Paracetamol

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Paracetamol

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 light yellow.

Pharmacotherapeutic group. Analgesics and antipyretics. ATC code N02BE01.

Pharmacological Properties

Pharmacodynamics

Paracetamol exerts analgesic and antipyretic effects. Its 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 gastrointestinal mucosa.

Paracetamol provides pain relief within 5–10 minutes after administration. 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 following intravenous infusion of 500 mg and 1 g 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 reached at the end of a 15-minute infusion of 500 mg or 1 g paracetamol, amounting to 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. After administration of 1 g paracetamol, a significant concentration (approximately 1.5 µg/mL) was detected in cerebrospinal fluid 20 minutes after infusion.

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 cases of massive overdose, the amount of this toxic metabolite increases.

Excretion

Paracetamol metabolites are primarily excreted in urine. Within 24 hours, 90% of the administered dose is eliminated by the kidneys, predominantly 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/hour.

Neonates, Infants, and Children

The pharmacokinetics of paracetamol in children is nearly 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 capacity.

Table 1

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

*CLstd - estimate of the patient group with respect to 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 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-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.
• Severe hepatic cell dysfunction.

Interaction with other medicinal products and other forms of interaction.

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 severe hepatic disorders even with minor overdosage (see section "Overdose").

Concomitant administration of paracetamol (4 g daily for at least 4 days) with oral anticoagulants may result in 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 using paracetamol concomitantly with flucloxacillin, as their combined use has been associated with metabolic acidosis with a high anion gap, particularly in patients with risk factors (see section "Special precautions").

Special precautions for use

The risk of liver damage during treatment with paracetamol increases in patients with alcoholic hepatosis.

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

Long-term treatment requires monitoring of peripheral blood picture and liver function.

As soon as possible, further treatment should be continued using oral forms of analgesics.

The risk of liver injury increases when paracetamol is used at doses exceeding the recommended ones. Clinical signs of liver damage (including liver failure, hepatitis, including fulminant, cholestatic, cytolytic forms) usually 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").

WARNING! Risk of medication error

Due to potential confusion between milligrams (mg) and milliliters (ml), dosing errors may occur, potentially leading to accidental overdose and fatal outcomes (see section "Dosage and administration").

Therefore, the medicinal product Paracetamol, 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.

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

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

Paracetamol should be used with caution when administered concomitantly with flucloxacillin due to an increased risk of high anion gap metabolic acidosis (HAGMA). Patients at high risk of HAGMA include those with severe renal impairment, sepsis, or marasmus, as well as other conditions causing glutathione deficiency (e.g., chronic alcoholism), particularly when maximum daily doses of paracetam0l are used.

Careful monitoring for acid-base disturbances, particularly HAGMA, including measurement of urinary 5-oxoproline levels, is recommended after concomitant use of paracetamol and flucloxacillin.

If flucloxacillin treatment continues after discontinuation of paracetamol, it is recommended to confirm the absence of HAGMA signs, as flucloxacillin may sustain the clinical picture of HAGMA (see section "Interaction with other medicinal products and other types of interactions").

The drug should be used with caution in the following conditions:

• Hepatocellular insufficiency, Gilbert’s syndrome;
• Severe renal impairment (creatinine clearance less than 30 ml/min);
• Chronic alcoholism;
• Chronic malnutrition (reduced hepatic glutathione reserves);
• Dehydration;
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency (favism).

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 of intravenously administered paracetamol in animals have not been conducted. Oral administration studies in animals did not demonstrate 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 during paracetamol use in breastfeeding women. Therefore, paracetamol can be used in women who are breastfeeding.

Ability to influence reaction rate when driving or operating machinery

No effect.

Method of administration and dosage.

Paracetamol, 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 over 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 a 24-hour period.

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 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 chronic malnutrition (low hepatic glutathione reserves), dehydration, hepatocellular insufficiency, or chronic alcoholism: the maximum daily dose should not exceed 3 g.

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

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

The product should be used immediately after opening the packaging.

Any unused volume of infusion solution must be discarded.

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

Children.

Paracetamol infusion solution is indicated for children with body weight exceeding 33 kg.

Overdose.

The risk of liver injury (including fulminant hepatitis, cholestatic hepatitis, cytolytic hepatitis, and liver failure) increases in elderly patients, young children, patients with liver disease, chronic alcoholics, patients with chronic malnutrition, 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 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 damage appear after 48 hours and peak on days 4–6.

Emergency measures:

• Immediate hospitalization;
• As soon as possible, before starting treatment, measure 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 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 all paracetamol-containing products, adverse reactions to the medicinal product occur rarely (>1/10,000, <1/1,000) or very rarely (<1/10,000), as described below:

General disorders:

Common: malaise.

Cardiovascular system:

Common: arterial hypotension.
Very rare: tachycardia.

Hepatobiliary system:

Common: increased levels of liver transaminases.

Blood and lymphatic system disorders:

Very rare: thrombocytopenia, leukopenia, neutropenia.

Immune system disorders:

Very rare: hypersensitivity reactions (rash, urticaria; anaphylactic shock, which may require discontinuation of treatment).

Administration site reactions:

Very rare: pain and burning sensation, erythema, flushing, pruritus.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization of the medicinal product is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: 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 and sight of children.

Packaging

100 ml of the preparation in a polypropylene container. 1 container per cardboard box.

Prescription status

Prescription only.

Manufacturer

Subsidiary company "Farmatreyd".

Manufacturer's address and location of operations

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

Marketing Authorization Holder

Subsidiary company "Farmatreyd".

Address of Marketing Authorization Holder

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