10,000 — < 1/1,000) or very rarely (< 1/10,000) — see Table 2.

In clinical studies, frequent (≥ 1/100 — < 1/10) adverse reactions at the site of administration (pain and burning) were reported in patients.

Table 2

*Very rare cases of hypersensitivity reactions such as anaphylactic shock, urticaria, and skin rashes requiring discontinuation of treatment have been reported.

**During the post-marketing period, when paracetamol was used concomitantly with flucloxacillin; usually in the presence of risk factors.

***Very rare cases of serious skin reactions requiring discontinuation of treatment have been reported.

Description of selected adverse reactions

Cases of metabolic acidosis with a high anion gap due to 5-oxoproline acidosis (pyroglutamic acidosis) have been observed in patients with risk factors who were taking paracetamol (see section "Special precautions for use"). 5-Oxoproline acidosis may occur due to low glutathione levels in these patients.

Reporting of adverse reactions following marketing authorization is important. It allows ongoing monitoring of the benefit-risk balance of this medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 1.5 years.

Storage conditions.

Store at temperatures not exceeding 25 °C, in a place protected from light and inaccessible to children.

Incompatibilities.

The medicinal product must not be mixed with other medicinal products.

Packaging.

100 ml in a container, placed in a protective outer packaging.

Prescription category. Prescription only.

Manufacturer.

ALTAAN FARMACÉUTICA, S.A.

Manufacturer's address and location of its operations.

Polígono Industrial de Bernedo s/n, Bernedo, Álava, 01118, Spain