Paracetamol-Novo solution for infusions 10 mg/ml bottle 100 ml No. 1

Instructions Paracetamol-Novo solution for infusions 10 mg/ml bottle 100 ml No. 1

Composition

active ingredient: paracetamol;

1 ml of solution contains 10 mg of paracetamol;

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

Dosage form

Solution for infusion.

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

Pharmacotherapeutic group

Analgesics and antipyretics. ATX code N02B E01.

Pharmacological properties

Pharmacodynamics

Mechanism of action

The exact mechanism of paracetamol's analgesic and antipyretic properties has not yet been established, and it may involve central and peripheral actions.

Pharmacodynamic effects

Paracetamol provides pain relief within 5-10 minutes of administration. The peak analgesic effect is reached within 1 hour, and the duration of this effect is usually 4-6 hours.

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

Pharmacokinetics

Adults

Absorption: The pharmacokinetics of paracetamol are linearly dose-dependent up to 2 g after both single and multiple doses over 24 hours.

The bioavailability of paracetamol after intravenous infusion of 500 mg and 1 g is similar to that after infusion of 1 g and 2 g propacetamol (containing 500 mg and 1 g 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 paracetamol is 15 μg/ml and 30 μg/ml, respectively.

Distribution: The volume of distribution of paracetamol is approximately 1 l/kg. Paracetamol is poorly bound to plasma proteins. After administration of 1 g of paracetamol, significant concentrations (approximately 1.5 μg/ml) were established in the cerebrospinal fluid 20 minutes after infusion.

Metabolism. Paracetamol is extensively metabolized in the liver by two main pathways: glucuronic acid conjugation and sulfuric acid conjugation. The latter pathway is rapidly saturated at doses exceeding therapeutic doses. A small part (less than 4%) is metabolized by cytochrome P450 to form an intermediate metabolite (N-acetylbenzoquinoneimine), which under normal conditions of use is rapidly neutralized by reduced glutathione and excreted in the urine after binding to cysteine and mercaptopuric acid. However, in severe overdose, the amount of this toxic metabolite increases.

Excretion. Paracetamol metabolites are excreted mainly in the urine. 90% of the administered dose is excreted within 24 hours, mainly as glucuronide (60–80%) and sulfate (20–30%) conjugates. Less than 5% is excreted unchanged. The half-life is 2.7 hours, and the total clearance is 18 l/h.

Children

The pharmacokinetics of paracetamol in children are almost the same as in adults, with the exception of a shorter plasma half-life (1.5-2 hours). In newborns, the plasma half-life is longer than in children, approximately 3.5 hours. In newborns and children under 10 years of age, significantly less glucuronide and more sulfate conjugates are excreted than in adults.

Table 1

Age-related pharmacokinetic values

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

*CLstd — population clearance estimate

Special categories of patients

Kidney failure

In cases of severe renal impairment (creatinine clearance 10–30 ml/min), the elimination of paracetamol is slightly slowed down, the half-life is from 2 to 5.3 hours.

The rate of excretion of glucuronides and sulfates in patients with severe renal insufficiency is three times slower than in healthy volunteers. Therefore, when administering paracetamol to patients with severe renal impairment (creatinine clearance ≤ 30 ml/min), the minimum interval between each administration should be increased to 6 hours (see section "Method of administration and dosage").

Elderly patients

The pharmacokinetics and metabolism of paracetamol are not altered in elderly patients. No dose adjustment is required.

Indication

Short-term treatment of moderate pain, especially in the postoperative period, and short-term treatment of hyperthermic reactions when intravenous administration is clinically justified or other routes of administration are unacceptable.

Contraindication

Hypersensitivity to paracetamol, propacetamol hydrochloride (precursor to paracetamol) or to any of the excipients of the medicinal product.

Severe liver failure.

Interaction with other medicinal products and other types of interactions

Probenecid halves the clearance of paracetamol by inhibiting its conjugation with glucuronic acid. If paracetamol is used concomitantly with probenecid, a reduction in the dose of paracetamol should be considered.

Salicylamide may prolong the half-life of paracetamol.

Caution should be exercised when using the drug together with enzyme-inducing drugs (see section "Overdose").

Concomitant use of paracetamol (4000 mg daily for at least 4 days) with oral anticoagulants may lead to minor changes in the international normalized ratio (INR). In this case, the INR should be monitored during treatment and for 1 week after stopping paracetamol treatment.

Caution should be exercised when using paracetamol with flucloxacillin, as such co-administration is associated with metabolic acidosis with an increased anion gap, especially in patients with risk factors (see section "Special warnings and precautions for use").

Application features

Dosing errors due to confusion between milligrams (mg) and milliliters (ml) should be avoided, which could lead to accidental overdose and death (see section “Method of administration and dosage”).

Prolonged or frequent use of the drug is not recommended. It is recommended to use the oral form of paracetamol as soon as this method of administration becomes possible.

To avoid overdose, it is necessary to ensure that other prescribed medicines do not contain paracetamol or propacetamol. Dosage may need to be adjusted (see section "Method of administration and dosage").

The risk of liver damage increases when paracetamol is administered in doses higher than recommended. Clinical symptoms of liver damage (including fulminant hepatitis, hepatic failure, cholestatic hepatitis, cytolytic hepatitis) are usually first observed 2 days after administration of the drug, reaching a peak after 4-6 days. An antidote should be administered as soon as possible (see section "Overdose").

Caution is advised when using paracetamol concomitantly with flucloxacillin due to an increased risk of high anion gap metabolic acidosis (HAGMA), particularly in patients with severe renal impairment, sepsis, malnutrition and other causes of glutathione deficiency (e.g. chronic alcoholism), and when maximum daily doses of paracetamol are used. Close monitoring, including urinary 5-oxoproline, is recommended.

Paracetamol should be used with caution if the patient has:

liver failure, Gilbert's syndrome;

severe renal insufficiency (creatinine clearance ≤ 30 ml/min) (see sections “Pharmacokinetics” and “Method of administration and dosage”);

chronic alcoholism;

chronic malnutrition (reduction in glutathione reserves in the liver);

dehydration;

glucose-6-phosphate dehydrogenase deficiency (which can cause hemolytic anemia).

The use of paracetamol may cause a positive doping control result.

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

Use during pregnancy or breastfeeding

Pregnancy

A large amount of data on pregnant women indicate no malformations or foetal/neonatal toxicity. Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero have shown inconclusive results.

If clinically necessary, paracetamol can be prescribed during pregnancy, but it should be used at the lowest effective dose, for the shortest possible duration, and with the least possible frequency.

Breast-feeding

After oral administration, paracetamol is excreted in breast milk in small quantities. No adverse effects have been reported in infants when paracetamol is used during breastfeeding. Therefore, paracetamol can be used by women who are breastfeeding.

Ability to influence reaction speed when driving vehicles or other mechanisms

There is no significant impact.

Method of administration and doses

The medicine should be administered intravenously.

The 100 ml bottle is intended only for adults, adolescents and children weighing more than 33 kg.

The dose to be administered depends on the patient's body weight. The volume to be administered should not exceed the prescribed dose. If necessary, the required volume should be diluted in a suitable infusion solution before administration or a syringe pump should be used.

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

For dosage based on patient weight, see Table 2.

Table 2

* Lower body weight patients require smaller volumes. The interval between administrations should be at least 4 hours. No more than 4 doses should be administered in 24 hours.

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

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

Patients with severe renal insufficiency

When prescribing paracetamol to patients with severe renal insufficiency (creatinine clearance ≤ 30 ml/min), it is recommended to reduce the dose and increase the minimum interval between administrations to 6 hours (see section "Pharmacokinetics").

Patients with hepatic insufficiency

For patients with chronic liver failure or compensated active liver disease, with hepatocellular insufficiency, chronic alcoholism, patients who are chronically malnourished (have low hepatic glutathione reserves), patients with dehydration, Gilbert's syndrome, and body weight less than 50 kg - the maximum daily dose should not exceed 3 g (see section "Special instructions").

Elderly patients

Elderly patients usually do not require dose adjustment of the drug.

Method of application

Administer the paracetamol solution as a 15-minute intravenous infusion.

It is imperative to follow dosage recommendations.

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

When using any infusion solutions, it is important to remember the need to monitor the procedure, especially at the end of the infusion, regardless of the route of administration. Monitoring at the end of the infusion is used, in particular, with intravenous administration, to avoid air embolism.

Children

The 100 ml bottle is intended only for children weighing more than 33 kg.

Overdose

Symptoms

There is a risk of liver damage (including fulminant hepatitis, hepatic failure, cholestatic hepatitis, cytolytic hepatitis), especially in the elderly, young children, patients with liver disease, chronic alcoholism, chronic malnutrition, and patients taking enzyme-inducing drugs. Overdose can be fatal in these cases.

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

Overdose in adults can occur with a single administration of 7.5 g or more, in children - at a dose of 140 mg / kg body weight. In this case, liver cytolysis, liver failure, metabolic acidosis, encephalopathy develop, which can lead to coma and death. Within 12-48 hours, the level of hepatic transaminases (alanine aminotransferase, aspartate aminotransferase), lactate dehydrogenase, bilirubin increases and the level of prothrombin decreases.

Clinical symptoms of liver damage appear after 2 days and reach a maximum after 4−6 days.

Treatment

Immediate hospitalization.

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

Treatment involves administering the antidote N-acetylcysteine (NAC) intravenously or orally, if possible, before 10 hours after the overdose. However, NAC may provide some protection even after 10 hours, but in these cases, long-term use of NAC is required.

Symptomatic treatment.

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

Side effects

Adverse reactions that occurred with the use of paracetamol are listed in Table 3 by frequency: common (≥ 1/100 to < 1/10), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency unknown (cannot be estimated from the available data).

Table 3

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

(2) Isolated cases.

(3) Very rare cases of serious skin reactions requiring discontinuation of treatment have been reported.

(4) In the post-marketing period, when paracetamol is used concomitantly with flucloxacillin; usually in the presence of risk factors.

Reporting of adverse reactions

Reporting adverse reactions after the registration of a medicinal product is important. This allows monitoring of the benefit/risk ratio when using this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance at the link: https://aisf.dec.gov.ua.

Expiration date

2 years.

Storage conditions

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

Keep out of reach of children.

Incompatibility.

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

Vacation category

According to the recipe.

Packaging

100 ml in a bottle; 1 bottle in a cardboard pack.

Producer

Limited Liability Company "Novopharm-Biosynthes".

Location of the manufacturer and address of its place of business

Ukraine, 11700, Zhytomyr region, Novograd-Volynskyi, Zhytomyrska st., b. 38.