Paracetamol-novopharm

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

Composition:

Active substance: paracetamol;

1 ml of solution contains 10 mg of paracetamol;

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

Pharmaceutical form. Infusion solution.

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

Theoretical osmolarity 305 mOsmol/l; pH 4.5–5.5.

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 begins to relieve pain within 5–10 minutes after the start of administration. The peak analgesic effect is reached 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, 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 at doses 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 of paracetamol (approximately 1.5 µg/mL) was observed in cerebrospinal fluid starting from the 20th minute after infusion.

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 when doses exceeding therapeutic levels are administered. A small fraction (less than 4%) is metabolized by cytochrome P450 to a reactive intermediate metabolite (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.

Elimination. 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 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 the plasma elimination half-life, which is slightly shorter (1.5 to 2 hours) compared to adults. In neonates, the plasma elimination half-life is longer than in older children, approximately 3.5 hours. In neonates and children under 10 years of age, significantly less glucuronide conjugate is excreted and more sulfate conjugates are excreted compared to adults.

Table 1

Pharmacokinetic values according to age

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

*CLstd — population clearance estimate

Special patient categories

Renal impairment

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

The elimination rate of glucuronide and sulfate conjugates is 3 times slower in patients with severe renal impairment compared to healthy individuals. Therefore, when administering paracetamol 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. There is no need to adjust the dosage of the medicinal product in these patients.

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, 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 by inhibiting its conjugation with glucuronic acid. When paracetamol is administered 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 inducers (see section "Overdose").

Concomitant use of paracetamol (4000 mg per day for at least 4 days) with oral anticoagulants may slightly alter the international normalized ratio (INR). In such cases, INR should be monitored during concomitant therapy and for 1 week after discontinuation of paracetamol treatment.

Caution should be exercised when administering paracetamol concomitantly with flucloxacillin, 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. The oral form of paracetamol should be used as soon as such a route of administration becomes possible.

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

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).

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 impairment and sepsis, or in patients with malnutrition or other causes of glutathione deficiency (e.g., chronic alcoholism), who were treated with paracetamol at therapeutic doses for prolonged periods or in combination with flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol and careful monitoring are recommended. 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.

This medicinal product contains less than 1 mmol (23 mg) / 100 mL of sodium, i.e. essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy

A large body of data on use in pregnant women indicates no malformative or fetotoxic/neonatal toxic effects. Epidemiological studies on neurological development in children exposed to paracetamol in utero have yielded inconclusive results. If clinically indicated, paracetamol may be administered during pregnancy; however, it should be used at the lowest effective dose, for the shortest possible duration, and with the least possible frequency.

Breastfeeding

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

Ability to affect reaction speed when driving or operating machinery.

No significant influence.

Administration and dosage.

For intravenous use only.

The medicinal product in a 100 ml vial is intended solely for adults, adolescents, and children with a body weight exceeding 33 kg.

The dose to be administered depends exclusively 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.

Table 2

Dosage according to patient's body weight

* Patients with lower body weight require smaller volumes.

The interval between administrations should be at least 4 hours. The interval between administrations for patients with severe renal impairment should be at least 6 hours. No more than 4 doses should be administered within 24 hours.

** The maximum daily dose is indicated for patients who are not receiving other medicinal products containing paracetamol; otherwise, the daily dose should be appropriately adjusted, taking into account the use of such medicinal products.

Patients with severe renal impairment

When administering paracetamol to patients with severe renal function impairment (creatinine clearance ≤ 30 mL/min), it is recommended to reduce the dose and increase the minimum interval between each administration to 6 hours (see section "Pharmacokinetics").

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 (see section "Special precautions for use").

The solution of paracetamol should be administered as a 15-minute intravenous infusion.

The medicinal product may be used undiluted; however, if necessary, it can be diluted with sodium chloride 9 mg/mL (0.9%) solution, glucose 50 mg/mL (5%) solution, or a combination of these solutions—up to 1/10 of paracetamol (one-tenth of the volume of 10 mg/mL paracetamol solution in nine-tenths of diluent). In such cases, the diluted solution must be used within 1 hour after preparation, including the time required for infusion. Immediately after connecting the vial to the infusion set, the infusion should be started. To avoid microbiological contamination, the medicinal product should be used immediately.

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

Before administration, the medicinal product should be visually inspected for the presence of particles and discoloration.

When administering any infusion solutions, it is important to remember the necessity of monitoring the procedure, especially at the end of the infusion, regardless of the route of administration. Monitoring at the end of the infusion is particularly used during intravenous administration to prevent air embolism.

Children

The medicinal product in a 100 mL vial is intended only for children with body weight above 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 patients taking enzyme-inducing drugs. Overdose may be fatal in these patients.

Symptoms usually appear within the first 24 hours and include: nausea, vomiting, anorexia, pallor, and abdominal pain. Immediate measures should be taken in case of paracetamol overdose, even if symptoms are absent.

Overdose following a single dose of 7.5 g or more of paracetamol in adults, or a single dose of 140 mg/kg body weight in children, causes hepatic cytolysis, which may lead to complete and irreversible necrosis, and consequently to hepatocellular failure, metabolic acidosis, and encephalopathy, potentially resulting in coma and death. Concurrently, elevated levels of liver transaminases (aspartate aminotransferase [AST], alanine aminotransferase [ALT]), lactate dehydrogenase, and bilirubin occur together with decreased prothrombin levels, which may appear 12–48 hours after administration. Clinical symptoms of liver injury typically first manifest around two days and peak at 4–6 days.

Treatment

Immediate hospitalization.

Before initiating treatment and as soon as possible after overdose, a blood sample should be taken to determine the plasma paracetamol level.

Treatment includes administration of the antidote N-acetylcysteine (NAC) either intravenously or orally, if possible—prior to the 10th hour after overdose. However, NAC may still provide some degree of protection even after 10 hours, although prolonged NAC administration 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 one to two weeks, with full recovery of liver function. In individual cases, liver transplantation may be required.

Adverse reactions.

The adverse reactions that occurred during the use of paracetamol are listed in Table 3 below. Frequency is defined as follows: rare — from ≥ 1/10,000 to < 1/1,000, very rare — < 1/10,000, frequency not known — cannot be estimated based on available data.

Table 3

• Very rare cases of hypersensitivity reactions have been reported — ranging from simple skin rashes or urticaria to anaphylactic shock, requiring discontinuation of treatment.
  • Isolated cases.
    • Very rare cases of serious skin reactions requiring discontinuation of treatment have been reported.
      • During the post-marketing period, when paracetamol was used concomitantly with floxacillin; usually in the presence of risk factors.

Description of selected adverse reactions

Metabolic acidosis with high anion gap

Cases of metabolic acidosis with high anion gap, resulting from 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.

During clinical trials, injection site reactions (pain and burning sensation) were frequently reported.

Reporting of adverse reactions

Reporting of adverse reactions after marketing authorization of the medicinal product is of great importance. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or 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. 2 years.

Storage conditions.

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

Keep out of reach of children.

Incompatibilities. The medicinal product should not be mixed with other solutions except those specified in the section "Method of administration and dosage".

Prescription status. Prescription only.

Packaging. 100 ml in a bottle; 1 bottle in a carton.

Manufacturer. Limited liability company "Novofarm-Biosyntez".

Manufacturer's address and location of its business activities.

38, Zhytomyrska Street, city of Zviahel, Zviahel district, Zhytomyr region, 11700, Ukraine.