Paracetamol-novo

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

Composition:

Active substance: paracetamol;

1 ml of solution contains 10 mg of paracetamol;

Excipients: mannitol (E 421), sodium citrate dihydrate, glacial acetic acid, water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear, colorless or pale pink-orange solution (perception may vary), free from particles.

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

Pharmacological Properties

Pharmacodynamics

Mechanism of action

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.

Pharmacodynamic effects

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.

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

Pharmacokinetics

Adults

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

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

Metabolism. Paracetamol is extensively metabolized in the liver via two major pathways: glucuronidation and sulfation. 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 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, 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.

Children

The pharmacokinetics of paracetamol in children is almost similar to that in adults, except for a shorter plasma elimination half-life (1.5–2 hours). In neonates, the plasma elimination half-life is longer than in children, approximately 3.5 hours. In neonates and children up to 10 years of age, significantly less glucuronide and more sulfate conjugates are excreted compared to adults.

Table 1

Age-related pharmacokinetic values

(standardized clearance, *CLstd/Foral (L × h–1 × 70 kg–1))

*CLstd — estimate of clearance for the population

Special patient categories

Renal impairment

In cases of severe renal function impairment (creatinine clearance 10–30 mL/min), elimination of paracetamol is slightly slowed, with a half-life ranging from 2 to 5.3 hours.

The elimination rate of glucuronides and sulfates in patients with severe renal impairment is three times slower than in healthy volunteers. Therefore, when administering paracetamol to patients with severe renal function impairment (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.

Clinical Characteristics

Indications

Short-term treatment of moderate 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, propacetamol hydrochloride (a paracetamol precursor), or to any of the excipients of the medicinal product.

Severe hepatic impairment.

Interaction with other medicinal products and other forms of interaction

Probenecid reduces paracetamol clearance by half through inhibition of its conjugation with glucuronic acid. When paracetamol is used concomitantly with probenecid, consideration should be given to reducing the paracetamol dose.

Salicylamide may prolong the elimination half-life of paracetamol.

Caution should be exercised when co-administering the medicinal product with enzyme-inducing medicinal products (see section "Overdose").

Concomitant administration of paracetamol (4000 mg daily for at least 4 days) with oral anticoagulants may result in minor changes in the international normalized ratio (INR). In such cases, INR should be monitored during treatment and for 1 week after completion of paracetamol therapy.

Caution should be exercised when administering paracetamol concomitantly with flucloxacillin, as this combination has been associated with metabolic acidosis with an increased anion gap, particularly in patients with risk factors (see section "Special precautions for use").

Special precautions for use

Dosage errors due to confusion between milligrams (mg) and milliliters (ml) must be avoided, as they may lead to accidental overdose and death (see section "Dosage and administration").

Prolonged or frequent use of the medicinal product is not recommended. Oral formulations of paracetamol should be used as soon as such administration becomes feasible.

To avoid overdose, ensure that other prescribed medications do not contain paracetamol or propacetamol. Dosage may require adjustment (see section "Dosage and administration").

The risk of hepatotoxicity increases when paracetamol is administered in doses exceeding the recommended levels. Clinical signs of liver injury (including fulminant hepatitis, hepatic failure, cholestatic hepatitis, cytolytic hepatitis) typically first appear approximately 2 days after administration, peaking at 4–6 days. An antidote should be administered as soon as possible (see section "Overdose").

Concomitant use of paracetamol with flucloxacillin is recommended with caution due to an increased risk of high anion gap metabolic acidosis (HAGMA), especially in patients with severe renal impairment, sepsis, malnutrition, or other conditions associated with glutathione deficiency (e.g., chronic alcoholism), as well as when maximum daily doses of paracetamol are administered. Close monitoring is recommended, including testing for urinary 5-oxoproline.

Paracetamol should be used with caution in patients with:

• hepatic insufficiency, Gilbert’s syndrome;
• severe renal impairment (creatinine clearance ≤ 30 ml/min) (see sections "Pharmacokinetics" and "Dosage and administration");
• chronic alcoholism;
• chronic malnutrition (reduced hepatic glutathione reserves);
• dehydration;
• glucose-6-phosphate dehydrogenase deficiency (which may cause hemolytic anemia).

Paracetamol use may result in a positive doping test.

This medicinal product contains less than 1 mmol (23 mg) / 100 ml of sodium, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding

Pregnancy

Extensive data from pregnant women indicate no evidence of fetal malformations or fetal/neonatal toxicity. Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero have shown inconclusive results.

Paracetamol may be administered during pregnancy if clinically necessary, but should be used at the lowest effective dose, for the shortest possible duration, and with the lowest possible frequency.

Breastfeeding

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

Effect on ability to drive and use machines

No significant effect.

Administration and Dosage

The medicinal product is for intravenous use.

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

The dose to be administered depends on the patient's body weight. The volume administered must not exceed the specified dose. If necessary, the required volume should be diluted in an appropriate infusion solution prior to administration or administered using a syringe pump.

The medicinal product may be used undiluted or, if necessary, diluted with 9 mg/mL (0.9%) sodium chloride solution for infusion, 50 mg/mL (5%) glucose solution for infusion, or a combination of both, up to one-tenth of the medicinal product volume.

Dosage according to patient body weight is shown in Table 2.

Table 2

* Patients with lower body weight require smaller volumes. The interval between administrations should be at least 4 hours. No more than 4 doses should be administered within 24 hours.

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

** The maximum daily dose is intended for patients who are not receiving other medicinal products containing paracetamol and should be appropriately adjusted when such products are used.

Patients with severe renal impairment

In patients with severe renal impairment (creatinine clearance ≤ 30 mL/min), dose reduction and an increased minimum dosing interval to 6 hours are recommended (see section "Pharmacokinetics").

Patients with hepatic impairment

For patients with chronic hepatic impairment or compensated active liver disease, hepatocellular insufficiency, chronic alcoholism, chronically undernourished patients (with 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 (see section "Special precautions for use").

Elderly patients

Elderly patients generally do not require dose adjustment.

Method of Administration

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

Recommended dosage guidelines must be strictly followed.

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

When administering any infusion solutions, it is essential to monitor the procedure, particularly at the end of the infusion, regardless of the route of administration. Monitoring at the end of the infusion is particularly important during intravenous administration to prevent air embolism.

Children

The 100 ml vial is intended only for children with 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 pre-existing liver disease, chronic alcoholism, chronic malnutrition, and in patients taking enzyme-inducing drugs. Overdose may be fatal in these cases.

Symptoms typically appear within the first 24 hours and include nausea, vomiting, anorexia, pallor, and abdominal pain. Immediate action must be taken in case of paracetamol overdose, even if symptoms are not present.

Overdose in adults may occur with a single dose of 7.5 g or more; in children, with a dose of 140 mg/kg body weight. This leads to hepatic cytolysis, liver failure, metabolic acidosis, encephalopathy, which may result in 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 manifest after 2 days and peak at 4–6 days.

Treatment

Immediate hospitalization is required.

A blood sample should be taken as soon as possible after overdose, prior to initiating treatment, to determine plasma paracetamol levels.

Treatment includes administration of the antidote N-acetylcysteine (NAC) either intravenously or orally, if possible—within 10 hours of overdose. However, NAC may still provide some protective effect even after 10 hours, although prolonged NAC treatment is required in such cases.

Symptomatic treatment.

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

Adverse reactions

Adverse reactions observed during the use of paracetamol are listed in Table 3 according to frequency: common (from ≥ 1/100 to < 1/10), rare (from ≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Table 3

• Very rare cases of hypersensitivity reactions such as anaphylactic shock, urticaria, and rashes requiring discontinuation of treatment have been reported.
  • Isolated cases.
    • Very rare cases of serious skin reactions requiring discontinuation of treatment have been reported.
      • In the post-marketing period, during concomitant use of paracetamol and flucloxacillin; usually in the presence of risk factors.

Reporting of adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical 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. 2 years.

Storage conditions

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

Keep out of the reach of children.

Incompatibilities. The medicinal product should not be mixed with other solutions except those specified in the section "Instructions for use and dosage".

Prescription status. Prescription only.

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

Manufacturer. Limited liability company "Novofarm-Biosyntez".

Manufacturer's address and location of operations

38, Zhytomyrska Street, Novohrad-Volynskyi, Zhytomyr Oblast, 11700, Ukraine.