Arsétam

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ARSETAM

Composition:

Active ingredient: paracetamol;

100 ml of solution (1 container) contains 1000 mg of paracetamol;

Excipients: mannitol (E 421), disodium phosphate dihydrate, water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear liquid, colorless to pale yellow.

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

Pharmacological properties.

Pharmacodynamics.

Paracetamol exerts analgesic and antipyretic effects. The mechanism of action involves inhibition of cyclooxygenase (COX) I and II only within the central nervous system, affecting pain and thermoregulatory centers. In activated tissues, cellular peroxidases neutralize the effect of paracetamol on COX, explaining the almost complete absence of anti-inflammatory activity. The lack of influence on prostaglandin synthesis in peripheral tissues accounts for the absence of adverse effects on water-electrolyte balance (sodium and water retention) and the gastrointestinal mucosa.

Paracetamol provides pain relief within 5–10 minutes after administration. The peak analgesic effect is achieved within 1 hour, and the duration of this effect typically lasts 4–6 hours.

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

Pharmacokinetics.

Adults.

Absorption.

After single or repeated administration within 24 hours of doses up to 2 g, the pharmacokinetics of paracetamol are linear.

The bioavailability after intravenous infusion of 500 mg and 1 g of paracetamol is equivalent to that after administration of 1 g and 2 g of propacetamol (containing 500 mg and 1 g of paracetamol, respectively). Maximum plasma concentration (Cmax) is achieved at the end of a 15-minute infusion of 500 mg or 1 g of paracetamol, reaching 15 µg/mL or 30 µg/mL, respectively.

Distribution.

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

Metabolism.

Paracetamol is extensively metabolized in the liver via two major 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 massive overdose, the amount of this toxic metabolite increases significantly.

Elimination.

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

Neonates, infants, and children.

The pharmacokinetics of paracetamol in children is almost identical to that in adults, except for a shorter plasma elimination half-life (1.5–2 hours). In neonates, the elimination half-life is longer than in infants—approximately 3.5 hours. Compared to adults, children under 10 years of age have significantly reduced glucuronidation and increased sulfation.

Table 1

Pharmacokinetic parameters according to age (standardized clearance, * CLstd/Foral (L·h⁻¹·70 kg⁻¹))

*CLstd - assessment of the patient group regarding CL (clearance).

Special patient groups.

Patients with renal impairment.

In patients with severe renal impairment (creatinine clearance 10–30 mL/min), elimination of paracetamol is slightly prolonged, and the elimination half-life ranges from 2 to 5.3 hours. The elimination rate of glucuronide and sulfate metabolites in patients with severe renal impairment is three times slower than in healthy volunteers. Therefore, in patients with severe renal impairment (creatinine clearance ≤ 30 mL/min), the minimum dosing interval should be increased 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 propacetamol hydrochloride (a prodrug of paracetamol), or to any of the excipients of the medicinal product.
• Severe hepatic insufficiency.

Interaction with other medicinal products and other types of interactions.

Probenecid reduces paracetamol clearance by half by inhibiting its conjugation with glucuronic acid; therefore, when paracetamol is used concomitantly with probenecid, the dose of paracetamol should be reduced.

Salicylamide may increase the elimination half-life of paracetamol.

Inducers of hepatic microsomal oxidation (phenytoin, ethanol, barbiturates, rifampicin, phenylbutazone, tricyclic antidepressants) may enhance the risk of developing severe hepatic disorders even with minor overdosage (see section "Overdose").

Concomitant use of paracetamol (4 g daily for at least 4 days) with oral anticoagulants may lead to minor changes in the international normalized ratio (INR). Therefore, INR should be monitored during concomitant use and for one week after discontinuation of paracetamol treatment.

Caution is advised when administering paracetamol concomitantly with flucloxacillin, as co-administration has been associated with metabolic acidosis with a high anion gap due to pyroglutamic acidosis, particularly in patients at risk (see section "Special precautions").

Special precautions for use

Due to the potential for confusion between milligrams (mg) and milliliters (ml), there is a risk of dosing errors, which may lead to accidental overdose and fatal outcomes. Therefore, Arsetam, infusion solution 1000 mg/100 ml, must be used with caution, and when prescribing, both the total dose in milligrams (mg) and the total volume of the dose in milliliters (ml) must be clearly specified.

The risk of hepatotoxicity during treatment with paracetamol increases in patients with alcoholic hepatopathy.

Paracetamol use may interfere with laboratory test results, particularly in the quantitative determination of plasma glucose and uric acid levels.

During prolonged treatment, monitoring of peripheral blood parameters and liver function is required.

As soon as possible, it is recommended to switch to oral analgesics for further treatment.

To avoid the risk of overdose, ensure that other prescribed medicinal products do not contain paracetamol or propacetamol.

The risk of liver injury increases when paracetamol is administered in doses exceeding the recommended levels. Clinical signs of liver damage (including hepatic failure, hepatitis—such as fulminant, cholestatic, or cytolytic forms) typically first appear on day 2 after initiation of treatment and peak on days 4–6. The antidote should be administered as soon as possible (see section "Overdose").

Arsetam, infusion solution 1000 mg/100 ml, contains less than 1 mmol (23 mg) of sodium per 100 ml of solution, i.e., it is nearly sodium-free.

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 or sepsis, or in patients with malnutrition or other sources of glutathione deficiency (e.g., chronic alcoholism), who received prolonged therapeutic doses of paracetamol or a combination of paracetamol and flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, paracetamol should be discontinued immediately and careful monitoring initiated. Measurement of urinary 5-oxoproline levels may be useful in identifying pyroglutamic acidosis as the underlying cause of HAGMA in patients with multiple risk factors (see section "Interaction with other medicinal products and other forms of interaction").

Use with caution in the following conditions:

• Hepatocellular insufficiency;
• Severe renal impairment (creatinine clearance <30 ml/min);
• Chronic alcoholism;
• Chronic malnutrition (reduced hepatic glutathione stores);
• Dehydration.

Use during pregnancy or breastfeeding

Pregnancy

Clinical experience with intravenous administration of paracetamol is limited. However, epidemiological data on the use of therapeutic doses of oral paracetamol indicate no adverse effects on pregnancy or fetal/neonatal health.

Prospective data on paracetamol overdose during pregnancy do not suggest an increased risk of fetal malformations.

Reproductive toxicity studies with intravenous paracetamol in animals have not been conducted. However, similar studies with oral administration have not demonstrated fetotoxic effects.

Nevertheless, paracetamol should be used during pregnancy only after careful assessment of the benefit-risk ratio, at the lowest effective dose, for the shortest possible duration, and with the least possible frequency.

Breastfeeding period

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

Ability to affect reaction speed when driving or operating machinery

No effect.

Method of administration and dosage.

Arsetam, infusion solution 1000 mg/100 ml, is administered intravenously.

Dosage depends on the patient's body weight.

Dosage for adults, adolescents, and children with body weight above 33 kg (see Table 2).

Table 2

* Patients with lower body weight require smaller volumes.

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

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

** 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 products are used.

Patients with severe renal impairment.

When prescribing 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 who are chronically undernourished (have low hepatic glutathione stores), dehydrated, or have hepatocellular insufficiency, chronic alcoholism

The maximum daily dose should not exceed 3 g.

WARNING! To avoid dosing errors due to confusion between milligrams (mg) and milliliters (mL), doses must be carefully calculated when prescribing and administering Arsetam, infusion solution. Such confusion may lead to accidental overdose and even fatal outcomes. When writing prescriptions, the total dose should be indicated both in mg and in mL.

Paracetamol solution is administered by intravenous infusion over 15 minutes.

The medicinal product should be used immediately after opening the packaging.

Any unused infusion solution should be discarded.

Do not use if the container seal is broken or if the solution is not clear.

Children.

Arsetam, infusion solution, is used in children with body weight greater than 33 kg.

Not recommended for premature newborns.

Overdose.

The risk of liver damage (including fulminant hepatitis, cholestatic hepatitis, cytolytic hepatitis, and liver failure) increases in elderly individuals, young children, patients with liver disease, chronic alcoholism, chronically undernourished patients, and individuals with reduced enzymatic activity. In these cases, overdose may be fatal.

Symptoms usually appear within the first 24 hours and include nausea, vomiting, anorexia, pallor, and abdominal pain. Overdose in adults may occur after a single dose of 7.5 g or more; in children, after 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 death. Within 12–48 hours, levels of liver transaminases (alanine aminotransferase, aspartate aminotransferase), lactate dehydrogenase, bilirubin increase, and prothrombin levels decrease.

Clinical signs of liver injury appear after two days and peak on days 4–6.

Emergency measures:

• Immediate hospitalization;
• As soon as possible, before starting treatment, determine plasma paracetamol concentration after overdose;
• Intravenous or oral administration of the antidote N-acetylcysteine (NAC), preferably within 10 hours after overdose. NAC may still be administered later than 10 hours after overdose, but in such cases, treatment will be longer;
• Symptomatic therapy.
• Liver function tests should be performed before starting treatment 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.

Side effects.

As with all paracetamol-containing products, adverse reactions to the drug occur rarely

(≥1/10,000 to <1/1,000) or very rarely (<1/10,000).

1Very rare cases of hypersensitivity reactions have been reported, ranging from simple skin rashes or urticaria to anaphylactic shock, which require discontinuation of treatment.

2Isolated cases.

Very rare cases of serious skin reactions have been reported.

During clinical trials, adverse reactions at the injection site (pain and burning sensation) were frequently 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 receiving paracetamol (see section "Special precautions"). Pyroglutamic acidosis may occur as a consequence of low glutathione levels in these patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy 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.

18 months.

Storage conditions.

Store at a temperature not exceeding 25 °C in the original packaging.

Do not refrigerate. Do not freeze.

Keep out of reach of children.

Packaging.

100 mL in a polypropylene container; 1 container in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Subsidiary enterprise "Farmatreyd".

Manufacturer's address and location of its business activity.

85 Sambirska Street, Drohobych, Lviv Oblast, 82111, Ukraine.

Marketing Authorization Holder.

LLC "WORWARDS PHARMA".

Address of the Marketing Authorization Holder.

4 Omelyan Prytsaka Street, Kyiv, 03142, Ukraine.