Pyreticol

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

Composition:

Active substance: paracetamol;

1 ml of solution contains 10 mg of paracetamol;

Excipients: mannitol; cysteine hydrochloride monohydrate; sodium hydrogen phosphate dihydrate; sodium hydroxide; hydrochloric acid; water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear, slightly yellowish 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 begins to exert analgesic effects within 5–10 minutes after the start of administration. Maximum analgesic effect is achieved within 1 hour, and the duration of this effect typically lasts 4–6 hours.

Paracetamol reduces elevated body temperature within 30 minutes after the start of administration, with the antipyretic effect lasting at least 6 hours.

Pharmacokinetics

Adults

Absorption.

The pharmacokinetics of paracetamol are linearly dose-dependent up to 2 g, both after single administration and repeated dosing within 24 hours.

The bioavailability of paracetamol following infusion of 500 mg and 1 g is comparable to that following infusion of 1 g and 2 g of propacetamol (containing 500 mg and 1 g of paracetamol, respectively). The maximum plasma concentration (Cmax) of paracetamol observed at the end of a 15-minute intravenous infusion of 500 mg and 1 g is 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 (approximately 1.5 µg/mL) was observed in cerebrospinal fluid starting from 20 minutes after infusion.

Metabolism.

Paracetamol is primarily metabolized in the liver via two main pathways: conjugation with glucuronic acid and conjugation with sulfuric acid. The latter pathway becomes rapidly saturated when doses exceeding therapeutic levels are administered. A small fraction (less than 4%) is metabolized by cytochrome P450 to a reactive intermediate (N-acetylbenzoquinoneimine), 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 severe overdose, the amount of this toxic metabolite increases.

Excretion.

Paracetamol metabolites are primarily excreted in urine. Approximately 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. The elimination half-life (t1/2) from plasma is 2.7 hours, and total clearance is 18 L/h.

Children

The pharmacokinetic parameters of paracetamol in children are similar to those observed in adults, except for t1/2, which is slightly shorter (1.5 to 2 hours) compared to adults. In neonates, t1/2 is longer than in older children, approximately 3.5 hours. Neonates and children under 10 years of age excrete significantly less glucuronide and more sulfate conjugates compared to adults.

Age-related pharmacokinetic values (standardized clearance, CLstd*/Foral (L×h–1×70 kg–1))

*CLstd — population clearance estimate.

Special patient categories

Patients with renal impairment.

In cases of severe renal dysfunction (creatinine clearance 10–30 mL/min), elimination of paracetamol is slightly slowed, with t1/2 ranging from 2 to 5.3 hours. The rate of elimination of glucuronide and sulfate conjugates is 3 times slower in patients with severe renal impairment compared to healthy individuals. Therefore, when administering the drug to patients with severe renal dysfunction (creatinine clearance ≤ 30 mL/min), the minimum interval between doses should be increased to 6 hours (see section "Dosage and administration").

Geriatric patients.

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

Clinical characteristics

Indications

• For short-term treatment of moderate pain, particularly postoperative pain.
• For short-term treatment of fever.

The medicinal product should be administered when intravenous administration is clinically justified by an urgent need to treat pain or hyperthermia and/or when other routes of administration are not feasible.

Contraindications

• Hypersensitivity to paracetamol, propacetamol hydrochloride (a paracetamol prodrug), and/or to any of the excipients of the medicinal product.
• Severe hepatic impairment.

Interaction with other medicinal products and other types of interactions

Probenecid

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

Salicylamide

When administered concomitantly, a prolonged elimination half-life of paracetamol is possible.

Substances inducing liver enzymes

When paracetamol is used concomitantly with such agents, caution is required (see section "Overdose").

Oral anticoagulants

When paracetamol (4000 mg daily for at least 4 days) is used concomitantly with oral anticoagulants, slight changes in INR (International Normalized Ratio) values may occur. In such cases, INR values should be monitored closely during concomitant treatment and for 1 week after discontinuation of paracetamol therapy.

Flucloxacillin

Concomitant use of paracetamol with flucloxacillin should be undertaken with 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 for use").

Special precautions for use

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

To avoid overdose, it is necessary to ensure that other administered medicinal products do not contain paracetamol or propacetamol. Dosage may require adjustment (see section "Method of administration and dosage").

Administration of the medicinal product in doses exceeding the recommended ones poses a risk of severe liver damage. Clinical signs and symptoms of liver injury (including fulminant hepatitis, hepatic failure, cholestatic hepatitis, cytolytic hepatitis) typically appear only 2 days after paracetamol administration, with peak severity usually occurring 4–6 days after administration. Antidote treatment must be administered as quickly as possible (see section "Overdose").

The medicinal product should be used with caution in the following conditions:

• hepatic impairment;
• severe renal impairment [creatinine clearance ≤ 30 ml/min] (see sections "Method of administration and dosage" and "Pharmacokinetics");
• chronic alcoholism;
• chronic malnutrition (low hepatic glutathione stores);
• dehydration;
• genetically determined deficiency of glucose-6-phosphate dehydrogenase (favism) —

due to the possible occurrence of hemolytic anemia resulting from reduced glutathione availability after paracetamol administration.

Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported. Caution is recommended when using paracetamol concomitantly with flucloxacillin due to an increased risk of HAGMA, particularly in patients with severe conditions such as severe renal impairment and sepsis, or in patients with poor nutrition or other sources of glutathione deficiency (e.g., chronic alcoholism), who have been treated with paracetamol at therapeutic doses for prolonged periods or in combination with flucloxacillin, as well as in those receiving maximum daily doses of paracetamol. If HAGMA due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol is recommended, along with close monitoring, including measurement of urinary 5-oxoproline levels. Measurement of urinary 5-oxoproline may be useful in identifying pyroglutamic acidosis as the underlying cause of HAGMA in patients with multiple risk factors.

The medicinal product contains less than 1 mmol of sodium (23 mg) per vial, i.e., it is practically sodium-free.

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 show inconclusive results. If clinically indicated, the medicinal product may be used during pregnancy at the lowest effective dose, for the shortest possible duration, and with the least possible frequency.

Breastfeeding period.

After oral administration, paracetamol passes into breast milk in small amounts. No adverse effects in newborns have been reported. The medicinal product may be used in women during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

No effect.

Dosage and Administration

Dosing

The medicinal product is intended only for adults, adolescents, and children with a body weight exceeding 33 kg.

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

*The maximum daily dose indicated is for patients who are not receiving other medications containing paracetamol; otherwise, the daily dose should be appropriately adjusted according to the dose of these medications.

**Patients with lower body weight require smaller volumes.

Special patient categories

Patients with severe renal impairment. For patients with severe renal function impairment (creatinine clearance ≤ 30 mL/min), a reduced dose and an increased minimum interval between doses to 6 hours are recommended (see section "Pharmacokinetics").

Patients with hepatic insufficiency, chronic alcoholism, chronic malnutrition (low hepatic glutathione stores), dehydration. For these patients, the daily dose should not exceed 3 g (see section "Special precautions for use").

Method of administration

The medicinal product is intended for intravenous use.

Paracetamol solution should be administered as a 15-minute intravenous infusion.

The medicinal product is intended for single use only. Any unused solution should be discarded.

Before administration, the medicinal product should be visually inspected for the presence of particles and discoloration. The solution may be used only if it is clear and slightly yellowish.

From a microbiological standpoint, unless the method of opening and subsequent handling excludes the risk of microbial contamination, the medicinal product should be used immediately. If not used immediately, responsibility for the time and storage conditions after opening lies with the user.

As with the administration of any other infusion solution supplied in containers containing air, careful monitoring of the infusion is required regardless of the method of administration. Particular attention is needed at the end of the infusion, especially during central venous infusion, to avoid air embolism.

Children.

The medicinal product is intended only for children with a body weight greater than 33 kg.

Overdose

Symptoms.

There is a risk of liver damage (including fulminant hepatitis, hepatic failure, cholestatic hepatitis, cytolytic hepatitis), particularly in elderly individuals, young children, patients with liver disease, chronic alcoholism, chronic malnutrition, and in patients receiving enzyme inducers. Overdose may be fatal in these cases.

Symptoms usually appear within the first 24 hours and include: nausea, vomiting, anorexia, pallor, and abdominal pain. Overdose of 7.5 g or more of paracetamol administered as a single dose in adults or 140 mg/kg body weight administered as a single dose in children causes liver cytolysis, which may lead to complete and irreversible necrosis, hepatocellular failure, metabolic acidosis, encephalopathy, coma, and fatal outcome. Concurrently, elevated levels of liver transaminases (AST [aspartate aminotransferase], ALT [alanine aminotransferase]), lactate dehydrogenase, and bilirubin occur together with decreased prothrombin levels, which may appear 12–48 hours after administration. Clinical symptoms of liver injury typically become apparent initially after 2 days and peak at 4–6 days.

Regardless of the presence and severity of possible liver function disturbances, acute renal failure symptoms may develop in cases of overdose.

Treatment.

Immediate hospitalization.

A blood sample should be taken as soon as possible after overdose, but before starting treatment, to determine the concentration of paracetamol in plasma.

Treatment includes administration of the antidote N-acetylcysteine (NAC) either intravenously or orally, if possible, no later than 10 hours after overdose. However, NAC may still provide some degree of protection even more than 0 hours after overdose, but in these cases prolonged NAC treatment should be administered.

Symptomatic treatment.

Liver function tests should be performed at the beginning of treatment and repeated every 24 hours. Liver transaminase levels most often return to normal within 1–2 weeks, with full recovery of normal liver function. However, in very severe cases, liver transplantation may be required.

Adverse Reactions

Adverse reactions are classified according to the frequency of occurrence into the following categories: rare (> 1/10,000, < 1/1,000), very rare (< 1/10,000), unknown (frequency cannot be estimated based on available data).

Blood and lymphatic system disorders:

very rare — thrombocytopenia, leukopenia, neutropenia.

Immune system disorders:

very rare — hypersensitivity reactions*.

Cardiac disorders:

unknown — tachycardia.

Vascular disorders:

rare — hypotension; unknown — flush.

Hepatobiliary disorders:

rare — increased levels of liver transaminases.

Skin and subcutaneous tissue disorders:

very rare — serious skin reactions**; unknown — pruritus, erythema.

Metabolism and nutrition disorders:

unknown — metabolic acidosis with high anion gap.

General disorders and administration site conditions:

rare — weakness.

* Very rare cases of hypersensitivity reactions have been reported, ranging from mild skin rashes or urticaria to anaphylactic shock — such reactions require discontinuation of treatment.

** 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 for use"). Pyroglutamic acidosis may occur due to low glutathione levels in these patients.

Reporting of suspected adverse reactions

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

Shelf life. 3 years.

Storage conditions.

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

Incompatibilities.

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

Packaging.

100 ml in a vial; 1 vial in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Mefar Ilac San. A.Ş. /
Mefar Ilac San. A.S.

Manufacturer's address and location of operations

Ramazanoglu Mah. Ensar Cad. No: 20, 34906 Kurtkoy – Pendik/Istanbul, Turkey /
Ramazanoglu Mah. Ensar Cad. No: 20, 34906 Kurtkoy – Pendik/Istanbul, Turkey.

Marketing Authorization Holder.

WORLD MEDICINE, LLC, Ukraine /
WORLD MEDICINE, LLC, Ukraine.