Paracetamol agetan 10 mg/ml

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PARACETAMOL AGENTAN 10 mg/ml

Composition:

Active substance: paracetamol;

1 ml of solution contains 10 mg of paracetamol;

a 50 ml pack contains 500 mg of paracetamol;

a 100 ml pack contains 1000 mg of paracetamol;

osmolarity: 270–310 mosm/kg;

pH from 5.5 to 6.5;

Excipients: sodium acetate trihydrate anhydrous, glacial acetic acid, and sodium hydroxide 1N (for pH adjustment), water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical characteristics: clear solution, colorless to slightly yellowish or reddish.

Pharmacotherapeutic group. Other analgesics and antipyretics.

ATC code N02B E01.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

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

"PARACETAMOL AGENTAN 10 mg/mL" allows pain relief within 5–10 minutes after the start of administration. The peak analgesic effect is reached within 1 hour, and the duration of this effect usually lasts from 4 to 6 hours.

"PARACETAMOL AGENTAN 10 mg/mL" reduces body temperature within 30 minutes after the start of administration, and the duration of the antipyretic effect lasts for at least 6 hours.

Pharmacokinetics

Adults

Absorption. Paracetamol pharmacokinetics remains linear at doses up to 2 g, both after single administration and repeated administration within 24 hours.

The bioavailability of paracetamol after intravenous infusion at doses of 500 mg and 1 g is comparable to the bioavailability observed after infusion of 1 g and 2 g of propacetamol (containing 500 mg and 1 g of paracetamol, respectively).

The maximum plasma concentration of paracetamol (C_max) observed at the end of a 15-minute intravenous infusion of 500 mg and 1 g of "PARACETAMOL AGENTAN 10 mg/mL" is approximately 15 µg/mL and 30 µg/mL, respectively.

Distribution. The volume of distribution of paracetamol is approximately 1 L/kg.

Paracetamol is weakly bound to plasma proteins.

After administration of 1 g of paracetamol, a significant concentration of paracetamol (about 1.5 µg/mL) was detected in cerebrospinal fluid as early as 20 minutes after infusion.

Metabolism. Paracetamol is primarily metabolized in the liver via two main hepatic pathways: glucuronidation and sulfation. The latter pathway becomes rapidly saturated at doses exceeding therapeutic levels. A small fraction of paracetamol (less than 4%) is converted by cytochrome P450 into a reactive intermediate metabolite (N-acetyl-p-benzoquinone imine), which under normal conditions is rapidly detoxified by reduced glutathione and excreted in urine following conjugation with cysteine and mercapturic acid. However, in cases of significant overdose, the amount of this toxic metabolite increases sharply.

Elimination. Paracetamol metabolites are primarily excreted in urine. Approximately 90% of the administered dose is excreted in urine within 24 hours, mainly in glucuronide-conjugated form (60–80%) and sulfate-conjugated form (20–30%).

Less than 5% is excreted unchanged.

The elimination half-life from plasma is 2.7 hours, and total clearance is approximately 18 L/h.

Children

Pharmacokinetic parameters of paracetamol in infants and children with body weight >10–≤33 kg are similar to those in adults, except for a slightly shorter plasma elimination half-life (1.5 to 2 hours). In neonates, the plasma elimination half-life is longer than in older children—approximately 3.5 hours. Infants and children under 10 years of age excrete significantly less glucuronide conjugates and more sulfate conjugates compared to adults.

Pharmacokinetic parameters according to age (standardized clearance CL_std/Foral) are presented in Table 1.

Table 1

*CLstd — population clearance estimate.

Special patient groups

Renal impairment. In cases of severe renal impairment (creatinine clearance 10–30 mL/min), elimination of paracetamol is slightly slowed, with elimination half-life ranging from 2 to 5.3 hours. The elimination rate of glucuronide and sulfate conjugates in severe renal impairment is three times lower than in healthy individuals.

Patients with renal impairment should increase the dosing interval (see section "Administration and dosage").

Geriatric patients

The pharmacokinetics and metabolism of paracetamol in geriatric patients are not altered. There is no need to adjust the dosage of the medicinal product for these patients.

Preclinical safety data

Preclinical data do not indicate any additional specific risks beyond those already mentioned in other sections of the instructions.

Standard studies according to current guidelines on reproductive toxicity and developmental toxicity have not been conducted.

Local tolerance studies in rats and rabbits demonstrated that the "PARACETAMOL AGENTAN 10 mg/mL" infusion solution is well tolerated.

The absence of delayed-type hypersensitivity has been confirmed in studies on guinea pigs.

Clinical characteristics

Indications

«PARACETAMOL AGENTAN 10 mg/ml» is indicated for the short-term treatment of moderate pain, particularly in the postoperative period, and for the short-term treatment of fever, when intravenous administration is clinically justified by the urgency of treating pain or hyperthermia and/or when other routes of administration are not acceptable.

Contraindications

«PARACETAMOL AGENTAN 10 mg/ml» is contraindicated:

• in cases of hypersensitivity to paracetamol or propacetamol hydrochloride (a paracetamol precursor), or to any of the excipients;
• in cases of severe hepatic parenchymal insufficiency.

Interaction with other medicinal products and other types of interactions

Probenecid reduces paracetamol clearance by half 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 required when paracetamol is used concomitantly with enzyme-inducing agents. Such agents include, in particular, barbiturates, isoniazid, carbamazepine, rifampicin, and ethanol (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 is required during concomitant use and for 1 week after discontinuation of paracetamol treatment.

Caution should be exercised when using paracetamol concomitantly with flucloxacillin, as this 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 for use»).

Special precautions for use

It is recommended to use appropriate oral analgesic therapy as soon as this route of administration becomes possible.

To avoid overdose, it is necessary to check whether other medicinal products being administered contain paracetamol or propacetamol.

Administration of doses exceeding the recommended doses 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) usually appear only 2 days after administration of the medicinal product and peak at 4–6 days. Antidote treatment should be initiated as soon as possible (see section "Overdose").

Precautions for use

Caution is recommended in the presence of factors that may reduce the hepatic toxicity threshold. Dose adjustment is required, and the maximum daily dose should not be exceeded in patients with the following risk factors:

• hepatocellular insufficiency, Gilbert’s disease;
• severe renal impairment (see sections "Method of administration and dosage" and "Pharmacokinetics");
• chronic alcoholism;
• chronic malnutrition (low hepatic glutathione stores);
• dehydration;
• body weight less than 50 kg (see section "Method of administration and dosage");
• glucose-6-phosphate dehydrogenase deficiency (which may cause hemolytic anemia).

Cases of high anion gap metabolic acidosis (HAGMA) due to 5-oxoproline (pyroglutamic acid) accumulation have been reported in patients with severe underlying conditions such as severe renal impairment and sepsis, as well as in patients with malnutrition 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. Measurement of urinary 5-oxoproline levels may be useful in identifying pyroglutamic acidosis as the underlying cause of high anion gap metabolic acidosis in patients with multiple risk factors.

Serious skin reactions

This medicinal product may cause serious skin reactions. Patients should be informed about the early signs of serious skin reactions. If a rash or other signs of hypersensitivity appear, administration of the drug should be discontinued immediately.

Sodium content

This medicinal product contains 126 mg (5.5 mmol) of sodium per 50 ml bag, which corresponds to 6.3% of the maximum daily sodium intake (2 g) recommended by WHO for adults.

This medicinal product contains 252 mg (11 mmol) of sodium per 100 ml bag, which corresponds to 13% of the maximum daily sodium intake (2 g) recommended by WHO for adults.

The maximum daily dose of this product (corresponding, for example, to 4 bags of 100 ml) for an individual weighing over 50 kg without additional risk factors for hepatotoxicity is equivalent to 50% of the maximum daily sodium intake recommended by WHO.

The "PARACETAMOL AGENTAN 10 mg/ml" infusion solution contains a significant amount of sodium. This should be taken into account, particularly in patients on a low-sodium diet.

Use during pregnancy or breastfeeding

Pregnancy

Extensive data on the use of paracetamol in pregnant women indicate no malformations or fetotoxicity/neonatal toxicity. Epidemiological studies on the neurological development of children exposed to paracetamol in utero have yielded inconclusive results. When clinically indicated, paracetamol may be used during pregnancy; however, it should be administered at the lowest effective dose, for the shortest possible duration, and with the least possible frequency.

Breastfeeding

After oral administration, paracetamol passes into breast milk in small amounts. No adverse effects on the infant have been reported. Therefore, "PARACETAMOL AGENTAN 10 mg/ml" may be used in women who are breastfeeding.

Ability to affect reaction speed when driving vehicles or operating machinery. The medicinal product has no significant influence on the ability to drive vehicles or operate machinery.

Instructions for Use and Dosage

The medicinal product is intended for intravenous administration.

"PARACETAMOL AGTAN 10 mg/ml", solution for infusion in 50 ml bag, is indicated for neonates and children with body weight >10 kg to ≤ 33 kg.

"PARACETAMOL AGTAN 10 mg/ml", solution for infusion in 100 ml bag, is indicated for adults, adolescents, and children with body weight exceeding 33 kg.

Dosage

Dosage is calculated according to the patient's body weight (see Table 2).

Table 2

Dosage according to patient's body weight

* Patients with lower body weight require smaller volumes.

The interval between administrations should be at least 4 hours.

** The maximum daily dose is defined for patients who are not receiving other medicinal products containing paracetamol. In other cases, the daily dose should be appropriately adjusted, taking into account the use of such medicinal products.

Do not administer more than 4 doses within 24 hours!

Renal function impairment

For patients with renal insufficiency, the minimum interval between administrations should be adjusted as indicated in Table 3:

Table 3

Liver function impairment

For adult patients with chronic hepatic insufficiency or compensated active liver disease, hepatocellular insufficiency, chronic alcoholism, chronic malnutrition (low hepatic glutathione stores), dehydration, Gilbert's disease, or with body weight less than 50 kg, the maximum daily dose should not exceed 3 g (see section "Special precautions").

Elderly patients

Dose adjustment is not required for elderly patients. However, it should be borne in mind that renal and/or hepatic impairment occurs more frequently in patients aged 65 years and older (see section "Pharmacokinetics").

Method of administration

Warning!

The solution of paracetamol should be administered as a 15-minute intravenous infusion.

The paracetamol solution may additionally be diluted in 0.9% sodium chloride solution or 5% glucose solution to a ratio of 1:10. In this case, the diluted medicinal product should be used within 2 hours after preparation (including infusion time).

Remove the bag from its packaging and check for integrity. Use the solution immediately after opening the bag.

Before any administration, the product should be visually inspected for the presence of any particles. The medicinal product is intended for single use only. Any unused solution should be discarded.

The solution diluted with 0.9% sodium chloride solution or 5% glucose solution should be visually monitored and must not be used if opalescence, visible particles, or precipitate are present.

Check the expiry date.

Ensure the bag is not leaking. Any damaged or partially used bag, or one whose hanging hole has not been opened, should be discarded.

Do not vent or connect in series with other infusions.

Before infusion, remove the protective cover from the puncture site.

The infusion set should be connected to the bag.

Children

"PARACETAMOL AGENTAN 10 mg/ml", infusion solution in 50 ml bag, is indicated for neonates and children with body weight from >10 kg to ≤ 33 kg.

"PARACETAMOL AGENTAN 10 mg/ml", infusion solution in 100 ml bag, is indicated for adolescents and children with body weight greater than 33 kg.

Overdose

Paracetamol overdose can lead to liver damage, which may be fatal.

Symptoms usually appear within the first 24 hours and include nausea, vomiting, anorexia, pallor, and abdominal pain. Some patients may not exhibit symptoms.

A single ingestion of 7.5 g of paracetamol in adults and 140 mg/kg body weight in children may cause hepatic cytolysis and lead to complete and irreversible necrosis. This, in turn, may result in hepatocellular insufficiency, metabolic acidosis, encephalopathy, which may progress to coma and fatal outcome.

Concurrently, increased levels of liver transaminases (aspartate aminotransferase, alanine aminotransferase), lactate dehydrogenase, and bilirubin with elevated prothrombin levels may appear 12–48 hours after ingestion.

Liver injury (fulminant hepatitis, hepatic failure, cholestatic hepatitis, cytolytic hepatitis) may occur in patients who have taken more than the recommended amount of paracetamol. It is believed that excessive amounts of toxic metabolites bind irreversibly to liver tissue.

Some patients have an increased risk of liver injury due to the toxic effect of paracetamol. These patients include:

• patients with liver disease;
• elderly patients;
• young children;
• patients receiving hepatic enzyme inducers;
• patients suffering from chronic alcoholism;
• patients who are chronically undernourished.

Clinical symptoms of liver injury usually appear after two days and peak at 4–6 days.

Acute renal failure with acute tubular necrosis may also develop.

In addition, cardiac arrhythmias and pancreatitis have been reported.

Emergency measures

• Immediate hospitalization.
• Blood sample for plasma paracetamol concentration should be taken as early as possible after overdose and before starting treatment; in cases of acute overdose following a single oral ingestion, the sample should be taken 4 hours after ingestion.
• Treatment of overdose includes administration of the antidote N-acetylcysteine either intravenously or orally, preferably within the first 10 hours after overdose. N-acetylcysteine can also be administered later, but in such cases a longer treatment duration is required.
• Symptomatic treatment.
• Liver function tests should be performed at the beginning of treatment and then every 24 hours.
• Liver transaminase levels usually return to normal within 1–2 weeks, with complete restoration of normal liver function. However, in very severe cases, liver transplantation may be required.

Adverse reactions

When using medicinal products containing paracetamol at therapeutic doses, a low incidence of adverse effects is expected.

The adverse reactions of the medicinal product are listed below by organ systems and by frequency (see Table 4).

Table 4

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

** Cases of high anion gap metabolic acidosis due to pyroglutamic acidosis have been observed in patients with risk factors receiving paracetamol (see section "Special precautions"). Pyroglutamic acidosis may occur due to low glutathione levels in these patients.

Suspected adverse reactions reporting

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

Shelf life. 2 years.

After opening the packaging: immediate use is recommended.

Chemical and physical stability during use has been demonstrated for 24 hours at temperatures from 15 °C to 25 °C.

After dilution of the medicinal product in 0.9% sodium chloride solution or 5% glucose solution, chemical and physical stability of the solution has been demonstrated for 2 hours (including infusion time).

From a microbiological standpoint, the product should be used immediately. If not used immediately, responsibility for storage duration and conditions lies solely with the user.

Storage conditions

Do not store in the refrigerator. Do not freeze.

Keep out of reach and sight of children.

Storage conditions after first opening or reconstitution of the medicinal product are specified in the section "Shelf life".

Incompatibilities. "PARACETAMOL AGUETTANT 10 mg/mL", infusion solution, must not be mixed with other medicinal products except as indicated in the section "Administration and dosage".

Packaging. 50 mL or 100 mL in a sealed bag, enclosed in foil; 50 bags per cardboard box.

Prescription status. Prescription only.

Manufacturer. Aguettant Mouvaux, France / Aguettant Mouvaux, France

Manufacturer's address and location of its operations

Rue Michel Raillard, Mouvaux, 59420, France / Rue Michel Raillard, Mouvaux, 59420, France