ANAPYRON

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ANAPIRON (ANAPIRON)

Composition:

Active substance: paracetamol;

100 ml of solution contain 1000 mg of paracetamol;

Excipients: mannitol (E 421); disodium hydrogen phosphate dihydrate; water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear, colorless to pale yellow solution.

Pharmacotherapeutic group.

Analgesics and antipyretics. ATC code N02BE01.

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

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

Anopyron reduces elevated temperature within 30 minutes after the start of administration, with the antipyretic effect lasting for 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 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, and amounts 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 of paracetamol, a significant concentration level (approximately 1.5 µg/mL) was detected in cerebrospinal fluid 20 minutes 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 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.

Elimination

Paracetamol metabolites are primarily excreted in urine. Approximately 90% of the administered dose is eliminated by the kidneys 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.

Neonates, infants, and 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 elimination half-life is longer than in infants—approximately 3.5 hours. In children under 10 years of age, glucuronidation is significantly reduced and sulfation is increased compared to adults.

Pharmacokinetic parameters according to age (standardized clearance,

*CLstd/Foral (l·h⁻¹·70 kg⁻¹)

*CLstd – estimate of the patient group regarding 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 slower than in healthy volunteers. Therefore, in patients with severe renal impairment (creatinine clearance ≤30 mL/min), the minimum interval between doses 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 in this patient group.

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 an urgent need to treat pain or hyperthermia, and/or when other routes of administration are unavailable.

Contraindications.

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

Safety precautions.

Extreme caution must be exercised when prescribing and administering Anapidol to avoid dosing errors due to confusion between milligrams (mg) and milliliters (ml), which may lead to accidental overdose and fatal outcomes. When prescribing, both the total dose in milligrams and the volume of the total dose in milliliters must be clearly indicated.

To prevent overdose, ensure that other prescribed medicinal products do not contain paracetamol.

Interaction with other medicinal products and other forms of interaction.

Probenecid reduces paracetamol clearance by half 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.

Hepatic microsomal enzyme inducers (phenytoin, ethanol, barbiturates, rifampicin, phenylbutazone, tricyclic antidepressants) may increase the risk of severe toxicity even after a minor overdose.

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

Caution is advised when paracetamol is used concomitantly with flucloxacillin, as such 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").

Special precautions for use

Care must be taken to avoid dosing errors due to confusion between milligrams (mg) and milliliters (mL), which may lead to accidental overdose and fatal outcomes. Oral paracetamol is recommended when this route of administration is feasible.

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

The risk of hepatotoxicity increases with paracetamol doses exceeding the recommended amounts. Clinical signs of liver injury (including liver failure, hepatitis, including fulminant, cholestatic, and cytolytic forms) typically 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").

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 sign of skin rash or any other symptoms of hypersensitivity.

Cases of high anion gap metabolic acidosis (HAGMA) due to 5-oxoproline (pyroglutamic) acidosis have been reported in patients with severe underlying conditions such as severe renal insufficiency and sepsis, or in patients with malnutrition or other causes of glutathione deficiency (e.g., chronic alcoholism), who received paracetamol at therapeutic doses for prolonged periods or in combination with flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, paracetamol should be discontinued immediately and close monitoring initiated. Measurement of urinary 5-oxoproline levels 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:

• hepatic insufficiency, Gilbert’s syndrome;
• severe renal insufficiency (creatinine clearance <30 mL/min);
• chronic alcoholism;
• malnutrition (reduced hepatic glutathione stores);
• dehydration;
• glucose-6-phosphate dehydrogenase deficiency (may lead to hemolytic anemia).

The risk of liver damage during treatment with Anapyron increases in patients with alcoholic hepatopathy.

The use of the drug may interfere with laboratory test results, particularly in the quantitative determination of glucose and uric acid in plasma.

During prolonged treatment, periodic monitoring of peripheral blood parameters and liver function is required.

Excipients. Anapyron contains less than 1 mmol (23 mg)/dose of sodium, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

Clinical experience with intravenous administration of paracetamol is limited. Extensive data in pregnant women indicate no fetal malformations or fetotoxic/neonatal toxicity. Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero have shown inconclusive results. Paracetamol may be used during pregnancy if clinically necessary, but should be administered 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 observed in infants during breastfeeding while the mother is taking paracetamol. Therefore, paracetamol may be used in women who are breastfeeding.

Ability to affect reaction speed while driving or operating machinery.

No effect.

Method of administration and dosage.

The drug is administered intravenously.

The dosage depends on the patient's body weight (see the dosage table below).

* 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 24 hours.

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

** Maximum daily dose: the maximum daily dose indicated in the table above applies to patients who are not receiving other medications containing paracetamol; otherwise, the daily dose should be appropriately adjusted to account for such medications.

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 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").

Elderly patients

Elderly patients generally do not require dose adjustment.

To avoid dosing errors due to confusion between milligrams (mg) and milliliters (mL), doses must be carefully calculated when prescribing and administering Anapyron. Such confusion may lead to accidental overdose and even fatal outcomes. When writing prescriptions, the total dose should be specified in milligrams (mg) and the volume of the total dose in milliliters (mL).

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

Children

Not to be used in children under 1 year of age or with body weight less than 10 kg.

To be used in children aged 1 year and older with body weight over 10 kg only for symptomatic treatment of pain and hyperthermia in postoperative patients.

Overdose

The risk of liver injury (including fulminant hepatitis, hepatic failure, cholestatic hepatitis, cytolytic hepatitis) increases in elderly patients, children, patients with hepatic insufficiency, in cases of chronic alcoholism, presence of alimentary dystrophy, 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 with a single dose of 7.5 g or more, in children — at 140 mg/kg body weight. This leads to hepatic cytolysis, liver failure, metabolic acidosis, and encephalopathy, which may result in coma and death. Within 12–48 hours, levels of liver transaminases (AST, ALT), lactate dehydrogenase, and bilirubin increase, while prothrombin levels decrease. Clinical signs of liver damage appear after two days and peak at 4–6 days.

Emergency measures:

• Immediate hospitalization;
• As soon as possible, before starting treatment, determine plasma paracetamol concentration after overdose;
• Intravenous or oral administration of the antidote N-acetylcysteine (NAC), preferably within 10 hours of overdose; NAC may still be administered later than 10 hours after overdose, but in such cases treatment will be longer;
• Symptomatic treatment.

Before initiating treatment, liver function tests should be performed 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 other paracetamol-containing products, the adverse reactions listed below are categorized by frequency as follows: common (≥ 1/100 − < 1/10), uncommon (> 1/10000 − < 1/1000), rare (< 1/10000), and frequency not known (cannot be estimated from available data):

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

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

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging, in a place inaccessible to children, at a temperature not exceeding 25 °C.

Any unused medicinal product remaining should be destroyed.

Incompatibilities.

Anapyron should not be mixed with other medicinal products.

Packaging.

100 ml of the preparation in a vial, 1 vial in a pouch, in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Euro Life Healthcare Pvt. Ltd.

Manufacturer's address and place of business.

Hosur No. 520, Bhagwanpur, Roorkee, Haridwar, Uttarakhand, India.

Marketing Authorization Holder.

Ananta Medikare Ltd.

Address of the Marketing Authorization Holder and/or its representative.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.