Exopon

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EXOPON (EXOPON)

Composition:

Active substance: paracetamol;

1 ml of solution contains 10 mg of paracetamol;

Excipients: hydroxypropylbetadex, disodium edetate, sodium chloride, sodium dihydrogen phosphate dihydrate, disodium hydrogen phosphate dihydrate, water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear, colorless or slightly yellowish solution.

Pharmacotherapeutic group. Analgesics and antipyretics. ATC code N02B E01.

Pharmacological properties.

Pharmacodynamics.

The exact mechanism of the analgesic and antipyretic properties 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.

Paracetamol reduces body temperature within 30 minutes after administration; the antipyretic effect lasts for at least 6 hours.

Pharmacokinetics.

Adults.

Absorption.

After single doses of up to 2 g and after repeated administration over 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 (Cmax) 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. Approximately 20 minutes after infusion, a significant concentration level (about 1.5 µg/mL) was detected in cerebrospinal fluid following administration of 1 g paracetamol.

Metabolism.

Paracetamol is extensively metabolized in the liver via two major pathways: glucuronic acid conjugation and sulfuric acid conjugation. 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 significantly.

Elimination.

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

Special patient groups.

Patients with renal impairment.

In patients with severe renal impairment (creatinine clearance 10–30 mL/min), elimination of paracetamol is somewhat prolonged, with a half-life ranging from 2 to 5.3 hours. The rate of elimination of glucuronide and sulfate metabolites is three times slower in patients with severe renal impairment 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.

Short-term treatment of moderate-intensity pain, particularly in the postoperative period, and short-term treatment of hyperthermic reactions when intravenous administration is clinically justified or other routes of administration are not acceptable.

Contraindications.

Hypersensitivity to paracetamol or to any of the excipients.

Severe hepatic impairment.

Interaction with other medicinal products and other forms of interaction.

Probenecid causes an almost twofold reduction in paracetamol clearance by inhibiting its conjugation with glucuronic acid. When paracetamol is used concomitantly with probenecid, dose reduction of paracetamol should be considered.

Salicylamide may prolong the elimination half-life of paracetamol.

Caution is required 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 international normalized ratio (INR) values. In such cases, enhanced monitoring of INR values should be performed throughout the period of concomitant use and for 1 week after discontinuation of paracetamol.

When used concomitantly with hormonal contraceptives, elimination of paracetamol from the body may be accelerated, possibly reducing its analgesic effect. Anticonvulsants (phenytoin, phenobarbital, methylphenobarbital, primidone) reduce the bioavailability of paracetamol and enhance its hepatotoxicity.

Concomitant use with chloramphenicol may increase the toxicity of chloramphenicol, possibly due to inhibition of its hepatic metabolism.

Concomitant use with lamotrigine moderately increases lamotrigine elimination from the body.

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.

There are reports of a possible increase in zidovudine toxicity (neutropenia, hepatotoxicity) when used concomitantly with paracetamol.

Caution should be exercised when paracetamol is used concomitantly with flucloxacillin, as concomitant administration has been associated with metabolic acidosis with a high anion gap due to 5-oxoproline (pyroglutamic) acidosis, particularly in patients with risk factors (see section "Special precautions for use").

Special precautions for use.

Risk of medication errors!

To avoid dosing errors due to confusion between milligrams (mg) and milliliters (mL), careful dose calculation is essential when prescribing and administering the medicinal product. Errors may lead to accidental overdose and even fatal outcomes.

Cases of high anion gap metabolic acidosis (HAGMA) due to 5-oxoproline (pyroglutamic) acidosis have been reported in patients with severe conditions such as severe renal insufficiency and sepsis, or in patients with poor nutrition or other sources of glutathione deficiency (e.g., chronic alcoholism), who were treated with therapeutic doses of paracetamol over a prolonged period or with a combination of paracetamol and flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol is recommended, along with close monitoring. Measurement of urinary 5-oxoproline levels may be helpful in identifying pyroglutamic acidosis as the underlying cause of HAGMA in patients with multiple risk factors.

Appropriate oral analgesic therapy should be initiated as soon as this route of administration becomes feasible.

To avoid the risk of overdose, it is important to check whether other medicinal products being administered contain paracetamol or propacetamol.

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

For all infusion solutions in glass vials, it is important to monitor the infusion procedure, particularly as the infusion nears completion.

Paracetamol should be administered with caution in patients with:

• Hepatocellular insufficiency;
• Severe renal impairment (creatinine clearance ≤ 30 mL/min) (see sections "Pharmacokinetics" and "Dosage and administration");
• Chronic alcoholism;
• Chronic malnutrition (low hepatic glutathione stores);
• Dehydration.

Important information on excipients

This medicinal product contains less than 1 mmol of sodium (23 mg) per 0.1 L of solution, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding

Pregnancy. A substantial amount of data on the use of paracetamol in pregnant women confirms the absence of teratogenic effects or fetal/neonatal toxicity.

Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero have yielded inconclusive results. Reproductive studies with intravenous paracetamol in animals have not been conducted. However, studies with oral paracetamol 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 clinically necessary. In such cases, it should be administered at the lowest effective dose, for the shortest possible duration, and with the lowest frequency required.

Breastfeeding. After oral administration, paracetamol is excreted into breast milk in small amounts. No adverse effects have been observed in infants exposed to paracetamol during breastfeeding. Therefore, paracetamol may be used in breastfeeding women.

Ability to influence reaction speed when driving or operating machinery

No significant effect.

Administration and Dosage

The medicinal product EXOPON is administered intravenously.

The 100 ml vial is intended for adults and children with a body weight exceeding 33 kg.

Dosage:

The dosage depends on the patient's body weight (see table below).

Table 1

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

** Patients with lower body weight require smaller volumes.

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

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

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 increase the minimum interval between doses to 6 hours.

Patients with hepatic insufficiency, chronic alcoholism, chronically undernourished patients (low hepatic glutathione stores), and dehydrated patients.

The maximum daily dose should not exceed 3 g.

Method of administration

Exercise caution when prescribing and administering the medicinal product EXOPON to avoid dosing errors due to confusion between milligrams (mg) and milliliters (mL), which may lead to accidental overdose and even fatal outcomes. Doses must be carefully calculated when prescribing and administering the medicinal product. When writing prescriptions, indicate both the total dose in milligrams and the total dose in volume.

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

Information for 100 mL vial:

The required volume of the preparation should be drawn from the vial using a 0.8 mm needle; hold the vial vertically and pierce the stopper at the designated site.

As with all infusion solutions in glass vials, it is important to monitor the procedure, especially at the end of the infusion, regardless of the route of administration. Monitoring at the end of the infusion should be particularly applied during central intravenous administration to prevent air embolism.

Children.

Do not use in children with body weight less than 33 kg.

Overdose.

Symptoms. There is a risk of liver injury (including fulminant hepatitis, hepatic failure, cholestatic hepatitis, cytolytic hepatitis), especially in elderly individuals, young children, patients with liver disease, in cases of chronic alcoholism, in chronically undernourished patients, and in individuals 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; in children, at a dose of 140 mg/kg body weight. This leads to hepatic cytolysis, liver failure, metabolic acidosis, and encephalopathy, which may result in coma and patient death. Within 12–48 hours, levels of liver transaminases (alanine aminotransferase, aspartate aminotransferase), lactate dehydrogenase, and bilirubin increase, while prothrombin levels decrease.

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

Treatment. Emergency measures:

• Immediate hospitalization;
• Determination of paracetamol concentration in blood plasma 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 after overdose, but the treatment duration should be extended;
• Symptomatic treatment.

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

Adverse reactions

As with other medicinal products containing paracetamol, adverse reactions occurred rarely (> 1/10,000 - < 1/1,000) or very rarely (< 1/10,000); frequency unknown (cannot be estimated from available data)—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, skin rashes requiring discontinuation of treatment have been reported.

**In 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

Metabolic acidosis with high anion gap

Cases of metabolic acidosis with high anion gap as a result of pyroglutamic acidosis have been observed in patients with risk factors who were treated with paracetamol (see section "Dosage and Administration"). Pyroglutamic acidosis may occur due to low glutathione levels in these patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows ongoing monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives are encouraged to report any suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 ºC. Keep out of reach of children.

Incompatibilities.

Paracetamol should not be mixed with other medicinal products.

Packaging.

100 ml of solution in a container within a protective pouch; 12 containers in protective pouches in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

UNI-PHARMA CLEON CETIS PHARMACEUTICAL LABORATORIES S.A.

Address of the manufacturer and location of its business operations.

14th km National Road 1, Bldg. A and Bldg. B, Kato Kifisia, Attica, 14564, Greece.