Paracetamol s.a.l.f.

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PARACETAMOL S.A.L.F.

Composition:

Active substance: paracetamol;

1 ml contains 10 mg of paracetamol;

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

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear, colorless solution or slightly colored from amber-yellow to pink-pale orange (perception may vary).

Pharmacotherapeutic group. Analgesics and antipyretics. ATC code N02BE01.

Pharmacological properties.

Pharmacodynamics.

The exact 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. The 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, and the antipyretic effect lasts for at least 6 hours.

Pharmacokinetics.

Adults

Absorption

After single administration of up to 2 g of the drug and 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 (containing 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 of 1 g paracetamol.

Metabolism

Paracetamol is extensively metabolized in the liver via two major pathways: glucuronide conjugation and sulfate conjugation. The latter pathway becomes rapidly saturated at doses exceeding therapeutic levels. A small portion (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, 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 delayed, and the elimination half-life ranges 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 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 pain, particularly following surgery.

Short-term treatment of fever when intravenous administration is clinically justified by an urgent need for treatment of pain or hyperthermia, and/or when other routes of administration are not acceptable.

Contraindications.

Hypersensitivity to paracetamol, propacetamol hydrochloride (a paracetamol prodrug), or to any of the excipients of the medicinal product. 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, a reduction in paracetamol dosage 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 INR (International Normalized Ratio) values. In such cases, intensified INR monitoring should be performed during concomitant treatment and for 1 week after discontinuation of paracetamol therapy.

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 increase its hepatotoxicity.

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

Concomitant use with lamotrigine moderately increases lamotrigine elimination.

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.

Concomitant use of paracetamol with flucloxacillin requires caution, as this combination 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 drug is not recommended. Appropriate oral analgesic therapy should be initiated as soon as this route of administration becomes feasible.

To avoid the risk of overdose, it is essential to verify whether other medications administered concurrently contain paracetamol or propacetamol. Dosage adjustments may be required (see section "Dosage and administration").

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

Paracetamol may cause serious skin reactions. Patients should be informed about the early signs of serious skin reactions, and if skin rash or any other signs of hypersensitivity occur, the drug should be discontinued immediately.

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 poor 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 and close monitoring of the patient are recommended. Measurement of 5-oxoproline levels in urine 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 "Dosage and administration" and "Pharmacokinetics");
• chronic alcoholism;
• chronic malnutrition (low hepatic glutathione stores);
• dehydration;
• Gilbert’s syndrome;
• genetically determined glucose-6-phosphate dehydrogenase deficiency, which may lead to hemolytic anemia 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., essentially "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. However, studies with oral paracetamol have not demonstrated developmental abnormalities or fetotoxic effects. Nevertheless, paracetamol should be used during pregnancy only when clinically necessary and when the expected benefit to the mother outweighs the potential risk to the fetus or child. In such cases, it should be administered at the lowest effective dose, for the shortest duration, and with the lowest frequency possible.

Breastfeeding

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

Ability to affect reaction speed when driving or operating machinery.

No effect.

Method of administration and dosage.

The medication is administered intravenously.

Paracetamol S.A.L.F. 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

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

Before administration, ensure that the solution is clear and does not contain visible particles. The solution containing visible foreign matter must not be used.

Any unused medicinal product remaining should be destroyed.

Patients in special populations

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), dehydrated patients, Gilbert's syndrome, and patients with body weight less than 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 less than 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 alcoholics, chronically undernourished patients, and 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, and in children at 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 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 lethal.

Emergency measures

• Immediate hospitalization;
• Determination of paracetamol plasma concentration as soon as possible after overdose, prior to initiating treatment;
• Intravenous or oral administration of the antidote, N-acetylcysteine (NAC), if possible, no later than 10 hours after overdose. NAC may still be administered later than 10 hours after overdose, but treatment duration should be prolonged;
• Symptomatic treatment.

Liver function tests should be performed before initiating 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.

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); 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.

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 receiving paracetamol (see section "Special precautions for use"). 5-Oxoproline acidosis may occur due to low glutathione levels in these patients.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children. Do not refrigerate.

Incompatibilities.

Paracetamol S.A.L.F. must not be mixed with other medicinal products.

Packaging.

100 ml in a bottle №1.

100 ml in a bottle, 30 bottles in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

S.A.L.F. S.p.A. Laboratorio Farmacologico.

Manufacturer's address and location of its business operations.

Via G. Mazzini, 9, Senate Sotto, 24069, Italy.