Paracetamol-baxter

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PARACETAMOL-BAXTER (PARACETAMOL-BAXTER)

Composition:

Active substance: paracetamol;

1 ml of solution contains 10 mg of paracetamol;

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

Excipients: mannitol (E 421); sodium hydrogen phosphate; L-cysteine hydrochloride monohydrate; sodium hydroxide; hydrochloric acid concentrated; water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: the solution should be clear, colorless to slightly yellowish, practically free from visible particles.

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 effects.

Paracetamol-Baxter provides onset of analgesia within 5–10 minutes after the start of infusion. Peak analgesic effect is achieved within 1 hour, and the duration of this effect typically lasts 4–6 hours.

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

Pharmacokinetics.

Adults

Absorption. After single administration of up to 2 g of the drug and repeated administration over 24 hours, the pharmacokinetics of paracetamol are linear.

The bioavailability after intravenous infusion of 500 mg and 1 g of Paracetamol-Baxter 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 of Paracetamol-Baxter, and is 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. A significant concentration (approximately 1.5 µg/mL) was detected in cerebrospinal fluid 20 minutes after infusion of 1 g of paracetamol.

Metabolism. Paracetamol is extensively metabolized in the liver via two main pathways: conjugation with glucuronic acid and conjugation with sulfuric acid. 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-acetylbenzoquinone imine), 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. Approximately 90% of the administered dose is eliminated by the kidneys within 24 hours, predominantly as glucuronide conjugates (60–80%) and sulfate conjugates (20–30%). Less than 5% is excreted unchanged. The elimination half-life from plasma is 2.7 hours, and total clearance is 18 L/h.

Neonates, infants, and children

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

Table 1

Pharmacokinetic parameters according to 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 severe renal impairment (creatinine clearance 10–30 mL/min), elimination of paracetamol is somewhat prolonged, and the elimination half-life ranges from 2 to 5.3 hours. The elimination rate of glucuronides and sulfates in patients with severe renal impairment is three times lower than in healthy volunteers. Therefore, in patients with severe renal impairment, the minimum dosing interval should be increased to 6 hours (see section "Dosage and administration").

Elderly patients. The pharmacokinetics and metabolism of paracetamol in elderly patients are not altered. Dose adjustment is not required for this patient group (see section "Dosage and administration").

Clinical characteristics.

Indications.

Short-term treatment of moderate-intensity pain, particularly in the postoperative period, or short-term treatment of fever, when intravenous administration is clinically justified by the urgent need for pain or hyperthermia management and/or when other routes of administration are not available.

Contraindications.

Hypersensitivity to paracetamol or propacetamol hydrochloride (a prodrug of paracetamol) and other components of the medicinal product. Severe hepatocellular insufficiency.

Special safety precautions.

Care must be taken when prescribing and administering Paracetamol-Baxter to avoid dosing errors due to confusion between milligrams (mg) and milliliters (mL), which may lead to accidental overdose and fatal outcomes (see section "Dosage and administration").

Interaction with other medicinal products and other types of interactions.

Probenecid almost halves the clearance of paracetamol by blocking its conjugation with glucuronic acid; therefore, when used concomitantly with probenecid, the dose of paracetamol should be reduced.

Salicylates may prolong the elimination half-life of paracetamol.

Particular attention should be paid to concomitant use with enzyme inducers. Such drugs include, in particular, barbiturates, isoniazid, carbamazepine, rifampicin, and ethanol (see section "Overdose").

Concomitant use of paracetamol (4 g daily for at least 4 days) with oral anticoagulants may lead to minor fluctuations in the international normalized ratio (INR). Monitoring of INR values is required during concomitant therapy and for one week after discontinuation of paracetamol treatment.

Concomitant administration of paracetamol with flucloxacillin should be approached with caution, as it has been associated with metabolic acidosis with increased anion gap due to pyroglutamic acidosis, particularly in patients with risk factors (see section "Special precautions for use").

Special precautions for use

Oral paracetamol is recommended when this route of administration is feasible.

To avoid the risk of overdose, it is essential to check for the presence of paracetamol or propacetamol in other combination medications (including prescription and over-the-counter drugs).

The risk of liver damage increases with paracetamol doses exceeding the recommended amounts. Clinical signs of liver injury (including liver failure, hepatitis—such as fulminant, cholestatic, or cytolytic forms) typically first appear on the second day after starting treatment and peak on days 4–6. Immediate administration of an antidote is required (see section "Overdose").

Paracetamol may cause serious skin reactions. Patients should be informed about early signs of serious skin reactions, and treatment should be discontinued at the first appearance of skin rash or any other signs of hypersensitivity. As with any other injectable solutions packaged in glass vials, monitoring at the end of infusion is required (see section "Method of administration and dosage").

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

The drug should be used with caution in patients with:

• hepatocellular insufficiency, Gilbert’s syndrome;
• severe renal insufficiency (see sections "Pharmacokinetics" and "Method of administration and dosage");
• chronic alcoholism;
• low hepatic glutathione stores due to chronic malnutrition, anorexia, bulimia, or cachexia;
• dehydration;
• glucose-6-phosphate dehydrogenase deficiency (which may lead to hemolytic anemia).

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

Use during pregnancy or breastfeeding.

Pregnancy

Clinical experience with intravenous administration of paracetamol is limited. However, extensive data on oral administration of therapeutic doses in pregnant women indicate no fetal developmental abnormalities or fetotoxic/neonatal toxic effects. Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero have shown inconclusive results.

Reproductive studies in animals with intravenous administration have not been conducted. Studies with oral administration did not demonstrate teratogenic or fetotoxic effects. Nevertheless, Paracetamol-Baxter should be used during pregnancy only after careful assessment of the benefit-risk ratio. In such cases, the recommended dosage and duration of treatment must be strictly followed.

Breastfeeding period

After oral administration, paracetamol is excreted in breast milk in small amounts. No adverse effects have been observed in infants following maternal use of paracetamol. Therefore, paracetamol may be used in breastfeeding women.

Ability to influence the reaction rate when driving or operating machinery.

No effect.

Method of administration and dosage

The medicinal product is intended for intravenous use.

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

Dosage depends on the patient's body weight (see Table 2 below).

Table 2

Dosage of the medicinal product Paracetamol-Baxter

* Patients with lower body weight require smaller volumes.

The minimum interval between administrations should be 4 hours. The treatment course usually does not exceed 4 infusions within 1 day.

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

** The maximum daily dose indicated in the table above refers to patients who are not receiving other medications containing paracetamol; otherwise, the daily dose should be appropriately adjusted based on the paracetamol content in other medications.

Patients with renal impairment

For patients with impaired renal function, the minimum interval between administrations should be adjusted according to Table 3.

Table 3

Use in patients with renal impairment

Patients with hepatic impairment

For patients with chronic hepatic dysfunction or compensated active liver disease, hepatocellular insufficiency, chronic alcoholism, chronic malnutrition (low hepatic glutathione stores), dehydration, Gilbert's syndrome, or body weight less than 50 kg, the maximum daily dose should not exceed 3 g (see section "Special precautions").

Elderly patients

Elderly patients generally do not require dose adjustment.

Administration method

To avoid dosing errors due to confusion between milligrams (mg) and milliliters (ml), doses must be carefully calculated when prescribing and administering Paracetamol-Baxter. Such confusion may lead to accidental overdose and even fatal outcomes. Ensure that the correct dose is prescribed and administered. When prescribing, the total dose should be specified in milligrams (mg) and the volume of the total dose in milliliters (ml).

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

To withdraw the solution, use a needle with a diameter of 0.8 mm (21 gauge) and puncture the cap vertically at the designated site.

Before any administration, the solution should be visually inspected for the presence of particulate matter and discoloration. The medicinal product is intended for single use only. Any unused solution should be discarded.

The diluted solution should be visually controlled and must not be used if opalescence, visible particles, or precipitate are present.

Paracetamol 10 mg/ml solution for infusion can be diluted with 0.9% (w/v) sodium chloride solution or 5% (w/v) glucose solution to a final drug concentration of 1.0 mg/ml. The solution is stable for 48 hours when stored at controlled room temperature (20–25 °C) under fluorescent lighting in a non-PVC glass bottle.

From a microbiological standpoint, unless the method of opening precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, the user is responsible for the duration and conditions of storage.

As with any other injectable solutions packed in glass vials, careful monitoring at the end of the infusion is strongly recommended, regardless of the route of administration. This end-of-infusion monitoring is particularly essential in the case of central infusions to prevent gas embolism.

Children.

To be used in children with body weight ≥ 33 kg.

Overdose.

The risk of liver damage (including fulminant hepatitis, hepatic failure, cholestatic hepatitis, cytolytic hepatitis) increases in elderly patients, young children, patients with pre-existing liver disease, chronic alcoholism, chronic malnutrition, and in individuals with reduced enzymatic activity. In these cases, overdose may be life-threatening.

Symptoms 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, and in children at doses of 140 mg/kg body weight. This leads to hepatic cytolysis, which may result in complete and irreversible necrosis, causing hepatocellular failure, metabolic acidosis, encephalopathy, and may lead to coma and death. Within 12–48 hours after ingestion, levels of hepatic transaminases (aspartate aminotransferase [AST], alanine aminotransferase [ALT]), lactate dehydrogenase, and bilirubin increase, while prothrombin levels decrease. Clinical signs of liver damage typically manifest after two days and peak at 4–6 days.

Emergency measures:

• Immediate hospitalization;
• As soon as possible, before initiating 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 also be administered later than 10 hours after overdose, but in such cases treatment will be longer;
• Symptomatic treatment.

Liver function tests should be performed before starting treatment and repeated every 24 hours. In most cases, hepatic transaminase levels return to normal within one to two weeks, with complete recovery of liver function. In rare, very severe cases, liver transplantation may be required.

Adverse reactions.

As with the use of other medicinal products containing paracetamol, the frequency of adverse reactions listed below is defined as follows: common (≥ 1/100 — < 1/10), rare (≥ 1/10,000 — < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).

Table 4

Adverse reactions

*Very rare cases of hypersensitivity reactions such as anaphylactic shock, urticaria, and skin rashes requiring discontinuation of treatment have been reported.

**Very rare cases of serious skin reactions requiring discontinuation of treatment have been reported.

Description of individual adverse reactions

Metabolic acidosis with increased anion gap

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

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals and patients, as well as their legal representatives, are encouraged to 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.

24 months (2 years).

Storage conditions.

Store at a temperature not exceeding 25 ºC. Do not refrigerate or freeze. Keep out of reach of children.

Incompatibilities.

The medicinal product should not be mixed with other medicinal products except those specified in the section "Dosage and method of administration".

Packaging.

100 ml in a vial; 25 vials in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

BIEFFЕ MEDITAL S.P.A./ BIEFFE MEDITAL S.P.A.

Manufacturer's address and location of business operations.

Via Nuova Provinciale – 23034 Grosotto (SO), Italy / Via Nuova Provinciale – 23034 Grosotto (SO), Italy.